NZ791591A - A crystalline 19-nor C3, 3-disubstituted C21-N-pyrazolyl steroid - Google Patents

Abstract

This invention relates to a 19-nor C3, 3-disubstituted C21-pyrazolyl steroid of Formula (I) and crystalline solid forms and compositions thereof. Also disclosed herein are methods of making crystalline solid forms of the 19-nor C3, 3-disubstituted C21 pyrazolyl steroid of Formula (I) and methods of using the 19-nor C3, 3 disubstituted C2l-pyrazolyl steroid of Formula (I) or crystalline solid forms, pharmaceutically acceptable salts, and pharmaceutically acceptable compositions thereof. using the 19-nor C3, 3 disubstituted C2l-pyrazolyl steroid of Formula (I) or crystalline solid forms, pharmaceutically acceptable salts, and pharmaceutically acceptable compositions thereof.

Description

A CRYSTALLINE 19-NOR C3,3-DISUBSTITUTED C21-N-PYRAZOLYL STEROID CROSS-REFERENCE TO RELATED APPLICATIONS This ation claims priority to U.S.S.N. 62/378,582 filed August 23, 2016, which is orated herein by reference in its entirety.

The present application is a divisional of New Zealand patent application no. 750729, which was the national phase entry of , the entire specifications of which are incorporated herein by cross-reference.

BACKGROUND OF THE INVENTION Brain excitability is defined as the level of l of an animal, a continuum that ranges from coma to convulsions, and is regulated by various ransmitters. In general, ransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the neuronal membrane possesses a potential (or membrane voltage) of imately -70 mV, the cell interior being negative with respect to the cell exterior. The potential (voltage) is the result of ion (K+, Na+, Cl-, organic ) balance across the neuronal rmeable membrane. Neurotransmitters are stored in presynaptic vesicles and are released under the influence of neuronal action potentials. When released into the synaptic cleft, an excitatory chemical transmitter such as acetylcholine will cause membrane depolarization (change of potential from -70 mV to -50 mV). This effect is mediated by postsynaptic nicotinic receptors which are stimulated by choline to se membrane bility to Na+ ions. The reduced membrane potential stimulates neuronal bility in the form of a postsynaptic action potential.

In the case of the γ-aminobutyric acid receptor complex (GRC), the effect on brain excitability is mediated by γ-aminobutyricacid (GABA), a neurotransmitter. GABA has a profound nce on overall brain excitability because up to 40% of the neurons in the brain utilize GABA as a neurotransmitter. GABA regulates the bility of individual neurons by regulating the conductance of chloride ions across the neuronal membrane. GABA interacts with its recognition site on the GRC to facilitate the flow of chloride ions down an electrochemical gradient of the GRC into the cell. An intracellular increase in the levels of this anion causes hyperpolarization of the transmembrane potential, rendering the neuron less susceptible to excitatory inputs (i.e., reduced neuron excitability). In other words, the higher the chloride ion concentration in the neuron, the lower the brain excitability (the level of arousal).

New and improved neuroactive crystalline forms of steroids are needed that act as modulating agents for brain excitability, as well as agents for the prevention and treatment of lated diseases. Crystalline forms of such a d described herein are directed toward this end.

SUMMARY OF THE INVENTION The present invention s, in part, to novel forms (for example, certain crystalline forms described herein) of a l9-nor (i.e., C19 desmethyl) compound. Generally, a solid compound’s efficacy as a drug can be affected by the properties of the solid it comprises.

Thus, in one , described herein is a crystalline compound of Formula (I): Formula (I) also referred to herein as “Compound 1.” In some embodiments, a solubilized form of the crystalline form of nd 1 is converted to a different crystalline form of Compound 1 by slow evaporation, anti- solvent addition, slow-cooling, solution vapor diffusion, solid vapor diffusion, fast ation, reverse anti-solvent addition, and water activity experiments.

In some embodiments, a crystalline form of Compound 1 is converted to a different crystalline form of Compound 1 by slurry conversion.

In some embodiments, physical or chemical parameters of a solid form of Compound 1 are evaluated from one or more of the following analytical ques: X-ray powder ction (XRPD) analysis, e.g., le-temperature XRPD (VT-XRPD) analysis, single-crystal X-ray crystallography, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR) spectroscopy or solid-state NMR spectroscopy, Raman spectroscopy, or dynamic vapor sorption (DVS).

In embodiments, each solid form is characterized and identified with parameters ed from one or more of the aforementioned analytical methods: X-ray diffraction patterns presented with degrees 2-theta (20) as the abscissa and peak intensity as the ordinate as ined by analysis with XRPD. These patterns are also referred to herein as XRPD patterns; properties of the single-crystal structure of a solid form, e. g., unit cell, crystal system, and space group, as determined by single-crystal X-ray crystallography; ated XRPD ns for a crystalline form as determined by data from single-crystal X-ray crystallography; an endotherm specified by an onset temperature Tom, that indicates a loss of solvent, a transformation from one crystalline form to another, or a melting point as determined by DSC performed at a specific ramp rate; a value for weight loss as determined by TGA; a value for weight gain at a temperature of 25 oC and a relative humidity n % and 95% as determined by DVS; and an exemplary 1H NMR spectrum of Compound 1 dissolved in deuterated dimethyl sulfoxide (DMSO-d6).

In embodiments, a solid form is determined to be crystalline by the presence of sharp, distinct peaks found in the corresponding XRPD pattern.

In some embodiments, XRPD is used to determine if a solid form of Compound 1 transforms to another solid form at temperatures higher than room temperature.

In some embodiments, lline Compound 1 is an anhydrate.

In some embodiments, crystalline Compound 1 is a solvate.

In some embodiments, crystalline Compound 1 can have an XRPD n with characteristic peaks between and including the following values of 20 in degrees: 11.6 to 12.0 (e.g., 11.8), 13.7 to 14.1 (e.g., 13.9), 14.0 to 14.4 (e.g., 14.2), 16.6 to 17.0 (e.g., 16.8), 18.9 to 19.3 (e.g., 19.1), 19.1 to 19.5 (e.g., 19.3), 19.9 to 20.3 (e.g., 20.1), 21.1 to 21.5 (e.g., 21.3), 21.9 to 22.3 (e.g., 22.1), and 23.0 to 23.4 (e.g., 23.2).

In some embodiments, crystalline Compound 1 can have an XRPD pattern with teristic peaks between and including the following values of 20 in degrees: 11.6 to 12.0 (e.g., 11.8), 16.6 to 17.0 (e.g., 16.8), 18.9 to 19.3 (e.g., 19.1), 19.9 to 20.3 (e.g., 20.1), and 23.0 to 23.4 (e.g., 23.2).

In some ments, crystalline Compound 1 has an XRPD n with characteristic peaks at the following values of 20 in degrees: 11.8, 13.9, 14.2, 16.8, 19.1, 19.3, 20.1, 21.3, 22.1, and 23.2.

In some embodiments, lline Compound 1 has an XRPD pattern with characteristic peaks at the following values of 20 in degrees: 11.8, 16.8, 19.1, 20.1, and 23.2.

In some embodiments, crystalline Compound 1 has an XRPD pattern substantially as depicted in A.

In some embodiments, crystalline Compound 1 has an XRPD pattern with characteristic peaks between and including the following values of 20 in degrees: 9.3 to 9.7 (e.g., 9.5), 10.6 to 11.0 (e.g., 10.8), 13.0 to 13.4 (e.g., 13.2), 14.7 to 15.1 (e.g., 14.9), 15.8 to 16.2 (e.g., 16.0), 18.1 to 18.5 (e.g., 18.3), 18.7 to 19.1 (e.g., 18.9), 20.9 to 21.3 (e.g., 21.1), 21.4 to 21.8 (e.g., 21.6), and 23.3 to 23.7 (e.g., 23.5).

In some embodiments, crystalline Compound 1 has an XRPD pattern with teristic peaks between and including the following values of 20 in s: 9.3 to 9.7 (e.g., 9.5), 10.6 to 11.0 (e.g., 10.8), 13.0 to 13.4 (e.g., 13.2), 18.7 to 19.1 (e.g., 18.9), and 21.4 to 21.8 (e.g., 21.6).

In some embodiments, crystalline Compound 1 has an XRPD pattern with teristic peaks at the ing values of 20 in degrees: 9.5, 10.8, 13.2, 14.9, 16.0, 18.3, 18.9, 21.1, 21.6, and 23.5.

In some embodiments, lline Compound 1 has an XRPD pattern with characteristic peaks at the following values of 20 in degrees: 9.5, 10.8, 13.2, 18.9, and 21.6.

In some embodiments, lline Compound 1 has an XRPD pattern substantially as depicted in .

In some embodiments, crystalline Compound 1 has comprises a unit cell substantially as depicted in .

In some embodiments, a crystalline form of Compound 1, when subjected to a temperature from about 150 0C to about 1950C, e.g., from 157 0C to 170 oC, transforms into a different crystalline form as indicated by DSC at a ramp rate of 10 oC/min.

In some embodiments, crystalline Compound 1 melts at a Tom, from about 200 0C to about 225 oC, e.g., from about 205 0C to about 225 oC, e.g., from about 208 0C to about 215 0C, as measured by DSC at a ramp rate of 10 oC/min.

In some embodiments, crystalline Compound 1 can have an XRPD pattern with characteristic peaks between and including the following values of 20 in degrees: 9.7 to 10.1 (e.g., 9.9), 11.6 to 12.0 (e.g., 11.8), 13.2 to 13.6 (e.g., 13.4), 14.2 to 14.6 (e.g., 14.4), 14.6 to 15.0 (e.g., 14.8), 16.8 to 17.2 (e.g., 17.0), 20.5 to 20.9 (e.g., 20.7), 21.3 to 21.7 (e.g., 21.5), 21.4 to 21.8 (e.g., 21.6), and 22.4 to 22.8 (e.g., 22.6).

In some embodiments, crystalline Compound 1 can have an XRPD pattern with characteristic peaks between and including the following values of 20 in degrees: 9.7 to 10.1 (e.g., 9.9), 14.6 to 15.0 (e.g., 14.8), 16.8 to 17.2 (e.g., 17.0), 20.5 to 20.9 (e.g., 20.7), and 21.3 to 21.7 (e.g., 21.5).

In some embodiments, crystalline Compound 1 has an XRPD pattern with characteristic peaks at the following values of 20 in degrees: 9.9, 11.8, 13.4, 14.4, 14.8, 17.0, 20.7, 21.5, 21.6, and 22.6.

In some embodiments, crystalline Compound 1 has an XRPD pattern with characteristic peaks at the following values of 20 in degrees: 9.9, 14.8, 17.0, 20.7, and 21.5.

In some embodiments, crystalline Compound 1 has an XRPD pattern substantially as depicted in .

In some embodiments, crystalline Compound 1 has comprises a unit cell substantially as depicted in .

In some embodiments, a crystalline form of Compound 1, when subjected to a temperature from about 180 0C to about 200 oC, e.g., from about 184 0C to about 200 oC, e.g., from about 184 0C to about 190 oC, transforms into a different lline form as indicated by DSC at a ramp rate of 10 oC/min.

In some embodiments, crystalline Compound 1 melts at a Tom, from about 200 0C to about 225 oC, e.g., from about 211 0C to about 215 0C, as measured by DSC at a ramp rate of 10 oC/min.

In some embodiments, crystalline Compound 1 has any of the XRPD ns substantially as depicted in .

In some embodiments, crystalline Compound 1 has an XRPD pattern substantially as depicted in .

In some embodiments, crystalline Compound 1 has an XRPD pattern substantially as depicted in In some ments, crystalline Compound 1 has an XRPD pattern substantially as ed in .

In some ments, crystalline Compound 1 has an XRPD pattern substantially as depicted in .

In some embodiments, crystalline Compound 1 has an XRPD pattern substantially as depicted in .

In some embodiments, lline Compound 1 has an XRPD pattern ntially as depicted in .

In some embodiments, lline Compound 1 has an XRPD pattern substantially as depicted in A.

In some embodiments, crystalline Compound 1 has an XRPD n substantially as depicted in .

In some embodiments, crystalline Compound 1 has an XRPD pattern substantially as depicted in A.

In some embodiments, crystalline Compound 1 has an XRPD pattern substantially as depicted in A.

In some embodiments, crystalline Compound 1 has an XRPD pattern substantially as any of those depicted in .

In one aspect, the invention describes a method for orming the crystalline compound of claim 5 to the crystalline compound of claim 10, the method sing crystallization from a solubilized form of Compound 1 or slurry conversion.

In some ments, the transformation is performed using ethyl acetate as a solvent at a temperature from about 50 0C to about 70 oC, e.g., from 60 0C to 65 0C.

In some embodiments, the transformation is performed in the presence of seed ls of the crystalline compound of claim 10 at a loading from about 0.1% to about 5.0%, e.g. from 0.2% to 1.0%, of the total amount of Compound 1 present.

In one aspect, the present invention describes a pharmaceutical composition comprising a crystalline form of Compound 1, and a ceutically acceptable ent.

In one aspect, the present invention describes a method for treating a CNS—related disorder in a subject in need thereof, comprising administering to the subject an effective amount of Compound 1, e. g., a lline solid form of Compound 1 described herein, a pharmaceutically acceptable salt thereof, or a ceutical composition thereof.

In some embodiments, the CNS—related er is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a sive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, tic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus.

In some embodiments, crystalline Compound 1 is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, as a buccal, sublingually, rectally, as a topical, inhalation, intranasal, or transdermally.

In some embodiments, crystalline Compound 1 is administered cally.

In another aspect, provided herein is a method of treating a neurological disorder, a atric disorder, a seizure disorder, a nflammatory disorder, a glaucoma or metabolic disorder, a sensory deficit disorder, in a subject in need f, comprising administering to the subject an effective amount of Compound 1 or a ceutically acceptable composition thereof.

In another aspect, provided herein, is a method of using Compound 1 or a pharmaceutically acceptable composition thereof, as a neuroprotectant, comprising administering to a subject in need thereof an effective amount of Compound 1 or a ceutically acceptable composition thereof.

In another aspect, provided herein, is a method of using Compound 1 or a pharmaceutically acceptable composition thereof, as an analgesic or other agent for pain l, comprising administering to a subject in need thereof an effective amount of Compound 1 or a pharmaceutically acceptable ition thereof. In some embodiments, the compound or pharmaceutically acceptable composition is used as an analgesic or other agent for pain control to treat atory pain, neuropathic pain, fibromyalgia, or peripheral neuropathy.

As used herein, “XRPD” refers to X-ray powder diffraction. As used herein, “VT- XRP ” refers to variable temperature-X-ray powder diffraction. As used herein, “TGA” refers to thermogravimetric is. As used herein, DSC refers to differential scanning calorimetry.

As used herein, “NMR” refers to nuclear magnetic resonance. As used herein, “DVS” refers to dynamic vapor sorption. As used herein, “DCM” refers to dichloromethane. As used herein, “EtOAc” refers to ethyl acetate. As used herein, “MeOH” refers to methanol. As used herein, “MBTE” refers to methyl tert-butyl ether. As used herein, “RH” refers to ve humidity. As used , “RT” refers to room temperature.

As used herein, ”crystalline” refers to a solid having a highly regular chemical structure, i.e., having long range ural order in the crystal lattice. The molecules are ed in a regular, periodic manner in the 3-dimensional space of the lattice. In particular, a crystalline form may be ed as one or more single crystalline forms. For the purposes of this application, the terms ”crystalline formH H , single crystalline form, H 6‘crystalline solid form,” “solid form,” and ”polymorph” are synonymous and used interchangably; the terms distinguish between crystals that have different properties (e. g., different XRPD patterns and/or different DSC scan results).

The term ”substantially crystalline” refers to forms that may be at least a particular weight percent crystalline. Particular weight percentages are 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 70% and 100%. In n embodiments, the particular weight percent of crystallinity is at least 90%. In certain other ments, the particular weight percent of crystallinity is at least 95%. In some embodiments, Compound 1 can be a substantially crystalline sample of any of the crystalline solid forms described herein (e.g., Forms, A, B, C, D, E, F, H, I, J, K, L, M, N, O, and P).

The term ”substantially pure” relates to the composition of a ic lline solid form of Compound 1 that may be at least a particular weight percent free of impurities and/or other solid forms of Compound 1. Particular weight percentages are 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any percentage between 70% and 100%. In some ments, Compound 1 can be a substantially pure sample of any of the lline solid forms described . (e.g., Forms, A, B, C, D, E, F, H, I, J, K, L, M, N, O, and P). In some embodiments, Compound 1 can be substantially pure Form A. In some embodiments, Compound 1 can be substantially pure Form B. In some embodiments, Compound 1 can be ntially pure Form C. In some embodiments, Compound 1 can be substantially pure Form D. In some embodiments, nd 1 can be substantially pure Form E. In some embodiments, Compound 1 can be substantially pure Form F. In some embodiments, Compound 1 can be substantially pure Form H. In some embodiments, Compound 1 can be substantially pure Form I. In some embodiments, Compound 1 can be substantially pure Form J. In some embodiments, Compound 1 can be substantially pure Form K. In some embodiments, Compound 1 can be substantially pure Form L. In some embodiments, Compound 1 can be substantially pure Form M. In some embodiments, Compound 1 can be substantially pure Form N. In some embodiments, Compound 1 can be substantially pure Form 0. In some embodiments, Compound 1 can be substantially pure Form As used , the term “anhydrous” or “anhydrate” when referring to a crystalline form of Compound 1 means that no solvent molecules, ing those of water, form a portion of the unit cell of the crystalline form. A sample of an anhydrous crystalline form may nonetheless contain solvent molecules that do not form part of the unit cell of the anhydrous crystalline form, e. g., as residual solvent molecule left behind from the production of the crystalline form. In a preferred embodiment, a t can make up 0.5% by weight of the total composition of a sample of an anhydrous form. In a more preferred embodiment, a solvent can make up 0.2% by weight of the total composition of a sample of an anhydrous form. In some embodiments, a sample of an anhydrous crystalline form of Compound 1 contains no solvent molecules, e. g., no detectable amount of solvent. The term te” when ing to a lline form of Compound 1 means that solvent les, e.g., organic solvents and water, form a portion of the unit cell of the crystalline form. Solvates that contain water as the solvent are also referred to herein as “hydrates.” The term “isomorphic” when referring to a crystalline form of Compound 1 means that the form can comprise different chemical constituents, e. g., contain different solvent molecules in the unit cell, but have identical XRPD patterns. Isomorphic crystalline forms are sometimes referred to herein as “isomorphs.” A crystalline form of Compound 1 described herein, e. g., Form K, can melt at a specific temperature or across a range of temperatures. Such a specific temperature or range of temperatures can be ented by the onset ature (Toma) of the melting endotherm in the crystalline form’s DSC trace. In some embodiments, at such an onset temperature, a sample of a lline form of Compound 1 melts and undergoes a concurrently occurring side-process, e. g., recrystallization or chemical decomposition. In some ments, at such an onset temperature, a crystalline form of Compound 1 melts in the absence of other concurrently occurring processes.

The term “characteristic peaks” when ing to the peaks in an XRPD pattern of a crystalline form of Compound 1 refers to a collection of certain peaks whose values of 20 across a range of 00-400 are, as a whole, uniquely assigned to one of the crystalline forms of Compound BRIEF DESCRIPTION OF THE DRAWINGS depicts an ary XRPD pattern of Form A. depicts an exemplary unit cell of Form A along the b axis. depicts exemplary TGA (upper) and DSC ) curves of Form A. depicts an overlay of exemplary VT-XRPD patterns of Form A at selected temperatures, along with an exemplary XRPD pattern of Form K. depicts an exemplary DVS isotherm of Form A at 25 0C. depicts an exemplary XRPD patterns of Form A before and after an exemplary DVS measurement at 25 0C. depicts an exemplary XRPD pattern of an isomorph of Form B. depicts ary XRPD patterns of three isomorphs of Form B. depicts exemplary TGA (upper) and DSC (lower) curves of an isomorph of Form B. depicts an overlay of exemplary VT-XRPD patterns of an isomorph of Form B along with an exemplary XRPD pattern of Form K. depicts ary TGA curves of isomorphs of Form B. depicts exemplary DSC curves of isomorphs of Form B. depicts an exemplary 1H NMR spectrum of an isomorph of Form B dissolved in DMSO-d6. depicts an exemplary 1H NMR um of an isomorph of Form B dissolved in DMSO-d6. depicts an exemplary 1H NMR spectrum of an isomorph of Form B dissolved in DMSO-d6. depicts an exemplary XRPD pattern of Form C. depicts an exemplary unit cell of Form C along the b axis. s exemplary TGA (upper) and DSC (lower) curves of Form C. depicts an overlay of exemplary XRPD patterns of Form C at selected temperatures as well as an exemplary XRPD pattern of Form K. depicts an overlay of exemplary XRPD patterns of Form C at selected temperatures in the presence or absence of an N2 atmosphere. depicts an exemplary DVS isotherm of Form C at 25 0C. depicts an overlay of exemplary XRPD patterns of Form C before and after a DVS ement at 25 0C. depicts an ary XRPD pattern of Form D. depicts an overlay of exemplary XRPD patterns of Form D before and after drying at ambient conditions, along with an exemplary XRPD pattern of Form A. depicts an ary XRPD pattern of Form E. depicts an exemplary XRPD pattern of Form F. s ary TGA (upper) and DSC (lower) curves of Form F. depicts an overlay of exemplary XRPD patterns of Form F at selected temperatures along with an exemplary XRPD pattern of Form K. depicts an exemplary 1H NMR spectrum of Form F dissolved in DMSO-d6. depicts an exemplary XRPD pattern of Form H. depicts an y of ary XRPD patterns of Form H before and after drying at ambient conditions and an exemplary XRPD pattern of Form A. depicts an exemplary XRPD pattern of Form I. depicts an y of exemplary XRPD patterns of Form I before and after drying at ambient conditions for 3 days along with an XRPD pattern of Form A. depicts an exemplary XRPD pattern of Form J. depicts an overlay of exemplary XRPD patterns of Form J before and after drying at ambient conditions for 3 days, along with an XRPD pattern of Form A.

A depicts an exemplary XRPD pattern of Form K.

B depicts exemplary TGA (upper) and DSC (lower) curves of Form K.

C depicts an exemplary DVS isotherm of Form K at 25 0C.

D depicts an overlay of exemplary XRPD patterns of Form K before and after an exemplary DVS ement at 25 0C.

A depicts an exemplary XRPD n of Form L.

B depicts an y of exemplary XRPD patterns of Form L before and after 3 days, along with exemplary XRPD patterns of Form M and Form B.

C depicts an exemplary DSC curve of Form L. depicts an exemplary XRPD pattern of Form M.

A depicts an exemplary XRPD pattern of Form N.

B depicts an overlay of exemplary XRPD ns of Form N before and after drying at ambient ions overnight, along with an exemplary XRPD pattern of Form A.

C depicts exemplary TGA (upper) and DSC (lower) curves of Form N.

D depicts an exemplary 1H NMR um of Form N dissolved in DMSO-d6.

A depicts an exemplary XRPD pattern of Form 0.

B depicts exemplary TGA (upper) and DSC (lower) curves of Form 0.

C depicts an overlay of exemplary XRPD ns of Form 0 at selected temperatures along with an exemplary XRPD pattern of Form C.

D s an exemplary 1H NMR spectrum of Form 0 ved in DMSO-d6. ] depicts an overlay of exemplary XRPD patterns indicating the time-dependent sion of Form A to Form C in ethyl acetate at an elevated temperature in the presence of seed crystals of Form C. depicts exemplary XRPD patterns of Form P corresponding to wet sample (“Wet cake”), air dried sample at room temperature (“Air Dried”), and oven-dried sample at 40 oC (“Oven dried). An exemplary XRPD of a reference sample of Form A is also ed.

A depicts an exemplary 1H NMR spectrum of Form P after air-drying at room temperature.

B depicts an exemplary 1H NMR spectrum of Form P after oven-drying at 40 0C.

FIG 18A depicts an exemplary TGA curve of Form P after air-drying at room temperature.

B depicts an exemplary TGA curve of Form P after oven-drying at 40 0C.

FIG 19. depicts an exemplary plot of solubility data of Forms A, C, and P in ethyl acetate.

FIG 20. depicts an exemplary phase relationship n Forms A, C, and P.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION In one aspect, the present invention describes a compound of Formula (I), also ed to herein as “Compound 1,” has been found to exist as different crystalline forms as indicated by various ical methods. Compound 1 and its al sis are previously disclosed in U.S. Patent Application Publication No. US 20160083417 and PCT Application Publication No. WO 2014169831. Exemplary individual solid forms of the present invention are provided in Table 1 below: Table 1. y of exemplary Crystalline Forms of Compound 1.

Polymorph Form B Form C Form D Form E Form F Form H Form I Form J Form K Form L Form M Form N Form 0 Form P Solidforms of Compound 1 Methods ofMaking the Same Forms B, C, D, E, F, H, I, J, K, N, and 0 were prepared from Form A using various crystallization techniques described herein. Forms L and M were additionally prepared from Form B using other methods described herein. These forms were subsequently characterized by one or more of the following analytical techniques: X-ray powder diffraction , e.g., variable-temperature X-ray powder diffraction (VT-XRPD), thermogravimetric analysis (TGA), ential scanning calorimetry (DSC), or dynamic vapor sorption (DVS). The single-crystal structures, including the unit cells, of Form A and Form C were determined from data obtained with an X-ray diffractometer. Furthermore, calculated XRPD patterns for Form A and Form C were obtained using their single-crystal X-ray diffraction data. In the present invention, DSC and TGA data were ed using a ramp rate of 100C/min.

Form A Form A can be prepared by stirring crude Compound 1 as a slurry in ethyl acetate below 100C and then filtering and drying under vacuum or by dissolving crude Compound 1 in dichloromethane and then re-concentrating the solution twice with ethyl acetate under vacuum to dryness. Form A can be determined to be a crystalline form of Compound 1 by XRPD. TGA, together with single-crystal structure of Form A, can be used to de that Form A is anhydrous. DSC can be used to indicate the presence of two endotherms occurring at temperatures below 300 oC: one endotherm with a Tome, of 157.2 0C that represents the ormation of Form A into Form K, and another with a Tome, of 203.8 0C that represents the melting point of Form K. DVS can be used to demonstrate that Form A exhibits less than 0.30 weight percent water uptake at a relative humidity (RH) less than or equal to 95%.

In some embodiments, Form A can have an XRPD pattern ntially as ed in . Additionally, representative peaks from the XRPD n of Form A can be indicated by their values of 20, d-spacing, and relative intensities as, for example, in Table 2 below: Table 2. Selected experimental XRPD pattern data for Form A. \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\a\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\ (degrees) d-spacing (A) Relative Intensity (%) 9494611 931518 4049 .78823 8.20093 46.5 13.22776 5 37.69 23 5.94927 10.18 .99324 5.54174 15.09 18.28113 4.85302 31.96 18.93233 4.68754 100 21.05207 4.2201 10.38 21.64548 4.10573 24.16 05 3.78495 15.37 In some embodiments, Form A has an XRPD pattern with characteristic peaks between and including the following values of 20 in degrees: 9.3 to 9.7 (e.g., 9.5), 10.6 to 11.0 (e.g., 10.8), 13.0 to 13.4 (e.g., 13.2), 14.7 to 15.1 (e.g., 14.9), 15.8 to 16.2 (e.g., 16.0), 18.1 to 18.5 (e.g., 18.3), 18.7 to 19.1 (e.g., 18.9), 20.9 to 21.3 (e.g., 21.1), 21.4 to 21.8 (e.g., 21.6), and 23.3 to 23.7 (e.g., 23.5). In some embodiments, Form A has an XRPD pattern with characteristic peaks between and including the following values of 20 in degrees: 9.3 to 9.7 (e.g., 9.5), 10.6 to 11.0 (e.g., 10.8), 13.0 to 13.4 (e.g., 13.2), 18.7 to 19.1 (e.g., 18.9), and 21.4 to 21.8 (e. g., 21.6). In some embodiments, Form A has an XRPD pattern with characteristic peaks at the following values of 20 in degrees: 9.5, 10.8, 13.2, 14.9, 16.0, 18.3, 18.9, 21.1, 21.6, and 23.5.

In some embodiments, Form A has an XRPD pattern with characteristic peaks at the following values of 20 in degrees: 9.5, 10.8, 13.2, 18.9, and 21.6.

Calculated XRPD data for selected peaks can be obtained from X-ray ction data from a single l of Form A as provided in Table 3 below, which complement the experimental data in Table 2.

Table 3. Selected calculated XRPD pattern data for Form A. \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\a\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\ (degrees) d-spacing (A) Relative Intensity (%) 109265 8090762114 13.32097 6.64132 48.56 14.11329 6.27021 20.36 14.94619 5.92262 24.95 16.05232 5.5169 49.72 17.42404 5.08555 48.28 18.40825 4.81581 100 19.2493 4.60725 18.47 24.23572 3.66943 19.02 24.3725 3.64915 19.56 Form B Form B can exist as a crystalline form of Compound 1 as determined by XRPD and can be prepared from various techniques described herein, e.g., slow evaporation, slurry conversion, anti-solvent addition, solid vapor diffusion, or slow cooling. Furthermore, phs of Form B from ent solvent systems such as dichloromethane (DCM)/nheptane , ydrofuran (THF)/n-heptane, or chloroform (CHC13)/methyl tert-butyl ether (MBTE) can be ed. Table 4 izes the ties of these isomorphs as determined by various instrumental methods, e.g., TGA, DSC, and 1H NMR spectroscopy.

Table 4. Summary of exemplary phs of Form B TGA Tam, for Compound Solvent Crystallization Type of 1: Solvent Weight DSC Isomorph System Method solvate Loss Endotherm (molar (%) (0C) ratio) DCM/n- Slurry 5.7 to Form B-l 87.2, 211.7 1:0.4 Heptane heptane conversion 8.5 THF/n- Anti-solvent 4.6 to Form B-2 85.4, 212.2 1:0.3 Heptane heptane addition 8.5 solvate CHC13/ Anti-solvent CHC13 .2 69.2, 211.6 1:0.5 Form B-3 MBTE addition solvate Form C Form C is a crystalline anhydrate of Compound 1 as determined by XRPD and can be prepared from Form A using a slurry conversion crystallization technique in isopropyl alcohol and isopropyl acetate at 50 oC. TGA and single-crystal X-ray crystallography can be used to m the absence of solvent in Form C. DSC can be used to indicate two endotherms below 300 0C: a broad peak with a Tome, of 183.8 0C corresponding to the transformation of Form C into Form K and a sharp peak with a Tome, of 211.0 0C ponding to the melting of Form K. DVS can be used to demonstrate that Form C exhibits less than 0.32 weight percent water uptake at RH less than or equal to 95%.

In some embodiments, Form C can have an XRPD n substantially as depicted in . Additionally, representative peaks from the XRPD pattern of Form C can be indicated by their values of 20, ing, and relative intensities as, for example, in Table 5 below: Table 5. ed experimental XRPD pattern data for Form C. (degrees)dspac1ng(A)Relat1veIntens1ty(%) 22.60955 3.93279 26.76 .65623 4.30006 27.84 13.36358 6.62573 28.42 14.81188 5.98097 33.78 21.50066 4.12963 36.7 21.54634 4.12439 36.94 9.889125 8.94443 41.85 11.79075 7.50579 65.73 14.41313 6.14552 65.89 16.99542 5.21715 100 In some embodiments, Form C can have an XRPD n with characteristic peaks between and including the following values of 20 in degrees: 9.7 to 10.1 (e.g., 9.9), 11.6 to 12.0 (e.g., 11.8), 13.2 to 13.6 (e.g., 13.4), 14.2 to 14.6 (e.g., 14.4), 14.6 to 15.0 (e.g., 14.8), 16.8 to 17.2 (e.g., 17.0), 20.5 to 20.9 (e.g., 20.7), 21.3 to 21.7 (e.g., 21.5), 21.4 to 21.8 (e.g., 21.6), and 22.4 to 22.8 (e. g., 22.6). In some embodiments, Form C can have an XRPD pattern with characteristic peaks between and including the following values of 20 in degrees: 9.7 to 10.1 (e.g., 9.9), 14.6 to 15.0 (e.g., 14.8), 16.8 to 17.2 (e.g., 17.0), 20.5 to 20.9 (e.g., 20.7), and 21.3 to 21.7 (e.g., 21.5). In some embodiments, Form C can have an XRPD pattern with characteristic peaks at the following values of 20 in degrees: 9.9, 11.8, 13.4, 14.4, 14.8, 17.0, 20.7, 21.5, 21.6, and 22.6. In some embodiments, Form C can have an XRPD n with characteristic peaks at the following values of 20 in degrees: 9.9, 14.8, 17.0, 20.7, and 21.5.

Calculated XRPD data for selected peaks can be obtained using X-ray diffraction data from a single crystal of Form C, as provided in Table 6 below. These simulated peaks can complement the mental data in Table 5.

Table 6. Selected calculated XRPD pattern data for Form C. (degrees)dspac1ng(A)Relat1veIntens1ty(%) 98619238961621941 59 7.51938 37.75 13.33554 6.6341 31.9 14.38478 6.15248 43.36 21 5.98473 26.68 16.96659 5.22162 100 19.61234 4.52277 17.69 .60123 4.30785 30.39 21.48653 2 25.6 22.57956 3.93469 27.32 Form D Form D can be prepared using an anti-solvent addition crystallization technique in tetrahydrofuran water (H20) and, by XRPD analysis, can be subsequently found to be a crystalline form of Compound 1 that converted back to Form A upon drying at room temperature.

Form E Form E can be prepared from an anti-solvent crystallization technique in 1,4- dioxane/n-heptane at room temperature and can be ined to be a crystalline wet sample of Compound 1 by XRPD.

Form F Form F can be prepared with an olvent addition crystallization technique in 1,4-dioxane/n-heptane at ambient room-temperature conditions and determined to be a crystalline form of Compound 1 by XRPD. TGA on a sample of Form F exhibits a weight loss of 19.7% up to 200 °C. DSC can be used to show that Form F ts 2 ermic peaks at onset atures of 63.1 °C and 210.7 °C, corresponding to the loss of solvent formation to Form K) and the melting point of Form K, respectively. The transformation of Form F to Form K can be additionally confirmed through VT-XRPD measurements. Based on 1H NMR spectroscopy, Form F is a 1,4-dioxane solvate with a molar ratio of 1:0.9 with residual n-heptane present.

Form H Form H can be prepared from a solution vapor diffusion crystallization technique in n-heptane at room ature. The form was determined to be crystalline by XRPD, but metastable due to its transformation to Form A after drying at ambient conditions for 3 days.

Form I Form I can be made using a slow cooling crystallization technique performed in methanol at room temperature. Like Form H, Form I can be determined to be a crystalline material by XRPD analysis, but was found to be metastable due to its transformation to Form A after drying at ambient conditions for 3 days.

Form J Form J can be prepared using a solid vapor diffusion crystallization technique in methanol at room temperature. XRPD analysis can be used to conclude that Form J is a crystalline metastable sample that transforms to Form A after drying at ambient conditions for 3 days.

Form K ] Form K can be ed by heating various forms of Compound 1, e.g., Form A, Form B, Form C, Form E, and Form F, to ed temperatures. The analyzed sample of this form can be determined to be crystalline by XRPD analysis. TGA can be used to indicate no weight loss prior to the decomposition temperature and demonstrates that Form K is anhydrous.

DSC can be used to demonstrate that Form K can exhibit a single endotherm with a Tome, of 211.6 0C that corresponds to the melting point of the analyzed . DVS measurements were performed to demonstrate that Form K demonstrates less than 0.35 weight percent water uptake at RH less than or equal to 95%.

In some embodiments, Form K can have an XRPD pattern substantially as depicted in A. Additionally, entative peaks from the XRPD pattern of Form K can be indicated by their values of 20 and ve intensities as, for example, in Table 7 below: Table 7. Selected experimental XRPD pattern data for Form K. “\““\““\““\““\““\““\““\““\““\““\““\““\““\““\“9}““\““\““\““\““\““\““\“\\“\“\\“\“\“\\“\\“\“\\\ ‘ ‘W 139471634981912 .09767 9 20.68 23.20826 3.83268 23.69 22.05504 4.0304 24.27 19.10905 4.64459 24.93 21.32362 4.16697 26.68 19.33614 4.59055 28.07 14.16125 6.25426 47 16.84678 5.26284 61.56 11.75077 7.53124 100 ] In some embodiments, Form K can have an XRPD pattern with characteristic peaks between and including the following values of 20 in degrees: 11.6 to 12.0 (e. g., 11.8), 13.7 to 14.1 (e.g., 13.9), 14.0 to 14.4 (e.g., 14.2), 16.6 to 17.0 (e.g., 16.8), 18.9 to 19.3 (e.g., 19.1), 19.1 to 19.5 (e.g., 19.3), 19.9 to 20.3 (e.g., 20.1), 21.1 to 21.5 (e.g., 21.3), 21.9 to 22.3 (e.g., 22.1), and 23.0 to 23.4 (e. g., 23.2). In some embodiments, Form K can have an XRPD pattern with characteristic peaks between and including the following values of 20 in s: 11.6 to 12.0 (e.g., 11.8), 16.6 to 17.0 (e.g., 16.8), 18.9 to 19.3 (e.g., 19.1), 19.9 to 20.3 (e.g., 20.1), and 23.0 to 23.4 (e.g., 23.2). In some embodiments, Form K can have an XRPD pattern with characteristic peaks at the following values of 20 in degrees: 11.8, 13.9, 14.2, 16.8, 19.1, 19.3, .1, 21.3, 22.1, and 23.2. In some embodiments, Form K can have an XRPD pattern with characteristic peaks at the following values of 20 in degrees: 11.8, 16.8, 19.1, 20.1, and 23.2.

Form L Form L can be prepared by storing Form B in a sealed vial at t conditions for one month. This form can be determined to be a crystalline metastable form of Compound 1.

Analysis with XRPD can indicate that Form L transforms to a mixture of Form B and Form M at ambient conditions 3 days after preparation. Form L was determined to be a solvate of nd 1.

Form M Form M can be made by storing Form B in a sealed vial at ambient conditions for one month. The analyzed sample of this form was determined to have low crystallinity by analysis with XRPD.

Form N Form N can be prepared from a reverse anti-solvent addition crystallization technique in oxane/n-heptane and determined to be a crystalline form of Compound 1 by XRPD. TGA can be used to determine that Form N is a solvate that exhibits a weight loss of 2.5% up to 60 °C, ed by a weight loss of 7.1% up to 200 °C. DSC can be used to demonstrate two endotherms, one corresponding to the loss of solvent at a Tome, of 75.4 0C and the other at a Tome, of 210.4 0C, which represents the melting point of Form K. VT-XRPD can be used to m that Form N transforms to Form K at 100 oC. Based on 1H NMR spectroscopy, Form N is a 1,4-dioxane solvate with a molar ratio of 1:0.3 for Compound 1:1,4-dioxane.

Form 0 Form 0 can be ed using a water activity experiment in a water/acetonitrile mixture (0.041 water:0.959 acetonitrile volume/volume; aw=0.6) at room temperature and determined to be a lline form of Compound 1 by XRPD. TGA on a sample of Form 0 can te weight loss of 5.3% up to 55.1 0C, followed by 5.9% up to 200 °C. DSC can be used to show that Form 0 exhibits three endotherms, one at Tome, = 65.0 0C corresponding to the loss of solvent to create Form C, one at Tom, = 168.5 0C ponding to transformation to Form C to Form K, and one at Tome, = 210.8 0C corresponding to melting of Form K. Form 0 can be further characterized by 1H NMR spectroscopy dissolved in DMSO-d6.

Form P In addition the above-described forms, Form P is an ethyl acetate (EtOAc) solvate of Compound 1 and can be detected in (a) slurries of Form A in EtOAc at 5 °C (after 1 h) and 20 °C (after 2 days), (b) slurries of Form C in EtOAc at 5 °C (after 1 h) and 20 °C (after 7 days).

The wet cake of Form P (~5 min air) can be dried in two ways: (a) under air at room temperature overnight, and (b) under vacuum at 40 °C for 3 hours. Both dried cakes can be analyzed by XRPD, 1H-NMR, and TGA. An air dried cake of Form P can give an XRPD pattern ming to Form P, about 1% weight loss by TGA up to about 50 °C, and EtOAc peaks by 1H NMR. The sample of Form P post-oven drying, on the other hand, can give an XRPD pattern conforming to Form A, no weight loss S 100 °C by TGA, and no EtOAc peaks by 1H-NMR. Therefore, Form P can convert to Form A upon drying.

In another aspect, the present invention provides a method for transforming a solid form of Compound 1 or mixture of solid forms of Compound 1 to a different anhydrate of nd 1. In one embodiment, Form A, a mixture of Form A or Form K, or a e of Form A, Form C, and Form K can be ted to Form C through slurry conversion in ethyl acetate, n-butanol, or methyl tert-butyl ether at room temperature or elevated temperatures, e.g., 500C or 650C. In these 3 solvent systems, Form C is the only form remaining after slurry conversion, revealing that this solid form was more thermodynamically stable from room temperature to 50 °C when compared to Form A and Form K. In another embodiment, From C can be obtained through crystallization of solubilized Compound 1 (originally Form A) in ethyl acetate at an ed temperature, e.g., 65 0C, in the presence of a small , e.g. 0.2%- 1.0%, of seed crystals of Form C, followed by cooling the batch to a temperature no less than 25 0C to 30 oC. Seed crystals of Form C can be made using the procedure described in Example 4 described herein.

Pharmaceutical Compositions In another aspect, the invention es a pharmaceutical composition sing a solid form of a compound of the t invention (also referred to as the “active ingredient”) and a pharmaceutically able excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by ion) administration, rectal administration, topical administration, transdermal administration, intradermal stration, intrathecal stration, subcutaneous (SC) administration, uscular (IM) administration, sublingual / buccal, ocular, otic, vaginal, and intranasal or inhalation administration.

Generally, the solid forms of Compound 1 provided herein are administered in an effective amount. The amount of the solid forms of Compound 1 compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.

When used to prevent the onset of a CNS-disorder, the solid forms of Compound 1 provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above.

Subjects at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been fied by genetic testing or screening to be particularly susceptible to developing the condition.

The pharmaceutical itions provided herein can also be administered chronically (“chronic administration”). Chronic administration refers to administration of a solid form of nd 1 or pharmaceutical composition f over an extended period of time, e. g., for example, over 3 , 6 , 1 year, 2 years, 3 years, 5 years, etc, or may be continued nitely, for example, for the rest of the subject’s life. In certain embodiments, the chronic administration is intended to provide a consistent level of Compound 1 in the blood, e. g., within the therapeutic window over the extended period of time.

The pharmaceutical compositions of the present invention may be r delivered using a variety of dosing methods. For example, in certain embodiments, the pharmaceutical ition may be given as a bolus, e. g., in order to raise the tration of Compound 1 in the blood to an effective level. The placement of the bolus dose depends on the systemic levels of the active ingredient desired throughout the body, e. g., an intramuscular or subcutaneous bolus dose allows a slow release of the active ingredient. Furthermore, in still yet other embodiments, the pharmaceutical ition may be administered as first as a bolus dose, followed by continuous infusion.

The compositions for oral administration can take the form of bulk liquid solutions or suspensions or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically te units suitable as unitary dosages for human ts and other mammals, each unit containing a predetermined quantity of active material ated to produce the desired therapeutic effect, in ation with a suitable pharmaceutical excipient. Typical unit dosage forms e prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, a solid form of Compound 1 is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or ents and processing aids helpful for forming the desired dosing form.

With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose es from about 0.01 to about 20 mg/kg of a solid form of Compound 1 ed herein, with preferred doses each providing from about 0.1 to about 10 mg/kg, and especially about 0.2 to about 5 mg/kg.

Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses, generally in an amount ranging from about 0.01 to about % by weight of, e. g., the drug reservoir or drug-adhesive reservoir for the ermal patch, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.

Solid compositions may include, for example, any of the following ients, or a solid form of Compound 1 of a similar nature: s, surfactants, diluents or fillers, buffering agents, antiadherents, glidants, hydrophilic or hydrophobic polymers, ants, stabilizing agents or stabilizers, disintegrants or superdisintegrants, dispersants, antioxidants, antifoaming agents, fillers, flavors, colorants, ants, sorbents, preservatives, plasticizers, coatings, or sweeteners, or mixtures thereof, For example, the exipeint or excipients could be a binder such as microcrystalline cellulose, polyvinyl pyrrolidone, hydroxylpropyl cellulose, low viscosity hydroxypropylmethylcellulose, gum tragacanth or gelatin; a t such as mannitol, microcrystalline cellulose, maltodextrin, starch or lactose, a disintegrating agent such as alginic acid, el, sodium starch glycolate, sodium croscarmellose, crospovidone, or corn starch; a ant such as magnesium stearate, sodium stearyl fumarate or glyceryl behenate; a t such as colloidal silicon dioxide; a preservative such as potassium sorbate or methyl paraben, asurfactant, such as sodium lauryl sulfate, sodium docusate, poysorbate 20, polysorbate 80, cetyl triethyl ammonium bromide, polyethyelene oxide-polypropylene oxide copolymers, or Cremophor EL. an antioxidant such as butylhydroxy toluene, butyl yanisole, propyl gallate, ascorbic acid, tocopherol or tocopherol acetate, sodium sulphite, or sodium metabisulfite, a coating comprising one or more of hydroxypropykmethylcellulose, polyvinyl alcohol, methacrylate copolymers, cellulose acetate, hydroxypropylmethylcellulose e succinate, c and others, a sweetening agent such as sucrose, sucralose, acesulfame K, sodium aspartame or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange ng. Any of the well known pharmaceutical excipients may be incorporated in the dosage form and may be found in the FDA’s Inactive Ingredients Guide, Remington: The Science and Practice of Pharmacy, Twenty-first Ed., (Pharmaceutical Press, 2005); Hnadbook of Pharmaceutical Excipients, Sixth Ed. (Pharmacrutical Press, 2009) all of which are incorporated by reference.

Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s). When formulated as a ointment, the active ients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally e additional ingredients to enhance the dermal penetration and stability of the active ingredients or Formulation. All such known transdermal formulations and ients are included within the scope provided herein. Topical delivery compositions of interest include liquid ations, such as lotions (liquids containing ble material in the form of a suspension or emulsion, intended for external application, including spray lotions) and aqueous solutions, semi-solid formulations, such as gels (colloids in which the se phase has combined with the dispersion medium to produce a semisolid material, such as a jelly), creams (soft solids or thick liquids) and ointments (soft, unctuous preparations), and solid formulations, such as topical patches. As such, delivery vehicle components of interest include, but are not limited to: emulsions of the oil-in-water (O/W) and the water in-oil (W/O) type, milk preparations, lotions, creams, nts, gels, serum, powders, masks, packs, sprays, aerosols, sticks, and patches.

The solid forms of Compound 1 provided herein can also be stered by a transdermal device. Accordingly, transdermal administration can be lished using a patch either of the reservoir or membrane type, or of an adhesive matrix or other matrix variety.

Delivery compositions of interest include liquid formulations, such as lotions (liquids ning insoluble material in the form of a suspension or emulsion, ed for external application, including spray lotions) and aqueous ons, semi-solid formulations, such as gels (colloids in which the disperse phase has combined with the dispersion medium to produce a semisolid material, such as a jelly), creams (soft solids or thick liquids) and ointments (soft, unctuous preparations), and solid formulations, such as topical patches. As such, delivery vehicle components of interest include, but are not limited to: emulsions of the oil-in-water (O/W) and the water in-oil (W/O) type, milk preparations, lotions, creams, ointments, gels, serum, powders, masks, packs, sprays, aerosols, , and patches. For a transdermal patch, the active agent layer includes one or more active agents, one of which is Compound I. In certain embodiments, the matrix is an adhesive matrix. The matrix may e ric materials. le polymers for the adhesive matrix include, but are not limited to: polyurethanes, acrylates, styrenic block copolymers, silicones, and the like. For example, the adhesive matrix may include, but is not limited to, an acrylate polymer, polysiloxanes, polyisobutylene (PIB), polyisoprene, polybutadiene, styrenic block polymers, combinations of thereof, and the like.

Additional examples of adhesives are described in Satas, “Acrylic Adhesives,” Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed., pp. 396-456 (D. Satas, ed.), Van Nostrand ld, New York (1989), the disclosure of which is herein incorporated by nce.

In certain embodiments, the active agent layer includes a permeation enhancer.

The permeation er may include, but is not limited to the following: aliphatic ls, such as but not limited to saturated or unsaturated higher alcohols having 12 to 22 carbon atoms, such as oleyl alcohol and lauryl l; fatty acids, such as but not limited to linolic acid, oleic acid, nic acid, stearic acid, isostearic acid and palmitic acid; fatty acid esters, such as but not limited to isopropyl myristate, diisopropyl e, and isopropyl palmitate; alcohol amines, such as but not limited to triethanolamine, triethanolamine hydrochloride, and diisopropanolamine; polyhydric alcohol alkyl ethers, such as but not limited to alkyl ethers of polyhydric alcohols such as glycerol, ethylene glycol, ene , tylene glycol, diglycerol, polyglycerol, diethylene glycol, polyethylene , dipropylene glycol, polypropylene glycol, sorbitan, sorbitol, isosorbide, methyl glucoside, oligosaccharides, and reducing oligosaccharides, where the number of carbon atoms of the alkyl group moiety in the polyhydric alcohol alkyl ethers is preferably 6 to 20; polyoxyethylene alkyl ethers, such as but not limited to polyoxyethylene alkyl ethers in which the number of carbon atoms of the alkyl group moiety is 6 to 20, and the number of repeating units (e.g. -OCH2CH2-) of the polyoxyethylene chain is 1 to 9, such as but not limited to polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, and polyoxyethylene oleyl ether; glycerides (i.e., fatty acid esters of glycerol), such as but not d to glycerol esters of fatty acids having 6 to 18 carbon atoms, diglycerides, triglycerides or combinations thereof. In some embodiments, the polymer matrix includes a polyvinylpyrrolidone, The ition may further include one or more fillers or one or more antioxidants. In some embodiments, .the transdermal formulations described may have a multi-layer structure. For example, the transdermal formulation may have an adhesive matrix and a backing.

The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other als as well as processing techniques and the like are set forth in Part 8 of Remington ’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, lvania, which is orated herein by reference.

A solid form of Compound 1 of the present invention can also be stered in sustained e forms or from ned release drug ry systems. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

Methods of Use Provided herein are methods of treating a disorder, e. g., a CNS—related disorder, in a subject in need thereof, comprising administering to the subject an effective amount of the compound of Formula (I), e. g., Compound 1 as a solid form described , or a pharmaceutically acceptable salt or pharmaceutically acceptable composition thereof. In certain ments, the disorder is a CNS—related disorder selected from the group consisting of a sleep er, a mood er, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal me, and us. In some embodiments, the disorder is a comorbid disorder (e. g., depression comorbid with a personality disorder or a sleep disorder id with a personality disorder). In some embodiments, the disorder is a ogical disorder as described herein. In some embodiments, the disorder is a neurological disorder as described herein. In some embodiments, the disorder is a psychiatric disorder as bed herein. In some embodiments, the disorder is a seizure disorder as described herein. In some embodiments, the disorder is a neuroinflammatory disorder as described herein. In some embodiments, the disorder is a glaucoma or metabolic disorder as described herein. In some embodiments, the disorder is a sensory deficit disorder as described . Also provided herein are methods of using Compound 1, e. g., Compound 1 as a solid form described herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, as a neuroprotectant.

Also provided herein are methods of using Compound 1, e. g., Compound 1 as a solid form described herein, or a ceutically acceptable salt or pharmaceutical composition thereof, as an analgesic or other agent for pain control.

Neurological disorders The compound of Formula (I), e. g., a solid form of Compound 1, or a pharmaceutically acceptable salt or pharmaceutically able ition thereof, can be used in a method described herein, for e in the treatment of a disorder described herein such as a neurological disorder. Exemplary neurological disorders include, but are not limited to, egenerative disorders, neurodevelopmental disorders, ndocrine ers and dysfunction, movement disorders, and sleep disorders as described herein. egenerative disorders The compound of a (I), e.g., a solid form of Compound 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable composition thereof, can be used in a method described herein, for example in the treatment of a neurodegenerative disorder.

The term degenerative disease” includes diseases and disorders that are associated with the progressive loss of structure or function of neurons, or death of neurons.

Neurodegenerative diseases and disorders include, but are not d to, Alzheimer’s disease (including the associated symptoms of mild, moderate, or severe cognitive impairment); amyotrophic lateral sis (ALS); anoxic and ischemic injuries; benign forgetfulness; brain edema; cerebellar ataxia including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusive injuries (e. g., spinal cord injury and head injury); dementias including multi-infarct dementia and senile dementia; disturbances of consciousness; Down syndrome; fragile X syndrome; Gilles de la Tourette’s syndrome; head trauma; hearing ment and loss; Huntington’s disease; Lennox syndrome; mental retardation; neuronal damage including ocular damage, retinopathy or macular degeneration of the eye; neurotoxic injury which follows cerebral stroke, oembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest; Parkinson’s e; stroke; tinnitus; tubular sis, and viral infection induced neurodegeneration (e. g., caused by acquired immunodeficiency syndrome (AIDS) and encephalopathies). Neurodegenerative diseases also include, but are not limited to, oxic injury which follows cerebral stroke, thromboembolic , hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, tal asphyxia and cardiac arrest. Methods of ng or preventing a neurodegenerative disease also include treating or preventing loss of neuronal function characteristic of neurodegenerative disorder.

Neurodevelopmental disorders The compound of Formula (I), e.g., a solid form of Compound 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable composition thereof, can be used in a method described herein, for example in the treatment of a disorder described herein such as a neurodevelopmental disorder. In some embodiments, the neurodevelopmental disorders is autism spectrum disorder. In some ments, the neurodevelopmental disorder is Smith-Lemli-Opitz syndrome.

Neuroendocrine disorders Provided herein are methods that can be used for treating neuroendocrine disorders and dysfunction. As used herein, “neuroendocrine er” or “neuroendocrine dysfunction” refers to a variety of conditions caused by imbalances in the body’s hormone production directly d to the brain. Neuroendocrine disorders involve interactions between the nervous system and the endocrine system. Because the hypothalamus and the pituitary gland are two areas of the brain that regulate the production of hormones, damage to the hypothalamus or pituitary gland, e.g., by traumatic brain injury, may impact the tion of hormones and other neuroendocrine functions of the brain. In some embodiments, the neuroendocrine er or dysfunction is associated with a s health disorder or condition (e. g., a women’s health disorder or condition bed herein). In some embodiments, the neuroendocrine disorder or dysfunction is associated with a women’s health er or condition is polycystic ovary syndrome.

Symptoms of neuroendocrine disorder include, but are not limited to, behavioral, emotional, and related symptoms, symptoms related to reproductive function, and somatic symptoms; ing but not limited to e, poor memory, anxiety, depression, weight gain or loss, emotional lability, lack of concentration, attention difficulties, loss of libido, infertility, amenorrhea, loss of muscle mass, sed belly body fat, low blood pressure, reduced heart rate, hair loss, anemia, constipation, cold intolerance, and dry skin.

Movement disorders The nd of Formula (I), e. g., a solid form of Compound 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable composition thereof, can be used in a method described herein, for example in the treatment of a movement disorder. In some embodiments, the movement disorder is essential , Stiff-Person syndrome, spasticity, Freidrich’s ataxia, llar ataxia, dystonia, Tourette Syndrome, Fragile X- associated tremor or ataxia syndromes, drug-induced or tion-induced Parkinsonism (such as neuroleptic-induced acute akathisia, acute dystonia, Parkinsonism, or tardive dyskinesia, neuroleptic ant syndrome, or medication-induced postural tremor), ataxia, cerebellar ataxia including McLeod neuroacanthocytosis me (MLS), levodopa-induced dyskinesia, movement disorders including akinesias and akinetic (rigid) syndromes (including basal ganglia calcification, corticobasal degeneration, multiple system atrophy, Parkinsonism-ALS dementia complex, Parkinson’s e, postencephalitic parkinsonism, and progressively supranuclear palsy); ar spasms and disorders associated with muscular spasticity or weakness including chorea (such as benign hereditary chorea, drug-induced chorea, hemiballism, Huntington’s disease, neuroacanthocytosis, Sydenham’s chorea, and symptomatic chorea), dyskinesia (including tics such as complex tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal onus), tremor (such as rest tremor, postural tremor, and intention ), or ia (including axial dystonia, dystonic 's cramp, hemiplegic dystonia, paroxysmal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, and dic dysphonia and torticollis).

As used herein, “movement disorders” refers to a variety of diseases and disorders that are 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 (defined particularly by bradykinesia), dystonia, chorea and Huntington’s disease, ataxia, tremor (e.g., ial tremor), myoclonus and startle, tics and Tourette syndrome, Restless legs syndrome, stiff person syndrome, and gait disorders.

Exemplary movement disorders e, but are not d to, Parkinson’s disease and parkinsonism (defined particularly 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.

Tremor The methods described herein can be used to treat tremor, for example, the compound of a (I), e.g., a solid form of Compound 1, or a pharmaceutically acceptable salt or pharmaceutically able composition thereof, can be used to treat cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, parkinsonian tremor, physiological tremor, genic tremor, or rubral tremor. Tremor includes hereditary, degenerative, and thic disorders such as ’s disease, Parkinson’s disease, and essential tremor, respectively; lic diseases (e.g., thyoid-parathyroid-, liver disease and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth, Roussy-Levy, diabetes mellitus, complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, Manganese, arsenic, toluene); drug-induced (narcoleptics, tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, ate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be classified into physiologic tremor, enhanced physiologic , essential tremor syndromes (including classical essential tremor, primary orthostatic tremor, and task- and position-specific tremor), dystonic tremor, parkinsonian tremor, llar tremor, ’ tremor (i.e., rubral tremor), palatal tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic .

] Tremor is an involuntary, at times rhythmic, muscle contraction and tion that can involve ations or twitching of one or more body parts (e. g., hands, arms, eyes, face, head, vocal folds, trunk, legs).

Cerebellar tremor or intention tremor is a slow, broad tremor of the extremities that occurs after a purposeful movement. Cerebellar tremor is caused by lesions in or damage to the cerebellum resulting from, e. g., tumor, stroke, disease (e. g., multiple sis, an inherited rative disorder).

Dystonic tremor occurs in individuals affected by dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive motions and/or painful and abnormal es or positions. Dystonic tremor may affect any muscle in the body. Dystonic s occurs irregularly and often can be relieved by complete rest.

Essential tremor or benign essential tremor is the most common type of tremor.

Essential tremor may be mild and nonprogressive in some, and may be slowly progressive, starting on one side of the body but affect both sides within 3 years. The hands are most often affected, but the head, voice, tongue, legs, and trunk may also be involved. Tremor frequency may decrease as the person ages, but severity may increase. Heightened emotion, stress, fever, physical exhaustion, or low blood sugar may trigger tremors and/or increase their severity.

Symptoms generally evolve over time and can be both visible and persistent following onset.

Orthostatic tremor is characterized by fast (e. g., greater than 12 Hz) rhythmic muscle contractions that occurs in the legs and trunk immediately after standing. Cramps are felt in the thighs and legs and the patient may shake uncontrollably when asked to stand in one spot. tatic tremor may occurs in ts with essential tremor.

Parkinsonian tremor is caused by damage to structures within the brain that control movement. Parkinsonian tremor is often a precursor to Parkinson’s disease and is typically seen as a “pill-rolling” action of the hands that may also affect the chin, lips, legs, and trunk. Onset of parkinsonian tremor lly begins after age 60. Movement starts in one limb or on one side of the body and can progress to include the other side.

Physiological tremor can occur in normal individuals and have no clinical icance. It can be seen in all voluntary muscle groups. Physiological tremor can be caused by certain drugs, l withdrawl, or l conditions ing an overactive thyroid and hypoglycemia. The tremor classically has a frequency of about 10 Hz.

Psychogenic tremor or hysterical tremor can occur at rest or during postural or kinetic movement. Patient with psychogenic tremor may have a conversion disorder or another psychiatric disease.

Rubral tremor is characterized by coarse slow tremor which can be present at rest, at e, and with intention. The tremor is associated with conditions that affect the red nucleus in the midbrain, classical unusual strokes.

] Parkinson’s Disease affects nerve cells in the brain that produce dopamine.

Symptoms include muscle rigidity, tremors, and changes in speech and gait. Parkinsonism is terized by tremor, bradykinesia, rigidity, and postural ility. Parkinsonism shares symptons found in Parkinson’s Disease, but is a symptom complex rather than a progressive neurodegenerative disease.

Dystonia is a movement er characterized by ned or intermittent muscle ctions g abnormal, often repetitive movements or postures. Dystonic movements can be patterned, twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with w muscle activation.

Chorea is a neurological disorder characterized by jerky involuntary movements typically affecting the shoulders, hips, and face. Huntington’s Disease is an inherited disease that causes nerve cells in the brain to waste away. Symptoms include uncontrolled movements, clumsiness, and balance problems. Huntington’s disease can hinder walk, talk, and swallowing.

] Ataxia refers to the loss of full l of bodily movements, and may affect the fingers, hands, arms, legs, body, speech, and eye movements.

Myloclonus and Startle is a response to a sudden and unexpected stimulus, which can be acoustic, tactile, visual, or vestibular.

Tics are an involuntary movement usually onset suddenly, brief, repetitive, but non-rhythmical, lly imitating normal behavior and often occurring out of a background of normal activity. Tics can be classified as motor or vocal, motor tics associated with nts while vocal tics associated with sound. Tics can be characterized as simple or complex. For example simple motor tics involve only a few muscles restricted to a specific body part.

Tourette Syndrome is an inherited neuropsychiatric disorder with onset in childhood, characterized by multiple motor tics and at least one vocal tic.

] Restless Legs Syndrome is a neurologic sensorimotor disorder terized by an overwhelming urge to move the legs when at rest.

Stiff Person Syndrome is a progressive movement disorder characterized by involuntary painful spasms and rigidity of s, usually involving the lower back and legs.

Stiff-legged gait with exaggerated lumbar hyperlordosis lly results. Characteristic abnormality on EMG recordings with continuous motor unit activity of the paraspinal axial muscles is lly observed. Variants include “stiff-limb syndrome” producing focal stiffness typically affecting distal legs and feet.

Gait disorders refer to an abnormalitiy in the manner or style of walking, which results from uscular, arthritic, or other body changes. Gait is classified according to the system responsible for abnormal locomotion, and include hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait, ataxic gait, and sensory gait.

Sleep disorders The compound of Formula (I), e. g., a solid form of Compound 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable composition thereof, can be used in a method described herein, for e in the treatment of a sleep er. In some embodiments, the sleep disorder is comorbid with another disorder (e. g., a sleep er comorbid with a personality disorder).

Psychiatric disorders ] The nd of a (I), e. g., a solid form of Compound 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable composition thereof, can be used in a method described herein, for example in the treatment of a disorder described herein such as a psychiatric disorder. Exemplary psychiatric disorders e, but are not limited to, mood ers, anxiety disorders, psychotic disorders, and impulse control disorders as described herein.

Mood disorders Also provided herein are methods for treating a mood disorder, for example, clinical depression, postnatal depression or postpartum depression, perinatal depression, atypical sion, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar er or manic depressive disorder, depression caused by chronic medical conditions, comorbid depression, treatment- resistant depression, refractory depression, suicidality, suicidal ideation, or suicidal or.

In some embodiments, the method described herein provides therapeutic effect to a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with a disease or disorder described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremor (e.g., son’s Disease), women’s health disorders or conditions).

Clinical sion is also known as major sion, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, and refers to a mental er characterized by pervasive and persistent low mood that is accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities. Some people with clinical depression have trouble sleeping, lose weight, and generally feel agitated and irritable. Clinical depression s how an individual feels, thinks, and behaves and may lead to a variety of emotional and al problems. Individuals with clinical sion may have trouble doing day-to-day activities and make an individual feel as if life is not worth living.

Peripartum depression refers to sion in pregnancy. Symptoms include irritability, crying, feeling restless, trouble sleeping, extreme exhaustion (emotional and/or physical), changes in appetite, difficulty focusing, sed y and/or worry, disconnected feeling from baby and/or fetus, and losing interest in formerly pleasurable activities.

Postnatal depression (PND) is also referred to as rtum depression (PPD), and refers to a type of clinical depression that affects women after childbirth. Symptoms can include sadness, fatigue, changes in sleeping and eating habits, reduced sexual desire, crying episodes, anxiety, and irritability. In some embodiments, the PND is a treatment-resistant sion (e.g., a treatment-resistant depression as described herein). In some embodiments, the PND is refractory depression (e. g., a refractory depression as described herein).

In some embodiments, a subject having PND also experienced depression, or a symptom of depression during pregnancy. This depression is referred to herein as) perinatal depression. In an embodiment, a t experiencing perinatal depression is at increased risk of encing PND.

Atypical depression (AD) is characterized by mood reactivity (e. g., xical anhedonia) and positivity, significant weight gain or increased te. ts suffering from AD also may have excessive sleep or somnolence (hypersomnia), a sensation of limb heaviness, and significant social impairment as a consequence of hypersensitivity to perceived interpersonal rejection.

Melancholic depression is characterized by loss of pleasure (anhedonia) in most or all activities, failures to react to pleasurable stimuli, depressed mood more pronounced than that of grief or loss, excessive weight loss, or ive guilt.

Psychotic major depression (PMD) or psychotic depression refers to a major depressive episode, in particular of holic , where the individual experiences psychotic symptoms such as ons and hallucinations. nic depression refers to major depression involving disturbances of motor behavior and other symptoms. An individual may become mute and stuporous, and either is le or exhibits purposeless or bizarre movements.

Seasonal affective disorder (SAD) refers to a type of seasonal depression wherein an individual has seasonal patterns of depressive episodes coming on in the fall or winter.

Dysthymia refers to a condition d to unipolar depression, where the same physical and cognitive problems are evident. They are not as severe and tend to last longer (e. g., at least 2 years).

Double depression refers to fairly depressed mood (dysthymia) that lasts for at least 2 years and is punctuated by periods of major depression.

] Depressive Personality Disorder (DPD) refers to a personality disorder with depressive features.

Recurrent Brief Depression (RBD) refers to a condition in which individuals have sive episodes about once per month, each episode lasting 2 weeks or less and typically less than 2-3 days.

Minor depressive disorder or minor depression refers to a sion in which at least 2 ms are present for 2 weeks.

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

Treatment-resistant depression refers to a condition where the individuals have been treated for depression, but the symptoms do not improve. For example, antidepressants or psychological counseling otherapy) do not ease depression symptoms for duals with treatment-resistant depression. In some cases, individuals with treatment-resistant depression improve ms, but come back. Refractory sion occurs in patients suffering from depression who are resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple uptake inhibitors and/or anxiolytic drugs, as well as non-pharmacological treatments (e. g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation and/or transcranial magnetic stimulation).

] Post-surgical depression refers to feelings of depression that follow a surgical procedure (e.g., as a result of having to confront one’s mortality). For example, individuals may feel sadness or empty mood persistently, a loss of re or interest in hobbies and activities normally enjoyed, or a persistent felling of worthlessness or hopelessness.

Mood er associated with conditions or disorders of women’s health refers to mood disorders (e.g., depression) ated with (e.g., resulting from) a condition or disorder of s health (e.g., as described herein).

Suicidality, suicidal ideation, suicidal behavior refers to the tendency of an individual to commit suicide. Suicidal ideation concerns thoughts about or an l preoccupation with suicide. The range of suicidal ideation varies greatly, from e.g., fleeting thoughts to extensive thoughts, detailed planning, role g, incomplete attempts. Symptoms include talking about suicide, getting the means to commit suicide, withdrawing from social contact, being preoccupied with death, g trapped or hopeless about a situation, increasing use of alcohol or drugs, doing risky or self-destructive things, saying goodbye to people as if they won’t be seen again.

Depression or personality disorders may also be comorbid with another disorder.

For example, depression may be comorbid with a personality disorder. In r example, a personality disorder may be comorbid with a sleep disorder.

Symptoms of depression e persistent anxious or sad feelings, feelings of helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty ng, sleeplessness, irritability, fatigue, motor challenges, loss of interest in pleasurable activities or hobbies, loss of concentration, loss of energy, poor self-esteem, absence of positive thoughts or plans, excessive sleeping, overeating, appetite loss, insomnia, self-harm, thoughts of suicide, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary on a case to case basis. ms of depression, and relief of the same, may be ascertained by a ian or psychologist (e.g., by a mental state ation).

Anxiety Disorders ed herein are s for treating anxiety disorders (e. g., generalized anxiety disorder, panic disorder, obsessive compulsive disorder, phobia, post-traumatic stress disorder). Anxiety disorder is a blanket term covering l different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic ia recognize a wide variety of anxiety disorders. lized anxiety disorder is a common chronic disorder characterized by long- lasting anxiety that is not focused on any one object or situation. Those suffering from generalized anxiety experience non-specific persistent fear and worry and become overly ned with everyday matters. Generalized anxiety disorder is the most common anxiety disorder to affect older adults.

In panic disorder, a person suffers from brief attacks of intense terror and apprehension, often marked by trembling, shaking, ion, ess, nausea, difficulty breathing. These panic attacks, defined by the APA as fear or discomfort that abruptly arises and peaks in less than ten minutes, can last for several hours and can be triggered by stress, fear, or even se; although the specific cause is not always apparent. In addition to recurrent unexpected panic attacks, a diagnosis of panic disorder also requires that said attacks have chronic consequences: either worry over the attacks' potential implications, persistent fear of future attacks, or significant changes in behavior related to the attacks. ingly, those suffering from panic disorder experience symptoms even e of specific panic episodes.

Often, normal changes in heartbeat are noticed by a panic sufferer, leading them to think something is wrong with their heart or they are about to have another panic attack. In some cases, a heightened awareness (hypervigilance) of body functioning occurs during panic attacks, wherein any ved physiological change is interpreted as a possible life threatening illness (i.e. extreme hypochondriasis). ive compulsive disorder is a type of anxiety disorder primarily characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or ) and compulsions (urges to perform specific acts or rituals). The OCD t pattern may be likened to superstitions insofar as it involves a belief in a causative relationship where, in reality, one does not exist. Often the process is entirely illogical; for example, the compulsion of walking in a certain pattern may be employed to alleviate the obsession of impending harm.

And in many cases, the compulsion is entirely inexplicable, simply an urge to complete a ritual triggered by nervousness. In a minority of cases, sufferers of OCD may only experience obsessions, with no overt compulsions; a much smaller number of sufferers experience only compulsions.

The single t category of anxiety disorders is that of phobia, which includes all cases in which fear and anxiety is triggered by a specific stimulus or situation. Sufferers typically pate terrifying uences from encountering the object of their fear, which can be anything from an animal to a location to a bodily fluid.

Post-traumatic stress disorder or PTSD is an anxiety disorder which results from a traumatic experience. Post-traumatic stress can result from an extreme situation, such as , rape, hostage situations, or even serious accident. It can also result from long term (chronic) exposure to a severe stressor, for example soldiers who endure individual battles but cannot cope with continuous combat. Common symptoms include flashbacks, avoidant behaviors, and depression. tic ers The compound of Formula (I), e. g., a solid form of Compound 1, or a pharmaceutically able salt or pharmaceutically acceptable composition thereof, can be used in a method described herein, for example in the treatment of a psychotic disorder. In some embodiments, the impulse control disorder is schizophrenia or bipolar disorder. In some embodiments, the psychotic disorder is schizophrenia. In some embodiments, the psychotic disorder is bipolar disorder.

Bipolar disorder or manic sive disorder causes e mood swings that include emotional highs (mania or hypomania) and lows (depression).

Impulse control ers The compound of Formula (I), e. g., a solid form of Compound 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable composition thereof, can be used in a method bed herein, for example in the treatment of an impulse control disorder.

In some embodiments, the impulse control disorder is ia nervosa or alcohol withdrawal.

In some embodiments, the impulse l disorder is anorexia nervosa. In some embodiments, the impulse control disorder is ia nervosa.

Seizure disorders The compound of a (I), e. g., a solid form of nd 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable composition thereof, can be used in a method described herein, for example in the treatment of a seizure disorder. In some embodiments, the e disorder is epilepsy. In some embodiments, the seizure disorder is status epilepticus, e. g., sive status epilepticus, e. g., early status epilepticus, established status epilepticus, refractory status epilepticus, or super-refractory status epilepticus. In some embodiments, the seizure disorder is a focal seizure with either motor atisms, atonic, clonic, epileptic spasms, hyperkinetic, myoclonic, and tonic) or non-motor (autonomic, behavioral arrest, ion, emotional, and sensory) onset, a generalized seizure with either motor (tonic-clonic, clonic, myoclonic, nic-tonic-clonic, myoclonic-atonic, atonic, epileptic spasms) or non-motor (absence) onset, a seizure with unknown motor (tonic-clonic, epileptic spasms) or non-motor (behavioral arrest) onset, a seizure associated with clinical mes, such as Dravet syndrome, Rett syndrome, Lennox Gasteau syndrome, Tuberous sclerosis, Angelmans syndrome, catamenial epilepsy. In some embodiments, the seizure disorder is a seizure that is caused by schizoaffective disorder or by drugs used to treat schizophrenia.

Epilepsy ] Epilepsy is a brain disorder terized by repeated seizures over time. Types of epilepsy can include, but are not limited to generalized epilepsy, e. g., childhood absence epilepsy, juvenile nyoclonic epilepsy, sy with grand-mal seizures on awakening, West me, Lennox-Gastaut syndrome, partial epilepsy, e. g., al lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.

Status epilepticus (SE) Status epilepticus (SE) can include, e. g., convulsive status epilepticus, e. g., early status epilepticus, established status epilepticus, refractory status epilepticus, or super-refractory status epilepticus; non-convulsive status epilepticus, e. g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lized epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epileptic seizures, and can include early status epilepticus, ished status epilepticus, tory status ticus, super-refractory status epilepticus.

Early status epilepticus is treated with a first line therapy. Established status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, and a second line therapy is administered. Refractory status epilepticus is characterized by status epileptic seizures which t despite treatment with a first line and a second line therapy, and a general anesthetic is generally administered. Super refractory status epilepticus is terized by status epileptic seizures which persist e treatment with a first line therapy, a second line y, and a general anesthetic for 24 hours or more.

Non-convulsive status epilepticus can include, e. g., focal non-convulsive status epilepticus, e. g., complex partial non-convulsive status epilepticus, simple partial non- convulsive status epilepticus, subtle non-convulsive status ticus; generalized non- convulsive status epilepticus, e. g., late onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

Seizure A seizure is the physical findings or changes in behavior that occur after an episode of abnormal electrical activity in the brain. The term “seizure” is often used interchangeably with “convulsion.” Convulsions are when a person’s body shakes rapidly and rollably. During convulsions, the person’s muscles contract and relax repeatedly.

Based on the type of behavior and brain ty, seizures are divided into two broad categories: generalized and partial (also called local or focal). Classifying the type of seizure helps doctors diagnose whether or not a patient has epilepsy. lized seizures are produced by electrical impulses from throughout the entire brain, whereas partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain generating the seizures is sometimes called the focus.

There are six types of generalized seizures. The most common and ic, and therefore the most well known, is the generalized convulsion, also called the grand-mal seizure.

In this type of seizure, the patient loses ousness and usually collapses. The loss of consciousness is followed by generalized body stiffening d the ”tonic” phase of the seizure) for 30 to 60 seconds, then by violent g (the ”clonic” phase) for 30 to 60 seconds, after which the t goes into a deep sleep (the ”postictal” or after-seizure phase). During grand-mal seizures, injuries and nts may occur, such as tongue biting and urinary incontinence.

Absence seizures cause a short loss of consciousness (just a few seconds) with few or no symptoms. The patient, most often a child, lly interrupts an activity and stares blankly. These seizures begin and end abruptly and may occur several times a day. Patients are usually not aware that they are having a seizure, except that they may be aware of ”losing time.” ] Myoclonic seizures t of sporadic jerks, usually on both sides of the body.

Patients sometimes be the jerks as brief ical shocks. When violent, these seizures may result in dropping or involuntarily throwing objects.

Clonic seizures are repetitive, rhythmic jerks that involve both sides of the body at the same time.

Tonic es are characterized by stiffening of the muscles.

Atonic seizures consist of a sudden and general loss of muscle tone, particularly in the arms and legs, which often results in a fall.

] Seizures described herein can include epileptic seizures; acute repetitive seizures; cluster seizures; uous seizures; unremitting seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., tory convulsive status epilepticus, non- convulsive status epilepticus seizures; tory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; arily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic es; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized onset seizures; ile spasms; Jacksonian seizures; massive bilateral nus seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post traumatic seizures; subtle 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, us Sclerosis Complex, Rett Syndrome or PCDH19 Female Pediatric Epilepsy.

Neuroinflammatory disorders The compound of Formula (I), e. g., a solid form of Compound 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable composition f, can be used in a method described herein, for example in the treatment of a disorder described herein such as a neuroinflammatory er. In some embodiments, the neuroinflammatory disorder is multiple sclerosis or a pediatric autoimmune neuropsychiatric disorder associated with a streptococcal infection (PANDAS).

Analgesia/Pain control The nd of Formula (I), e. g., a solid form of Compound 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable composition thereof, can be used in a method described herein, for example as an analgesic or other agent for pain control.

In some embodiments, a solid form of Compound 1, or a pharmaceutically acceptable composition thereof, can be used as an analgesic or other agent for pain control to treat inflammatory pain, neuropathic pain, fibromyalgia, or peripheral neuropathy.

Sensory t disorders The compound of Formula (I), e. g., a solid form of Compound 1, or a pharmaceutically acceptable salt or ceutically acceptable composition thereof, can be used in a method described herein, for example in the treatment of a disorder described herein such as a sensory deficit disorder. In some embodiments, the sensory deficit er is us or synesthesia. In some embodiments, the sensory deficit disorder is hearing impairment and/or loss.

EXAMPLES In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are d to illustrate the crystalline solid forms provided herein and are not to be construed in any way as limiting their scope.

Example 1. ation of solid Form A.

Form A was prepared by stirring crude Compound 1 as a slurry in ethyl acetate below 100C and then filtering and drying under vacuum. It was also formed by ving crude Compound 1 in dichloromethane and then re-concentrating the solution twice with ethyl acetate under vacuum to s.

Example 2. s wet methods of crystallization to obtain other solid forms of the present invention.

To find new crystalline forms, different llization methods were evaluated using Form A as the starting material. In addition to Form A, thirteen crystalline forms (B, C, D, E, F, H, I, J, K, L, M, N, and 0) were identified with these methods.

Slow evaporation Slow evaporation crystallization experiments were performed across 8 different solvent systems. In each experiment approximately 10 mg of Form A was dissolved in 0.4 to 1.0 mL of solvent in a 1.5 mL glass vial. The glass vials were sealed using Parafilm® pierced with 3 to 5 holes to allow for solvent evaporation.

Slurry conversion In each experiment, approximately 10 to 20 mg of Form A was suspended in 0.5 mL of a solvent or mixture of solvents. After ng at RT or 50 0C for 48 hours, the solids were isolated by centrifugation for analysis (wet sample). If the suspensions turned into clear solution, the clear solutions were kept at ambient conditions for slow evaporation.

Anti-solvent addition ] In each experiment, approximately 10 mg of Form A was dissolved in 0.1 to 1 mL of each t to obtain a clear solution. The anti-solvent was added in increments of 50 [LL until precipitation was observed, or the total volume of anti-solvent reached 20 times that of the solvent volume. The precipitate was then isolated by centrifugation for is (wet sample). In the instances that clear solutions were observed, slow evaporation ments were performed.

Slow-cooling In each experiment, approximately 10 mg of Form A was suspended in 0.8 to 1.0 mL of each solvent mixture at 50 oC. The resulting suspensions were immediately filtered with a 0.2 pm filter, and the filtrates were collected and cooled from 50 0C to 5 0C at a rate of 0.1 oC/min. The precipitates were then ed by centrifugation at 10,000 rpm for 3 to 5 minutes for analysis (wet sample).

Solution vapor difiasion In each experiment, approximately 10 mg of Form A was dissolved in an appropriate solvent to obtain a clear solution in a 3-mL glass vial. The vial was then placed into a 20-mL glass vial containing 3 mL of the anti-solvent and sealed. The system was kept at RT for 7 days, allowing sufficient time for solid itation. The solids were isolated by centrifugation at 10,000 rpm for 3 to 5 minutes and analyzed (wet sample). In the cases where no precipitation was observed, the samples were kept at ambient conditions for slow evaporation.

Solid vapor on In each experiment, approximately 10 mg of Form A was placed into a 3-mL glass vial, which was then sealed into a 20-mL glass vial containing 3 mL of the specific solvent. The system was kept at RT for 7 days, allowing sufficient time for organic vapor to ct with the solids. The solids were then analyzed (wet sample).

Fast evaporation In each experiment, approximately 10 mg of Form A was dissolved in 0.5 to 1.0 mL of each solvent in a 1.5-mL glass vial. The visually clear ons were kept at ambient conditions for fast evaporation with the lid off. The solids obtained via ation were then analyzed (dry sample).

Reverse anti-solvent addition ] In each experiment, approximately 20 mg of Form A was dissolved in 0.2 to 0.6 mL of each t to obtain a clear solution. The solution was added to a glass vial containing 2.0 mL of each olvent at RT conditions. The precipitate formed was centrifuged at 10,000 rpm for 3 to 5 minutes for analysis (wet ). In the cases where no precipitation was observed, slow evaporation experiments were conducted for the remaining solutions.

Water activity experiments Water activity experiments, g from 0 to 1 water activity (aw) at 0.2 als, were performed with H20 and acetonitrile. About 10 mg of Form A was weighed into 1.5 mL vials and 0.5 mL of the solvent mixture was added. The suspension was stirred at a rate of 1000 rpm at room temperature. The residual solvent was d from the sample by centrifugation (10000 rpm for 3min).

Example 3. Preparation of solid Form B.

Form B was prepared via slow evaporation, slurry sion in a dichloromethane (DCM)/n-heptane solvent system, anti-solvent addition, solid vapor diffusion, and slow cooling crystallization techniques in a variety of solvent systems. Isomorphs of Form B characterized in the present invention were obtained from the slurry conversion technique in dichloromethane (DCM)/n-heptane and an anti-solvent addition technique in tetrahydrofuran (THF)/n-heptane or chloroform (CHC13)/methyl tert-butyl ether (MBTE).

Example 4. Preparation of solid Form C.

Form C was prepared from Form A via a slurry conversion crystallization technique in pyl alcohol (IPA) and isopropyl acetate (IPAc) at 50 °C.

Example 5. Preparation of solid Form D.

Form D was prepared from Form A via an anti-solvent addition crystallization que in tetrahydrofuran (THF)/water (H20) at room-temperature (RT) conditions.

Example 6. Preparation of solid Form E.

Form E was prepared from Form A via an anti-solvent addition crystallization que in 1,4-dioxane/n-heptane at ambient room-temperature (RT) conditions.

Example 7. Preparation of solid Form F.

Form F was prepared from Form A via a reverse anti-solvent on crystallization technique in 1,4-dioxane/n-heptane at ambient room-temperature (RT) conditions.

Example 8. Preparation of solid Form H.

Form H was prepared via a solution vapor diffusion crystallization technique in n- heptane at room-temperature (RT) conditions.

Example 9. Preparation of solid Form I.

Form I was prepared via a slow g llization technique in methanol (MeOH) at room-temperature (RT) conditions.

Example 10. Preparation of solid Form J.

Form J was prepared via a solid vapor diffusion crystallization technique in MeOH at room-temperature (RT) conditions.

Example 11. Preparation of solid Form K.

Form K was prepared by heating Forms A, B, C, E, or F to elevated temperatures.

The sample of Form K ed was prepared by heating Form F to 100 °C.

Example 12. Preparation of solid Form L.

Form L was prepared by g Form B in a sealed vial at ambient conditions for a month. e 13. Preparation of solid Form M.

Form M was prepared by storing Form B in a sealed vial at ambient conditions for a month.

Example 14. Preparation of solid Form N.

Form N was prepared from a e anti-solvent addition crystallization technique in 1,4-dioxane/n-heptane when attempting to replicate formation of Form F.

Example 15. Preparation of solid Form 0.

Form 0 was prepared from a water ty crystallization technique in etonitrile (ACN) (0.041:0.959 v/v; aw=0.6). Acetonitrile plays an essential role in Form 0 formation, and this solvent may be needed to produce this form.

Example 16. Characterization of solid Forms A-O by XRPD.

A PANalytical Empyrean X-ray powder diffractometer with a 12-well auto- sampler stage was used for analysis throughout this study. The XRPD parameters used are listed in Table 8. tion calibration of the instrument was performed every 6 months, and sensitivity measurements were performed after the sample stage was changed. A silicon (Si) pressed powder sample was used as the reference rd.

Table 8. Parameters for XRPD Parameters for Reflection Mode Cu, 1m, Kod (A): 1.540598, K0t2 (A): 26 X-Ray wavelength K0t2/K0t1 intensity ratio: 0.50 X-Ray tube setting 45 kV, 40 mA Divergence slit Automatic Scan mode uous Scan range (degrees 20) 3° to 400 Step size (degrees 20) 0.0170 Scan speed (degrees/min) ~10 Form A: Form A was observed to be crystalline by XRPD, as shown in .

Form B: The XRPD pattern in shows that Form B-l is crystalline. The XRPD patterns in shows that Forms B-l, B-2, and B-3 are crystalline.

Form C: The XRPD pattern in shows that Form C is crystalline.

Form D: As shown in the obtained XRPD pattern provided in , Form D is crystalline. XRPD is also ted that Form D was ormed to Form A after drying at ambient ions, as illustrated in .

Form E: Based on the obtained XRPD n of the wet sample in , Form E was observed to be crystalline. After drying at ambient room-temperature conditions, Form E transformed to a mixture of Forms A and C that exhibited low crystallinity.

Form F: The obtained XRPD pattern of the dried sample under vacuum in shows that Form F is crystalline.

Form H: The obtained XRPD pattern of the wet sample in shows that Form H is crystalline. XRPD analysis indicates that Form H transforms to Form A after drying at t conditions for 3 days, as illustrated in .

Form I: The obtained XRPD pattern of the wet sample in shows that Form I is crystalline. XRPD analysis indicates that Form I transforms to Form A after drying at t conditions for 3 days, as illustrated in .

Form J: The obtained XRPD pattern of the wet sample in shows that Form J is lline. XRPD analysis indicates that Form J transforms to Form A after drying at ambient conditions for 3 days, as illustrated in .

Form K: The obtained XRPD pattern in A shows that Form K is crystalline.

Form L: The obtained XRPD pattern in A shows that Form L is crystalline. After 3 days at ambient conditions, Form L transforms to a mixture of Forms B and M, as shown in the XRPD pattern presented in B.

Form M: The obtained XRPD pattern in shows that Form M has low crystallinity.

Form N: The XRPD pattern of the dried sample at ambient conditions in A shows that Form N is crystalline. The XRPD pattern in B shows that overnight, under ambient ions, Form N transforms to Form A.

Form 0: The obtained XRPD pattern in A shows that Form 0 is crystalline.

Example 17. Methods of producing single crystals of Form A and Form C.

Form A: Single crystals suitable for structure determination were ed Via slow cooling in pyl alcohol from 50 °C to 5 °C.

Form C: Single crystals suitable for structure determination were ed Via slow cooling at a rate of 0.01 oC/min in isopropyl acetate/acetone (6:1, V/V) co-solvents with Form C seeds, from °C to 5 0C. e 18. Single Crystal X-ray Diffraction data of Form A and Form C.

X-ray intensity data from prism-like crystals of Form A (Table 9) and Form C (Table 10) were ted at 290(2) K using a Bruker D8 Venture diffractometer (Mo Koc radiation, 7x. = 0.71073 A). The crystal structures of Forms A and C were solved from the obtained data.

Table 9. Crystal data and structural refinement for a single crystal of Form A: Crystal system, space group MonoclinicP21 a = 9.379(3) A b = 9.922(3) A Unit cell dimensions c = 12.092(4) A a: 90° -y=90°,6: 101.606(9)° 0.30 x 0.20 x 0.10 mm3 -12 S h S 12 Limiting indices -12 S k S 12 4531315 23466 / 5060 [R(int) = 0.0670] Full-matrix least-squares on F2 R1 = 0.0425 Final R indices [I>2sigma(I)] WRZ = 0.0989 Largest diff. peak and hole nd -0.368 e-A'3 Absolute structure parameter 1.5(11) Table 10. Crystal data and structural refinement for a single crystal of Form C: cal formula C25H35N302 a=9bmm&A b=986M8)A Unit cell dimensions on = 90° [3: 90° y=90° -12 Sh312 Limiting indices -12 S k S 12 -31£1£31 Reflections collected / unique 33905 / 5265 [R(int) = 0.0823] Completeness 99.3 % Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 5265/7/272 Goodness-of-fit on F2 1.042 R1 = 0.0647 Final R indices [I>2sigma(I)] sz = 0.1128 Largest diff. peak and hole 0.248 and -0.335 e-A'3 Absolute structure parameter 0.0(19) Example 19. Unit cells of the -crystal structures of Form A and Form C.

The unit cell of Form A along the b axis is depicted in . The unit cell of Form C along the b axis is depicted in .

Example 20. Characterization of solid Forms A-O by temperature-dependent instrumental methods (TGA, DSC, and VT-XRPD).

Thermogravimetric analysis (TGA) data were collected using a TA Q500/Q5000 TGA from TA ments, and differential scanning metry (DSC) was performed using a TA Q200/Q2000 DSC from TA Instruments. The instrument parameters used are provided in Table 11.

Table 11. Parameters for TGA and DSC Test Parameters TGA DSC Method Ramp Ramp Sample pan Platinum, open Aluminum, crimped ature RT to 350 oC RT to 300 oC Heating rate 10 oC/min 10 oC/min Purge gas N2 N2 To complement the temperature-dependent studies and confirm the solvation state of the solid forms, solution NMR was collected on a Bruker 400 MHZ NMR Spectrometer using ated dimethyl sulfoxide (DMSO-d6) as the solvent.

Form A: TGA and DSC were performed and the details ed in FIG 1C.

Thermogravimetric analysis of Form A resulted in a 1.0% weight loss up to 200 °C. An endotherm ed on the DSC curve at 157.2 °C (onset temperature), representing the transformation of Form A to Form K, was followed by a sharp melting peak for Form K at 203.8 °C (onset temperature). Verification of the transformation to Form K was performed by VT-XRPD, as shown in .

] Form B-1: TGA and DSC were performed, and their respective curves are provided in . The TGA curve shows a 2-stage weight loss, with a 5.7% loss of residual solvent up to 76 °C followed by an 8.5% loss (desolvation) up to 200 °C. The DSC curve exhibits 2 endothermic peaks at 87.2 °C and 211.7 °C (onset temperatures), corresponding to the loss of solvent (transformation to Form K) and the melting point of Form K, tively.

Analysis by XPRD indicates that Form B-1 transforms to Form K upon heating to 100 0C, as shown in . Based on the 1H NMR data shown in , Form B is an n-heptane solvate with a molar ratio of 1:0.4 Compound 1: ane (~8.9% n-heptane by weight), which is in good agreement with the TGA result. Residual DCM with a molar ratio of 1:0.06 Compound 1:DCM (1.2% by weight) was also observed in the 1H NMR data.

Form B-2: The TGA of this isomorph is shown in along with the TGA curves of the other two isomorphs. The DSC curve of this isomorph, which is depicted in along with an overlay of the other two isomorphs, ts two endotherms, one at a Tome, of 85.4 0C and one at a Tome, of 212.2 °C. The 1H NMR spectrum in showed that Form B is an n-heptane solvate in a molar ratio of 1:0.3 Compound 1: n-heptane, with no THF Form B-3: The TGA of this isomorph is shown in along with the TGA curves of the other two isomorphs. The DSC curve of this isomorph, which is depicted in along with an overlay of the other two isomorphs, exhibits two endotherms, one at a Tome, of 69.2 0C and one at a Tome, of 211.6 °C. The 1H NMR spectrum in showed that Form B is a chloroform solvate in a molar ratio of 1:0.5 Compound 1:chloroform, with al methyl tert-butyl ether ed.

Form C: TGA and DSC were performed, and their respective curves are provided in . The TGA curve shows that a weight loss of 4.3% occurs below 50 °C indicating loosely held solvent or adventitious solvent, possibly present due to insufficient drying. The DSC curve ts 2 endothermic peaks at 183.8 °C and 211.0 °C (onset temperatures). Further investigation of the endotherm at 183.8 °C was performed by heating Form C to 185 0C, which resulted in a form transformation to Form K, as shown in . Analysis by VT-XRPD was performed on Form C, with and without nitrogen (N2) flow, to igate possible rehydration from air. As shown in , no ences were observed with and without N2, indicating that Form C is an anhydrate.

Form F: TGA and DSC were performed, and their respective curves are provided in . The TGA curve shows a total weight loss of 19.7% up to 200 °C. The DSC curve exhibits 2 endothermic peaks at 63.1 °C and 210.7 °C (onset temperatures), corresponding to the loss of t (transformation to Form K) and the g point of Form K, respectively. This is further evidenced by the transformation of Form F to Form K after heating to 100 °C, as shown in . Based on the 1H NMR spectrum shown in , Form F is a 1,4-dioxane solvate with a molar ratio of 1:0.9 (16.2% 1,4-dioxane by weight), which is in good agreement with the TGA result. Residual n-heptane at a molar ratio of 1:0.03 (0.7% n-heptane by weight) is also observed in the 1H NMR data.

] Form K: TGA and DSC were performed, and their respective curves are provided in B. The TGA curve shows a weight loss of 1.6% up to 200 °C, and the DSC curve exhibits an endothermic peak at 211.6 °C (onset temperature), corresponding to the melting endotherm of Form K. Based on the low volatiles content, Form K is an unsolvated material.

Form L: The DSC curve of Form L, shown in C exhibits 2 endothermic peaks at 81.7 °C and 210.6 °C (onset temperatures). The first ermic peak is attributed to the possible loss of solvent or form transformation. The second endothermic peak in the DSC curve matches the melting endotherm of Form K.

Form N: The TGA curve in C shows a 2-step weight loss of 2.5% up to 60 °C, ed by 7.1% up to 200 °C. The DSC curve exhibits 2 endothermic peaks at 75.4 °C and 210.4 °C (onset temperatures), attributed to the loss of solvent (based on 1H NMR) and the melting point of Form K, respectively. Based on the 1H NMR result in D, Form N is a 1,4-dioxane solvate with a molar ratio of 1:0.3 Compound dioxane (6.1% 1,4-dioxane by weight), which is in ent with the second step weight loss in the TGA analysis.

Form 0: A 2-step weight loss of 5.3% up to 55.1 °C, followed by 5.9% up to 200 °C is observed in the TGA curve presented in B. The DSC curve exhibits 3 endothermic peaks at 65.0 °C, 168.5 °C, and 210.8 °C (onset temperatures), corresponding to the loss of solvent to create Form C, ormation of Form C to Form K, and the melting point of Form K, respectively. In order to investigate the erms observed in the DSC analysis, Form 0 was heated to 1200C resulting in a change to Form C, as shown in C. The 1H NMR spectrum ed a molar ratio of 1:0.2 for Form 0: ACN (1.9% by weight) after heating to 50 °C in order to remove residual solvent, as illustrated in D.

Example 21. Hygroscopicity of Forms A, C, and K as measured by DVS.

] Dynamic vapor sorption (DVS) was measured via an SMS (Surface Measurement Systems) DVS Intrinsic system. The relative humidity at 25 0C was calibrated against the deliquescence point of LiCl, Mg(N03)2, and KC]. Instrument ters for the DVS system used throughout this study are listed in Table 12.

Table 13. Parameters for DVS Test Parameters DVS Temperature 25 oC Sample size 10 ~ 20 mg Gas and flow rate N2, 200 mL/min dm/dt 0.002%/min Min. dm/dtstabilityduration 10 min Max. equilibrium time 180 min RH range 0%RH to 95%RH %RH from 0%RHto 90%RH RH step size (sorption) %RH from 90%RH to 95%RH %RH from 90%RH to 0%RH RH step size (desorption) %RH from 95%RH to 90%RH The hygroscopicity of Form A, Form C, and Form K were investigated at 25 0C using DVS. The XRPD patterns of each sample before and after DVS were compared in order to investigate any potential form change.

The DVS isotherm plot of Form A shown in exhibits 0.06% by weight water uptake at 80% RH and less than 0.12% by weight water uptake at 95% RH, revealing that Form A is non-hygroscopic. The XRPD pattern in indicates there is no form change before and after DVS for Form A.

Similarly, the DVS rm plot of Form C shown in exhibits 0.12% by weight water uptake at 80% RH and less than 0.30% by weight water uptake at 95% RH, indicating that Form C is non-hygroscopic. The XRPD pattern in shows there is no form change before and after DVS for Form C.

The DVS isotherm plot of Form K shown in C exhibits 0.18% by weight water uptake at 80% RH and less than 0.35% by weight water uptake at 95% RH, revealing that Form K is non-hygroscopic. The XRPD n in D shows there is no form change before and after DVS for Form K.

Example 22. Interconversion of Forms A, C, and K through slurry conversion.

In one embodiment, the inter-conversion between Forms A, C and K can be studied in a series of slurry conversion experiments ted in ethyl acetate, n-butanol, and methyl tert-butyl ether (MBTE) at both room temperature (RT) and 50 oC. Compound 1 can display moderate solubility, and may yield solvated forms during these screening experiments.

Results of the slurry conversion experiments are summarized in Table 14. The tion temperature n Forms A and C was estimated to be ~17 °C, and the transition ature between Forms K and C was above 100 °C.

Table 14. Summary of Slurry Conversion Experiments Solvent Condition Initial Form Final Form RT Forms A and K (with Form C seeds) Form C Ethyl acetate 50 °C Forms A and K Form C RT Forms A, C and K Form C Butanol 50 °C Forms A, C and K Form C RT Forms A, C and K Form C 50 °C Forms A, C and K Form C Example 23. Conversion of Form A to Form C with Form C seed crystals.

Approximately 200 g/L-225 g/L solubilized Compound 1(originally Form A) in ethyl acetate was heated to a temperature of 65 0C in the presence of 0.2 %-1.0 % of seed crystals of Form C for 1-3 hours. The batch can then be slowly cooled down to a temperature between 25 0C-30 0C for no less than 3 hours to obtain Form C. Seed crystals of Form C can be obtained using the procedure described in Example 4.

XRPD was med using a Rigaku MiniFlex 600 (Cu KOL radiation at 40 kV tube voltage and 15 mA tube current) with a scanning range of 20 to 40 0 for 20, a step size of 0.010, and a scanning speed of 1C) or 20 per minute. XRPD was used to monitor the conversion from 225 g/L Form A to Form C in ethyl acetate at 65 0C using 1.0% of seed crystals of Form C with time, as indicated in .

Example 24. Preparation and characterization of Form P.

] During solubility measurements, an XRPD pattern was detected in (a) slurries of Form A in EtOAc at 5 °C (after 1 h) and 20 °C (after 2 days), (b) es of Form C in EtOAc at 5 °C (after 1 h) and 20 °C (after 7 days). There was no direct match of this solid form’s XRPD pattern to other crystal forms of Compound 1. The results indicate that this solid form of Compound 1 in EtOAc, termed Form P, is more stable than both Forms A and C in EtOAc at least at S 20 °C.

] The wet cake of Form P (~5 min air) was dried in two ways: (a) under air at room temperature overnight, and (b) under vacuum at 40 °C for 3 hours. Both dried cakes were analyzed by XRPD, , and TGA. XRPD data are presented in . NMR data are presented in A B. TGA data are presented in A B. The air dried cake gave an XRPD pattern ming to Form P, about 1% weight loss by TGA up to about 50 °C, and EtOAc peaks by 1H NMR. This indicates that Form P is an EtOAc e of Compound 1. The sample of Form P post-oven drying, on the other hand, gave an XRPD pattern conforming to Form A, no weight loss S 100 °C by TGA, and no EtOAc peaks by 1H- NMR. Therefore, the data suggests that Form P is a solvate of Form A and converts to Form A upon drying. e 25. Solubility and Relative Stability of Forms A, C and P.

Solubility profiles of Forms A, C and P across a range of temperature can give an indication of the relative stability of different forms within different temperature ranges.

Sufficient equilibrium lity data were collected experimentally covering 5-70 °C. The results are presented in Table 15 and .

The data indicate that (1) Form C is more stable than Form A across the entire processing temperature range, (2) Form Pbecomes more stable than Form C £20 °C, (3) there is little onversion between the three forms around 25~30 °C due to slow sion kinetics, (4) Form P becomes unstable in EtOAc at 2 35 °C and converts to Form A; and (5) Form P converts into Form A upon drying in air or N2.

A phase relationship of Forms A, C and P in EtOAc is illustrated in FIG 20. In EtOAc at low temperatures Forms A and C can convert to Form P. Form A can also be ted from Form C at too low of a temperature (e. g., aimed for a better isolation yield).

Table 15. Solubility data of Forms A, C, and P.

OTHER EMBODIMENTS In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the ry or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the t.

The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise nt to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and ptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more tions found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e. g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as sing particular elements and/or features, n embodiments of the ion or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub—range within the stated ranges in different embodiments of the ion, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, hed patent applications, journal articles, and other publications, all of which are incorporated herein by nce. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular ment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims.

Because such embodiments are deemed to be known to one of ry skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any , whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present ments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that s changes and cations to this description may be made without ing from the spirit or scope of the present invention, as defined in the following claims. 1. A crystalline compound of Formula (I): Formula (I). 2. The crystalline nd of claim 1, having an XRPD pattern with characteristic peaks between and including the following values of 20 in degrees: 11.6 to 12.0, 13.7 to 14.1, 14.0 to 14.4, 16.6 to 17.0, 18.9 to 19.3, 19.1 to 19.5, 19.9 to 20.3, 21.1 to 21.5, 21.9 to 22.3, and 23.0 to 23.4. 3. The crystalline nd of claim 1, having an XRPD pattern with characteristic peaks at the following values of 20 in degrees: 11.8, 13.9, 14.2, 16.8, 19.1, 19.3, 20.1, 21.3, 22.1, and 23.2. 4. The crystalline compound of claim 1, having an XRPD pattern with characteristic peaks between and including the following values of 20 in degrees: 11.6 to 12.0, 16.6 to 17.0, 18.9 to 19.3, 19.9 to 20.3, and 23.0 to 23.4.

. The crystalline compound of claim 1, having an XRPD pattern with characteristic peaks at the following values of 20 in degrees: 11.8, 16.8, 19.1, 20.1, and 23.2. 6. The crystalline compound of any one claims 2 to 5, having an XRPD pattern ntially as depicted in A. 7. The crystalline compound of claim 1, having an XRPD pattern with characteristic peaks between and including the following values of 20 in degrees: 9.3 to 9.7, 10.6 to 11.0, 13.0 to 13.4, 14.7 to 15.1, 15.8 to 16.2, 18.1 to 18.5, 18.7 to 19.1, 20.9 to 21.3, 21.4 to 21.8, and 23.3 to 23.7. 8. The lline compound of claim 1, having an XRPD n with teristic peaks at the following values of 20 in degrees: 9.5, 10.8, 13.2, 14.9, 16.0, 18.3, 18.9, 21.1, 21.6, and 23.5. 9. The crystalline compound of claim 1, having an XRPD pattern with characteristic peaks between and including the following values of 20 in degrees: 9.3 to 9.7, 10.6 to 11.0, 13.0 to 13.4, 18.7 to 19.1, and 21.4 to 21.8.

. The crystalline compound of claim 1, having an XRPD pattern with characteristic peaks at the following values of 20 in degrees: 9.5, 10.8, 13.2, 18.9, and 21.6. 11. The lline compound of any one of claims 6 to 10, having an XRPD pattern substantially as depicted in . 12. The crystalline compound of any one of claims 6 to 11, comprising a unit cell substantially as depicted in . 13. The crystalline compound of any one of claims 6 to 11, wherein the crystalline compound, when ted to a temperature from about 157 0C to about 190 oC, transforms into the crystalline compound of claim 2 or 3 as indicated by DSC at a ramp rate of 10 oC/min. 14. The crystalline compound of any one of claims 6 to 11, wherein the crystalline compound of claim 2 melts at a Tom, from about 200 0C to about 225 0C.

. The crystalline compound of claim 1, having an XRPD pattern with characteristic peaks n and including the following values of 20 in degrees: 9.7 to 10.1, 11.6 to 12.0, 13.2 to 13.6, 14.2 to 14.6, 14.6 to 15.0, 16.8 to 17.2, 20.5 to 20.9, 21.3 to 21.7, 21.4 to 21.8, and 22.4 to 22.8. 16. The crystalline compound of claim 1, having an XRPD pattern with characteristic peaks at the following values of 20 in degrees: 9.9, 11.8, 13.4, 14.4, 14.8, 17.0, 20.7, 21.5, 21.6, and 22.6. 17. The crystalline compound of claim 1, having an XRPD pattern with characteristic peaks between and including the following values of 20 in degrees: 9.7 to 10.1, 14.6 to 15.0, 16.8 to 17.2, 20.5 to 20.9, and 21.3 to 21.7. 18. The crystalline compound of claim 1, having an XRPD pattern with teristic peaks at the following values of 20 in degrees: 9.9, 14.8, 17.0, 20.7, and 21.5. 19. The crystalline compound of any one of claims 14 to 18, having an XRPD pattern substantially as depicted in .

. The crystalline compound of any one of claims 14 to 19, comprising a unit cell substantially as depicted in . 21. The crystalline compound of any one of claims 14 to 18, wherein the crystalline compound, when ted to a temperature from about 184 0C to about 200 oC transforms into the lline compound of claim 2 or 3 as indicated by DSC at a ramp rate of 10 oC/min. 22. The crystalline compound of any one of claims 14 to 18, wherein the crystalline compound of claim 2 melts at a Tom, from about 205 0C to about 225 0C. 23. The lline compound of claim 1, having any of the XRPD patterns substantially as depicted in . 24. The crystalline compound of claim 1, haVing an XRPD pattern substantially as depicted in .

. The crystalline compound of claim 1, haVing an XRPD pattern substantially as depicted in 26. The lline compound of claim 1, haVing an XRPD pattern substantially as depicted in . 27. The crystalline compound of claim 1, haVing an XRPD pattern substantially as depicted in . 28. The lline compound of claim 1, haVing an XRPD pattern substantially as ed in . 29. The crystalline compound of claim 1, haVing an XRPD pattern substantially as depicted in .

. The crystalline compound of claim 1, haVing an XRPD pattern substantially as depicted in A. 31. The crystalline compound of claim 1, haVing an XRPD n substantially as depicted in . 32. The lline compound of claim 1, having an XRPD pattern substantially as depicted in A. 33. The crystalline nd of claim 1, having an XRPD pattern substantially as depicted in A. 34. The crystalline compound of claim 1, having any of the XRPD patterns substantially as depicted in .

. A method for transforming the lline compound of claim 11 to the lline compound of claim 19, the method comprising crystallization from a solubilized form of Compound 1 or slurry conversion. 36. The method of claim 35, wherein the transformation is performed using ethyl acetate as a solvent at a temperature from about 50 0C to about 70 0C. 37. The method of claim 35, wherein the transformation is performed in the presence of seed ls of the crystalline compound of claim 13 at a loading from about 0.1% to about .0%, of the total amount of Compound 1 present. 38. A pharmaceutical composition comprising a crystalline compound of any one of the preceding claims, and a pharmaceutically acceptable ent. 39. A compound of any one of claims 1 to 22, or pharmaceutically acceptable composition of claim 32, for use in treating a CNS—related disorder in a subject in need thereof, comprising stering to the subject an effective amount of a compound of any one of claims 1 to 22, or a pharmaceutically able composition of claim 38. 40. The compound of claim 39, wherein the CNS—related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain , a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus. 41. The compound of claim 39, wherein the lline compound is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, as a buccal, sublingually as a topical, inhalation, intranasal, or transdermally. , rectally, 42. The compound of claim 39, wherein the crystalline compound is administered chronically. 43. A compound of any one of claims 1 to 22, or pharmaceutically acceptable composition of claim 32, for use in treating a ogical disorder, a psychiatric disorder, a seizure disorder, a neuroinflammatory disorder, a glaucoma or metabolic disorder, a sensory t disorder, in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 22, or a pharmaceutically acceptable composition of claim 44. A compound of any one of claims 1 to 16, or pharmaceutically acceptable composition of claim 32, for use as a neuroprotectant, comprising administering to a subject in need thereof an effective amount of a compound of claims 1 to 16 or a ceutically acceptable composition of claim 32. 45. A nd of any one of claims 1 to 22, or pharmaceutically acceptable composition of claim 38, for use as an analgesic or other agent for pain control, comprising administering to a subject in need thereof an effective amount of a compound of claims 1 to 22 or a pharmaceutically acceptable composition of claim 38. 46. The compound of claim 45, wherein the nd is used as an analgesic or other agent for pain control to treat inflammatory pain, neuropathic pain, yalgia, or peripheral neuropathy.

Sage Therapeutics Inc.

By the Attorneys for the ant SPRUSON & FERGUSON s) 2500 Intensity 2000 ’ C\ “>>‘\\<x\\" » “-\\\\\‘ RAVw‘-\,.\\\\~\';.N ‘\\\\“A. ‘ \«\ 2Theta (deg) . . ..1,,,,,,.-.... 20812°c 50 1 00 150 200 250 300 Temperature (°C) FIG 1C. (counts) 360000 250000 Intensity -.-.-;.u.w;»” 160000 fizz-””11. ww fear Form K 90000 Backto 36°C_ F“ xiiiK ..-._~.. 0. 40000 Heating to 180 °C Form K .._. /\ «Aflwwumua...“ 10000 15 30 35 2Theta (deg) FIG ID.

DVS lsotherm Plot »»\\\»~ Cycle 1 Sorp -$——Cycle ”3550‘? Change Target RH (%) . (counts) 25000 20000 Intensity 15000 t :\ :1111111111crnu“ 10000 Form A: After DVS \ h . x x . . \ ‘ ‘ k \ \ \ ‘ .‘ u :. :\« .a ‘ .- A _ ' . ;\ .«x . \\ \« \“xrfiw‘ » « \ ' - \‘\\‘-\\«.\\\\\\\\««\\\‘ \ «MK‘ ‘ \u \\\v \\\\N‘\.e \m.‘ .H . : r. r u x“:‘\\““.‘.~‘\~‘u‘a m- \mw*\M“we.x“.3.~m\...\‘.v«\d ~ {\ m-\\ 5000 J - Form A: Before DVS . i 5; ‘ . MW“. NJ: Mmi Le‘lemw?“ 4; km!“ foAilk A a V‘wa-[5 ,L‘ w_ . 10 15 20 25 30 35 2Theta (deg) . (counts) ity 3000 ;.,{\.\.\_\\\\§v\xnv-‘ka‘fixm 2Theta (deg) . (countS) Intensity 3000 Form B-l A \ ' " ' 2000 “an" ..'\.‘2‘ \\\\ \M"k ‘ '> ‘ :l " ‘ N \\~\ \\.\~‘ 4%\x\m\~\\>‘:3“\<~‘“>\x-‘“-‘“‘\“\\I Form B-2 2Theta (deg) . 76.0°c\ >“"\~\»>,\-\.\*~‘\\\~‘-~\\‘»\«\‘-\-1a“‘;--\\\\\\A~~ A\-xx»w m 2000°C / ' 872 Co 211 .7°C \ Q} 2 . s \ * f . E g z \ g 877°C \ q \\_\ ~53 212:8°C 50 100 150 200 250 300 350 EX° ”P Temperature (°C) . (counts) 3000 ity 2500 :2:2y.v.«””.

Form K from Form B-l heated to 1 00°C Form B- 1 . ‘u‘ \ weXe"‘\\ \\\\\\ex\_‘x.:~\~\F\:.~ M.V\\\\,\\x\\\\.>\.\~‘\\‘\\\".\'. 10 15 20 25 30 35 2Theta (deg) . .a2scan '.A\.v -‘\\ (%) OO Weight AO 50 100 150 200 250 Temperature (°C) . 872°C 211.7°C .47J/g 71 .67J/g 85.4°C c 5 (W/g) 33-11J/9 67.27J/g Flow 211.6°C 692°C 71 .34J/g Heat 14.96J/ ‘85-‘80o _ 78.9°C 212.6°C 0 50 100 150 200 250 300 EX° UP Temperature (°C) . . ; 3%? g—2600 if i:' \‘E'.’ 3—2400 m...” E—2200 §—2000 .....,,.. 1800 ”nun/””111”,” 1600 ”(q/””1””;I“PPWan/”z””annually,” E\E 1200 §—400 g : :: \ 52 § 5-200: = =' s: .meMLMuW:: {f//////////////////////// - N‘wgw; _ 0Lg \ \ \\\\“\m\“\ L.............................._._._._._ Exxmxxxxx ; Q. .3; CDC} % §—-200 1... 013 2.39;; 10? N s a5 80 7.5 7.0 55 50 55 50 4.5 4.0 35 30 25 20 15 10 05 00 “(ppm . 8 8107 5.30 5.26 ‘ ‘ r 11 ~«1515L510 —427 Compound 1 . wmwxw mmmfi ........................ V\\\\\\\\\\\\\\\\\\\\\\\\\\\\ . \\\\\\ . ............... \\\\\\\\\\\\\\\x\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\ nd 1 \\\\\\\\\\\\.\ Jm,\\\\\\\\\\\\\ mg ..309 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 25 20 15 10 0.5 . /31 $2308 1500 ................... @225 .:.::::2222§§\\\\ ttitttttubcccr. “““ 1000 \\\\\\\\ \{kkkttkfi 2Theta (deg) . 11/31 1.....,;,W,,,W,,,J,,,,W-.,,W,;,,,,,,L,,,,,.,,,,,/,,,,,, 200.0°C g: 183.8°C 211.0°c 11.04J/g 7925.119 \ 7 X 1 90 .6°C "3:33.. ‘ .3 \x w ~13» 5* 3. \x :.‘ 1 31 ' “h:,~ a “g ‘ E jg; “N“. g ‘, AV “E ‘\ x «1 «a . 212.0%; a 3 -- -1 a 0 50 100 150 200 250 300 350 Exo Up Temperature (°C) . (counts) 4000 ity 3000 NW ‘5: 5- _j:_; ;- FormK \\ v.- ~-‘" _ z: \ \\\.am'.s\§\fi\~e“‘_ . .-.m_~\.\iu\~.e_ac\\\\<~‘.\~x:.-\\ 2000 w. a "Mn-1w “‘ -‘ :i x‘ :‘ -‘ , e , - wm‘ \> nxn\w‘\n “‘3 \~"\‘\\~~ \\-\\\~u~~'\»;\\1‘xuMN \\v‘\~.~,\w~.\\'_.~“.\\' 2Theta (deg) . 12/31 Intensity 15000 Cool to 30 ”C A 5 .‘\.\.\'\~" 'w\\"' \M‘v“ T\\A» 5“ 3. Heat to 50 6C 10000 I“, 1 R 05 «WV WW V Wbfillfiwwm"' With N2_30°C .\ F‘ i ,. 3'1 . ..

A yg-i‘v'fi'wllkwv’w «1'1” ”x "”4 A '\ . '1‘ “uv’wg’Lawflvwm (5'4 .~..-,.\«\.« «ms-v ‘\ .zNOi N2_§ 00C 5000 50““ my1 r WW Ref: Type C .~' : |‘1‘me. ‘ \\“‘.\\-‘ ' 3‘“ka~.»~“\“\._n"~\:“i- ,‘ .._.\\._.\:~. “Am» ...-\mM»-vx DVS Isotherm Plot .....\\ che 1 Sup +che 1 DesoIp DC .

. PN .1, m P _\ Target RH (%) FIG 3F. 13/31 (counts) 12000 10000 Intensity 8000 ”W E Form C: Before DVS , 3 4000 (I J Mill/ll! j: :1 .:.:; .mwwmfivwe"awe ;;w’z x; . a”wawrwfimmwféjfimjkfiwfim“k‘quww‘d 2000 ;~;;;; Form C: After DVS \\.H.H\ ‘ ~\ \ \. w NW“ \\“Wm-mum““wk“, ”(New “WK“. ‘ Q“ .~ . . > ‘ “New“NMKWN 10 15 20 25 30 35 2Theta (deg) . (counts) 2000 Intensity 1500 .-.-.-.-.-””””””,, '.'{r///aaa»4 10 15 20 25 30 35 2Theta (deg) . 14/31 (counts) 3000 Intensity 2500 Ref: Form A ‘ '2 ~ . _ . Dried after 6 days . . . , .. .. 0 ' WW’W‘W’SWmWWWMM 1000 . 500 FormD (wet sample) .0 ‘1. ‘ ‘ x ‘ ‘ 3i \X\\\\‘\_\‘\\\\\\“‘\\\\~ 3‘ \§\\\\\\‘\§‘\3\\\‘\\\\\ 2Theta (deg) . (counts) 2500 E Intensity 2000 § ‘\\\\§\\\\\<§\\\\\ \s'h 10 15 20 25 30 35 2Theta (deg) /31 s) 4000 Intensity 3000 2Theta (deg) 23.90C ‘2‘ 19.860A) f‘"".""‘r"‘-(""1”"7 ('3 200330 E \;~‘+~< E‘M'T‘"“\ "grin-“unnu- \\\>\ i}: _2 3-1 C ifN-‘i‘mmm------------------- 2.17:3 21o.7°c H \. 72.35J/g ; \ (W; \ , ¥ Féaw \ z ‘ z \ r \ , . Heat 211.9°C L“ E 0 50 100 150 200 250 300 350 EM" Temperature (°C) . 16/31 8:508 36:25 3000 *1 Form K NM:wk;340meMM».'Wv‘tx Form F heated to 100 °C $55M“;{\ ‘ \‘\‘m\;~\\\.\\“\ \’N\ $55w»\‘xxmwx-kk‘fi‘yw‘w.G“ . - ‘. 1000 .

Form F A ‘ u.5 w ..\ \ a q.3.“ W5wMV N. \A‘:w‘\\n"€i\vm\\\’>\-,.)_\-\“‘\;‘\\(-\‘.\\.\\«\' v, 15 20 25 30 35 2Theta (deg) .

“M. . wu. <3. mm? w?! «WW w (>0 0 :meG . x /r \\\\\\\\\\\\\\\\xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx\\\\\\\\\\\\\\\\\\\\\\\\““ a -3500 -3000 \\ \ \\\\\\\\\\\\\\\\\\\xxxxxxxxxxxxxxxxxxxxxxx\xxxxxxxxxxxxvvvvvaNNNWu-HW ..................................... \\\\\\\\\\ -2500 xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx \xxx\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\ _ Compound 1 \\\\\\\\\\\\\\\\\\\\\\\\\\\\\“\\ ‘ _ \\\\x \ \\m\\\m\\ y: W §--§-~§--§-~§~§§§§§nw ix _ : Kg.

G 4%? . n Q.. n F 85 7.5 6.5 5.5 4.5 3.5 25 L5 0 5 fl (ppm) FIG 6D. 17/31 10000 (counts) Intensity « 8000 « 6000 \ ,\ .

. NV...-x...~m.\.u“w-\xu“my“...x-xvhn. 2Theta (deg) . (counts) 8000 Intensity 6000 Form A R S. . . .s 31 . S u‘ \ - \\ .~‘\\_.-\.-.“..\u “5.x... «hm :\\-‘k\\x“‘ \\\\~;‘v»\\~“v\\\\"‘»‘\V\\“ L After Drying: Form H \ .. 5 ..L L wmmlxw: hm-~-"&\ws‘>w Amwflwkl“wfljflumfl is», Form H 3: .\ um» \: '\\-\- ..\ . .. \\\ ~\~ \vmx» ‘ w \\.\‘».~ \\\«.‘C\~\\~\\«U K ~.~.~\ o‘v . n . .. . , \uv. . V3,.- . . “Kw \- > u» L“ -.- 30 35 2Theta (deg) . 18/31 (counts) 12000 Intensity 10000 2Theta (deg) (counts) 15000 Intensity 10000 n‘ After Prying: Form I ‘3 1':1} t». ,5 N A ‘ .

“ “I quxvv‘b‘. \V‘w‘l’d‘WM' u“ \ -w'r.\%,.yf ‘1! \wm.

Form I 15 25 35 2Theta (deg) . 19/31 (counts) 25000 ity 20000 15000 10000 15 20 25 30 35 2Theta (deg) . nts) 20000 Intensity 15000 10000 After Drying: Form J \.J‘»..J A k~¢":-“\\«~J \Nflhwumm“\}«\~h-«»~«_....-'\.,..,~_M__m Form J 15 20 25 30 35 2Theta (deg) . /31 (counts) 5000 Intensity 4000 2000 3 3:. > X...» “ : ~\.\~.\~\a~\i§.\"~\\\‘&;‘” “5““ "N“ \\\$\\\\'\“. -~ h. ‘\“\‘.4.\\\‘\\.-‘x \‘i. . Ev \\\\\\\‘ \.\\E\\\\}.\\~\§v\\~"_ \.-\. : V\\‘\“\\.~\\\\SK\:x-‘\\\“.u\\xm‘.. 10 15 20 25 30 35 2Theta (deg) A. 256°C 200.0°C """""" 211.6°C ’\ _ \ __ 92.204/g \ E WM-.. _"“r"1"'z"'f"'("'I"1"‘1"‘1"‘1"‘v«‘{«‘r«‘r«<r«f«t«‘v«‘(«‘r‘"r"1"".‘";'"t"‘("'r"‘r"1"". z (2.) i C?! W. ~12 FE c l "A (J) . 0‘3 50 100 150 200 250 300 (JO 010 Temperature (°C) B. 21/31 DVS lsotherm Plot --\\-- Cycle 1 Sorp “Si-Cycle 1 Desotp . .\.. .... m. “a. .... .... .... fl... .... .... ... .... .... . .. .... .... n...

Change “@320 \~§9~--~" WTéEjé‘tiiiiE/é) C. (counts) 1200 Intensity 1000 800 .-.-.-.w.-.-.-.-.-”,, D. 22/31 s) \ 5000 \ Intensity \ 4000 \ -‘ Ix :‘x \ mums \Wux “WV“ ‘“"\‘“ ‘\'\u‘“\.~‘ \‘\‘\‘v\‘u~-\\.."\‘\~N\‘\\\-‘\v . w“ \‘V‘\‘\-\\‘.\k‘.‘\\\““»\\‘_\\".‘0»xv ‘ 15 25 30 35 2Theta (deg) A. (counts) 8000 Intensity 6000 é“-\ Form M "fixAWN“.-\\"~{-, W . . , ._ - :w~\\?~ ,\~,&\\\\\\\\w\\g._\\‘_,,x_g-\.\«\‘gps. >\qwnw\“55\umgmwmw“ 4000 Form L after 3 days ., n‘ffi‘ififik‘jx“ nntfiin. . ' kw‘k‘wfiw‘wfifiNfi-Jmm' \‘\.\*\\‘>&.§s~52\\\3‘ ~ . Form L 2000 ‘VAMNMVM’VVFNI‘ '0" 1"IWV‘iVWM—unN““\FN~~“NMW»Q.w“w.' 5 a 3‘ Form B :1 r. 3 ‘ $~ : A \xx-w “\MV mm ‘\\\_\~\~V.~\'\-*:»\~*\\\\“v wwxN“WA“.“y‘xawwgwmNEH,” 15 25 30 35 2Theta (deg) 1B. 23/31 210.6°C \ 80.72J/g \ /g \\‘ \x 5O 100 150 200 Temperature (°C) C.

AmEsoov . 55:25 400 ..$\\u.....:.\.\.\.\.... . .t..ixxh........h\.\............. “““““““ ..\\\\.‘...........\.\.\.uuunuuunnxuox .. :: . . h...........\.\.\.\.\ :E........:S.::::11:3... .umfimx 200 .......... ...E\.....n\\u......: : .533... .:\\\x\... . .3533? 1:53: . \\\t. ..:Q\\w\\\\\»\. \WPQHSS?: ....A\\§s\ \: . 3 ...\\.\N\:.

....\.W.\\\mu (\$V.n . \ \1:\‘Sxxér \\\\\u\ \.Rx\\\ 100 . . .. 2Theta (deg) . 24/31 3:508 3000 36:25 . 2000 . \«2\\\\‘.‘.‘.‘.‘ 1000 {11th. ‘~,\\?«\\\\~.\\\\\ngmmxxxx“.\3\\\.\w.‘\\-S§ 15 20 25 30 35 2Theta (deg) A. 8:508 :25 6000 Form A »\‘M\\N\ “Mu. . s \.\»5\\.\ . M w x«w «‘1 wmw- w"\\\‘~.\\' N«\-.M~.fi\v>\-\»\\‘ -”\~\'.~ After Drying: Form N ‘q\\i‘Maw x \\ 1.. . '. ‘1:\,\.‘§:\‘.‘_ «. « v. mm M .1 £1 in." $ Wm’ why. wkwwMQk,mmv.~...w.wwww~w.wm» 15 20 25 30 35 2Theta (deg) B. /31 75.4°C 63.13J/g {ng7 "fin...“«w... 3% «z Raw 4‘“ ,w«.z 211:6°C .‘ .‘~ \‘ \»‘ 5O 100 150 200 250 300 Exo Up Temperature (°C) C. 26fl31 3 "0‘ i “$5 -mm8£? \515 }1600 31500 }1400 1 ,4-dioxane y1300 y1200 nd 1 }1100 31000 E-100 :0 E-100 as 80 25 20 as 60 55 50 45 4o 35 30 25 20 15 10 05 D. (counts) 2500 Intensity 2000 .6». \‘a\\\ \mavxx_ ‘:~ :‘x\¢§y\\ \«-. \, 1‘ K . \\\\>\\\\xsxi‘kxv'iw‘yk‘vk\x«.\u'~H.‘\-s.\‘~‘\~.-.~\~\\\\\,\\,~‘A.\\-.“‘.,‘\,v.¢;._‘ 10 15 20 25 30 35 2Theta (deg) A. 27/31 ;.§ o E‘s) 168.5 C0 210.8 C \_ éxg126J/gmwff6J/N\9.‘a 65.000 . . 64.03J/ Wig 181.2°C g3 “4 g 73.5°C 5 m \ “5.3 a \ m g \ K i \ "“'r""t""‘r""{""'r""(""1u"'y"-'1"-"r'-"'.'-"1""'7""1""‘v""T"«(“«1'««(««f««r -9 \ ~23 212i0°c \. o 50 100 150 200 250 300 35 EX° up Temperature (°C) B. (counts) 4000 .-.e;;.-.-.-.-.u””.

Intensity . 3000 LLLLL’Irrrrrrtriiii Form C \\~‘ \‘\ ~ «xxx . . .~\. o> - w .-\ \\\ ~“ ~« \\\\~\\»«\» .‘\\\»\»»-.\~\Z».\\‘\‘~\\\n\_» M\\\\ “N 10 15 20 25 30 35 2Theta (deg) C. 28/31 xxxx\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\xxxx\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\§\\§\\Evil!!!\w\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\ 600 Compound 1' ACN .......... 550 33:. at“? 500 x\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\ \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\ 400 - 300 \-~\\\\\\\\\\\ 200 ,\\\\\\m. xxtxxxxx\\\\\\\\xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx\\\§§3§§3§§3§MN\\\\\\\\\\\\\\\\M 100 Fwd“ 0 90 £15 &0 7.5 7.06.56.055504540353025201510050.0 f1(ppm D.

LU:TUU% 8.Qe+003 $9: RnanfiwVN .. . 2.. .lmrvflul\ seems: 3 \ksx§\\ttt\%.:....\\\\\\\\\\ts:. _ .§s&~hn§§9$ .3 :xxxtu kauu. 36:35 \..x\§.:&\\: kn... n C 03.. . xx how...» . filtered & dried 4.0e+DE:3 ......................... ' \-\~r"\‘n~c\d“ .. . .\... .2S.\\\\\\\\x\ w an M...

NA\ .. \ ‘ txktti w§§~§n§3§x it§ttx§§ .»\\.\\NMR. pxwxc ......“ 2 ..Nw$.......u§. .xxvv..§.\5:\\.\\.sM\\\\\\\..\\\.<ttkt‘v..<t§\w:t§ .. v \\\\~ .6 . \ 2.06003 . ..\\\\\»~~ 4 hr . é v\»\»v \»\J N~v. ~x....~\¢-...,.\ .w “xv-V Fa S .£\ .ng .‘ 3 .9 :aier C51. 0.060052%“-.. a...x a...A » m « w. ~mwM .m mMv. m 3O 40 . 29/31 ccgccccccccccéav . m ..,,.$,................................................................. \ . __ a Em 3.3mm 1!‘2,MV-Mmmwwgm.5..... .,» 3 .2. .,,......... -.......r;;;;,.....

-,;;;;,,,. A and B. /31 A and B 3%. Form A $ Farm C‘ Form P Temperature {0’3} . 31/31 §\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\§ 7 A , \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\ \ \ \ \ § V § ‘ § > 3 § \\\\\ \\\ § § \\\\V‘ ' \\\\\\ § § \ §\\ Q 3* §\\\\§ §\\ $\\\\\\\x\\\\\\\\\\\\\\\m\mm\\m\m\M\m\xx\M\mmmm_\_§\xi %\\\ §\ §\‘ §\§\§ \ \_ 3 § \a\\5§§‘\\\ $ 3 § \\\‘§§§s \\- § \ \ \ \ \x\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\Y\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\§_ \ \ __\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\“““““““““\““§ s 20 °C in EiOAc .