Solid forms comprising a NR2b NAM antagonist

Abstract

Solid forms comprising (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one (Compound (I)), compositions comprising the same, and methods of making and using the same, for example, in the prevention or treatment of a central nervous system disease.

Description

SOLID FORMS COMPRISING A NR2B NAM ANTAGONIST

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application No.63 / 695,201, filed September 16, 2024, the contents of which are incorporated by reference herein in their entirety.

[0002] Disclosed herein are solid forms of (4S,5S)-1-({6-[4-(difluoromethyl)-2- fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one (Compound (I)), including co-crystals comprising Compound (I), processes for preparing the same, and uses of the same, for example, in the treatment or prevention of a disease, such as, e.g., a central nervous system disease, such as, e.g., depression, bipolar disorder, migraine, pain, peripheral symptoms of dementia, or the like.

[0003] Glutamic acid is the major excitatory neurotransmitter in the central nervous system (e.g., the brain and spinal cord). Glutamic acid-dependent signal transduction is carried out by the ion channel-conjugated N-methyl-D-aspartic acid (NMDA) receptor, the gamma-amino-3-hydroxy-5-methyloxazole-4-propionic acid (AMPA) / kainic acid (KA) receptor, and the metabotropic glutamate receptor. Among these receptors, the NMDA receptor has high permeability to certain cations (such as, e.g., calcium ions) and mediates excitatory neurotransmission by depolarization of nerve cells. Moreover, calcium that has flowed into the cell via the NMDA receptor functions as a secondary messenger and causes plastic changes in nerve function, for example, by altering intracellular phosphorylation signals and regulation of gene transcription and translation. As a result, NMDA receptors play an important role in the regulation of central nervous system function.

[0004] The NMDA receptor is composed of a tetramer in which two or three subunits from among NR1, NR2A, NR2B, NR2C, NR2D, NR3A, and NR3B subunits are associated; the presence of the NR1 subunit is believed to be essential to its function as a receptor for carrying out excitatory neurotransmission. Since the NR1 subunit is included in functional NMDA receptors, it is widely distributed throughout the central nervous system. However, the distribution and expression timing of the NR2 subunit vary by subunit. Illustratively, the NR2A and NR2C subunits are detected for the first time immediately before birth, while the NR2B and NR2D subunits are observed from the early stage of fetal development. In addition, the NR2A subunit is widely distributed in the brain, while the NR2B subunit is locally expressed in the forebrain and the NR2C subunit is locally expressed in the cerebellum.Attorney Docket No. 15496.0046-00304

[0005] The NMDA receptor containing the NR2B subunit, the target of a compound of the present disclosure, is highly expressed in the cerebral cortex (e.g., in layers 2 and 3), hippocampus, amygdala, ventral nucleus of the thalamus, and olfactory bulb of the adult rodent brain. Furthermore, the receptor is confined to the posterior horn of the spinal cord, particularly the second layer. Additionally, NMDA receptor containing the NR2B subunit in single cells is most highly expressed in the postsynaptic density, with expression also observed in the extrasynaptic region. This distribution suggests that the NMDA receptor containing the NR2B subunit is widely functional in the brain and may be effective in the prophylaxis or treatment of central nervous system diseases, such as, for example, depression, bipolar disorder, migraine, pain, peripheral symptoms of dementia, and the like.

[0006] Compound (I) and various solid forms thereof may be antagonists of an NMDA receptor containing an NR2B subunit and be useful in the treatment of diseases mediated by the NMDA receptor, including, for example, central nervous system diseases. Compound (I) is disclosed in, for example, Examples 17 and 38 of PCT International Application No. PCT / IB2020 / 000962, filed November 12, 2020, published as WO 2021 / 094832, and incorporated by reference herein in its entirety, and has the following structure:.

[0007] Solid forms (e.g., crystalline forms, such as, e.g., co-crystal forms) of bioactive compounds, such as Compound (I), are of interest in the pharmaceutical industry, where solid forms with specific physical, chemical, or pharmaceutical properties, such as solubility, dissociation, true density, dissolution, melting point, morphology, compaction behavior, particle size, flow properties, or solid-state stability, may be desirable or even required for pharmaceutical development. Crystalline forms occur where the same composition of matter crystallizes in different lattice arrangements, resulting in different thermodynamic properties and stabilities specific to each crystalline form. Each unique crystal form is known as a “polymorph.”

[0008] While polymorphs of a given substance have the same chemical composition, they may differ from each other with respect to at least one physical, chemical, and / or pharmaceutical property, such as solubility, dissociation, true density, dissolution, melting point, crystal habit or morphology, compaction behavior, particle size, flow properties, and / or solid-state stability. The solid-state form of a bioactive compound may determine its ease of preparation, ease ofAttorney Docket No. 15496.0046-00304 isolation, hygroscopicity, stability, solubility, storage stability, ease of formulation, rate of dissolution in gastrointestinal fluids, and in vivo bioavailability.

[0009] It is not yet possible to predict the possible solid forms (e.g., crystalline forms, such as, e.g., co-crystal forms) of a compound, whether any such forms will be suitable for commercial use in a pharmaceutical composition, or which form or forms will display desirable properties. Because different solid forms (e.g., crystalline forms, such as, e.g., co-crystal forms) may possess different properties, reproducible processes for producing a substantially pure solid form are also desirable for bioactive compounds intended for use as pharmaceuticals.

[0010] Accordingly, there is a need for novel solid forms, including novel crystalline and / or co-crystal forms, which are useful for treating disorders and conditions mediated by the activity of the NMDA receptor containing the NR2B subunit, e.g., Compound (I), and reproducible, scalable methods of making the same.

[0011] Disclosed herein are novel solid forms comprising Compound (I), compositions comprising the same, and methods of using and making the same. In some embodiments, the solid forms disclosed herein have properties that are useful for large-scale manufacturing, pharmaceutical formulation, and / or storage. In some embodiments, the solid forms disclosed herein consist of one crystalline form. In some embodiments, the solid forms are substantially pure. In some embodiments, the solid forms are chosen from co-crystals comprising Compound (I). In some embodiments, the solid forms are chosen from crystalline forms of Compound (I).

[0012] Some embodiments of the disclosure relate to a pharmaceutical composition comprising: at least one pharmaceutically acceptable excipient; and at least one solid form which is chosen from solid forms comprising Compound (I).

[0013] In some embodiments, the at least one solid form is crystalline Form (III) of Compound (I).

[0014] In some embodiments, the at least one solid form is a co-crystal comprising Compound (I) and a co-crystal former. In some embodiments, the co-crystal former is chosen from pamoic acid, benzoic acid, saccharin, hippuric acid, ascorbyl palmitate, (+)-camphoric acid, 4-acetamido-benzoic acid, and cholic acid. In some embodiments, Compound (I) and the co- crystal former are present in a 1:1 stoichiometric ratio in the at least one co-crystal. In some embodiments, the co-crystal comprises Compound (I) and cholic acid. In some embodiments, the co-crystal comprises Compound (I) and cholic acid in a 1:1 stoichiometric ratio.

[0015] Some embodiments of the disclosure relate to methods of antagonizing an NMDA receptor containing an NR2B subunit in a subject in need thereof, comprising administering aAttorney Docket No. 15496.0046-00304 therapeutically effective amount of at least one solid form which is chosen from solid forms comprising Compound (I).

[0016] In some embodiments, the at least one solid form is crystalline Form (III) of Compound (I).

[0017] In some embodiments, the at least one solid form is a co-crystal comprising Compound (I) and a co-crystal former. In some embodiments, the co-crystal former is chosen from pamoic acid, benzoic acid, saccharin, hippuric acid, ascorbyl palmitate, (+)-camphoric acid, 4-acetamido-benzoic acid, and cholic acid. In some embodiments, Compound (I) and the co- crystal former are present in a 1:1 stoichiometric ratio in the at least one co-crystal. In some embodiments, the co-crystal comprises Compound (I) and cholic acid. In some embodiments, the co-crystal comprises Compound (I) and cholic acid in a 1:1 stoichiometric ratio.

[0018] Some embodiments of the disclosure relate to methods of preventing or treating depression, bipolar disorder, migraine, pain, or peripheral symptoms of dementia in a subject in need thereof, comprising administering a therapeutically effective amount of at least one solid form which is chosen from solid forms comprising Compound (I).

[0019] In some embodiments, the at least one solid form is crystalline Form (III) of Compound (I).

[0020] In some embodiments, the at least one solid form is a co-crystal comprising Compound (I) and a co-crystal former. In some embodiments, the co-crystal former is chosen from pamoic acid, benzoic acid, saccharin, hippuric acid, ascorbyl palmitate, (+)-camphoric acid, 4-acetamido-benzoic acid, and cholic acid. In some embodiments, Compound (I) and the co- crystal former are present in a 1:1 stoichiometric ratio in the at least one co-crystal. In some embodiments, the co-crystal comprises Compound (I) and cholic acid. In some embodiments, the co-crystal comprises Compound (I) and cholic acid in a 1:1 stoichiometric ratio.

[0021] It should be understood that references herein to methods of treatment and / or preventing (e.g., methods of treating and / or preventing a central nervous system disease, such as, e.g., depression, bipolar disorder, migraine, pain, or peripheral symptoms of dementia) using at least one solid form of the present disclosure should also be interpreted as references to: - at least one solid form of the present disclosure for use in methods of treatment and / or prevention (e.g., methods of treating and / or preventing a central nervous system disease, such as, e.g., depression, bipolar disorder, migraine, pain, or peripheral symptoms of dementia); and / orAttorney Docket No. 15496.0046-00304 - the use of at least one solid form of the present disclosure in the manufacture of a medicament for use in methods of treatment and / or prevention (e.g., methods of treating and / or preventing a central nervous system disease, such as, e.g., depression, bipolar disorder, migraine, pain, or peripheral symptoms of dementia).

[0022] Also disclosed herein are methods of preparing at least one solid form which is chosen from solid forms comprising Compound (I).

[0023] In some embodiments, the at least one solid form is crystalline Form (III) of Compound (I).

[0024] In some embodiments, the at least one solid form is a co-crystal comprising Compound (I) and a co-crystal former. In some embodiments, the co-crystal comprises Compound (I) and cholic acid. In some embodiments, the co-crystal comprises Compound (I) and cholic acid in a 1:1 stoichiometric ratio. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] FIG. 1 shows an X-ray powder diffractogram for crystalline Compound (I) startingmaterial, showing degrees 2 (2-theta) on the X-axis and relative intensity on the Y-axis.

[0026] FIG. 2 shows a differential scanning calorimetry (DSC) thermogram and a thermogravimetric analysis (TGA) thermal curve for crystalline Compound (I) starting material.

[0027] FIG. 3A shows X-ray powder diffractograms for a co-crystal prepared by slurrying Compound (I) and cholic acid (1:1) in neat water and equilibrating for 2 weeks (A) and co-crystals slurrying Compound (I) and cholic acid in neat water and heat cycling at a 1:1 (B)or 1:2 (C) stoichiometric ratio, showing degrees 2 (2-theta) on the X-axis and relative intensityon the Y-axis.

[0028] FIG. 3B shows X-ray powder diffractograms for crystalline Compound (I) starting material, cholic acid, a co-crystal prepared by slurrying Compound (I) and cholic acid (1:1) in neat water and equilibrating for 2 weeks (A), and a co-crystal prepared by slurrying Compound (I) and cholic acid in neat water and heat cycling at a 1:2 stoichiometric ratio (C), showingdegrees 2 (2-theta) on the X-axis and relative intensity on the Y-axis.

[0029] FIG. 4 shows X-ray powder diffractograms for crystalline Compound (I) starting material, cholic acid, a co-crystal prepared by slurrying Compound (I) and cholic acid (1:1) in neat water and equilibrating for 2 weeks (A), and a co-crystal prepared by slurrying Compound (I) and cholic acid (1:1) in neat toluene, equilibrating for 2 weeks, isolating the crude material,Attorney Docket No. 15496.0046-00304 heating a water slurry comprising the crude material to 65ºC, and cooling to room temperature(D’), showing degrees 2 (2-theta) on the X-axis and relative intensity on the Y-axis.

[0030] FIG. 5 shows differential scanning calorimetry (DSC) thermograms for a co-crystal prepared by slurrying Compound (I) and cholic acid in neat water and heat cycling at a 1:2 stoichiometric ratio (C) and a co-crystal prepared by slurrying Compound (I) and cholic acid (1:1) in neat toluene, equilibrating for 2 weeks, isolating the crude material, heating a water slurry comprising the crude material to 65ºC, and cooling to room temperature (D’).

[0031] FIG. 6 shows a differential scanning calorimetry (DSC) thermogram and a thermogravimetric analysis (TGA) thermal curve for a co-crystal comprising Compound (I) and cholic acid in a 1:1 stoichiometric ratio.

[0032] FIG. 7 shows an X-ray powder diffractogram for a co-crystal comprising Compound(I) and cholic acid, showing degrees 2 (2-theta) on the X-axis and relative intensity on theY-axis.

[0033] FIG. 8 shows an X-ray powder diffractogram for a crystalline material comprising crystalline Form (III) of Compound (I), referred to as crystalline Form (III) herein, showingdegrees 2 (2-theta) on the X-axis and relative intensity on the Y-axis.

[0034] FIG. 9 shows a differential scanning calorimetry (DSC) thermogram and a thermogravimetric analysis (TGA) thermal curve for a crystalline material comprising crystalline Form (III) of Compound (I), referred to as crystalline Form (III) herein. Definitions:

[0035] As used herein, “a” or “an” entity refers to one or more of that entity, e.g., “a compound” refers to one or more compounds or at least one compound unless stated otherwise. As such, the terms “a” (or “an”), “one or more”, and “at least one” are used interchangeably herein.

[0036] As used herein, the term “active pharmaceutical ingredient” or “therapeutic agent” (“API”) refers to a biologically active compound.

[0037] As used herein, “administration” of an API to a patient refers to any route (e.g., oral delivery) of introducing or delivering the API to the patient. Administration includes self-administration and the administration by another.

[0038] As used herein, the term “ambient conditions” refers to room temperature (e.g., 20 ºC to 25 ºC), open air, and uncontrolled humidity conditions.Attorney Docket No. 15496.0046-00304

[0039] As used herein, the term “solid form” includes any solid form of a compound, such as Compound (I), including a substantially crystalline form, a crystalline form, an amorphous form, a solid dispersion, a solvate, a co-crystal, or a salt of the compound that is in solid form.

[0040] As used herein, the terms “crystalline form,” “crystal form,” and “Form” interchangeably refer to a solid having a particular molecular packing arrangement in the crystal lattice. Crystalline forms can be identified and distinguished from each other by one or more characterization techniques including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, solid state nuclear magnetic resonance (SS-NMR), differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and / or thermogravimetric analysis (TGA). Accordingly, as used herein, the terms “crystalline Form [X] of Compound ([Y])” refers to a unique crystalline form that can be identified and distinguished from other forms using one or more characterization techniques including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, SS-NMR, differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and / or thermogravimetric analysis (TGA). In some embodiments, the novel crystalline forms of this disclosure are characterized by an X- ray powder diffractogram having one or more signals at one or more specified two-theta values

[0041] As used herein, the term “solvate” refers to a crystal form comprising one or more molecules of a compound of the present disclosure and one or more molecules of a solvent or solvents incorporated into the crystal lattice in stoichiometric or nonstoichiometric amounts. When the solvent incorporated into the crystal lattice is water, the solvate is referred to as a “hydrate.”

[0042] As used herein, the term “co-crystal” refers to a crystalline material composed of two or more different molecules, such as Compound (I) and at least one co-crystal former (or co-former), in the same crystal lattice. In some embodiments, co-crystals components are in a neutral state and interact nonionically.

[0043] As used herein, the terms “X-ray powder diffractogram,” “X-ray powder diffraction pattern,” and “XRPD pattern” interchangeably refer to an experimentally obtained pattern plotting signal positions (on the abscissa) versus signal intensities (on the ordinate). For an amorphous material, an X-ray powder diffractogram may comprise one or more broad signals. For a crystalline material, an X-ray powder diffractogram may comprise one or more signals, of an X-ray powder diffractogram, which may be expressed as “a signal at . . . degrees two-Attorney Docket No. 15496.0046-00304 theta,” “a signal at [a] two-theta value(s) of . . .” and / or “a signal at at least . . . two-theta value(s) chosen from . . . .”

[0044] As used herein, a “signal” or “peak” refers to a point in the XRPD pattern where the intensity as measured in counts is at a local maximum. One of ordinary skill in the art would recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may, for example, not be apparent to the naked eye. Illustratively, one of ordinary skill in the art would recognize that some art-recognized methods are capable of and suitable for determining whether a signal exists in a pattern, such as, for example, Rietveld refinement.

[0045] As used herein, “a signal at . . . degrees two-theta,” “a signal at [a] two-theta value[] of . . .” and / or “a signal at at least . . . two-theta value(s) chosen from . . . ” refers to an XRPD pattern that comprises X-ray reflection positions as measured and observed in X-ray powder

[0046] i.e., the angular value can be at the recited angular value + 0.2 degrees two-theta, the angular value - 0.2 degrees two- theta, or any value between those two end points (angular value +0.2 degrees two-theta and angular value -0.2 degrees two-theta).

[0047] As used herein, the terms “signal intensities” and “peak intensities” interchangeably refer to relative signal intensities within a given X-ray powder diffractogram. Non-limiting examples of factors that can affect the relative signal or peak intensities include sample thickness and preferred orientation (e.g., the crystalline particles are not distributed randomly).

[0048] The term “X-ray powder diffractogram comprising a signal at . . . two-theta values,” as used herein, refers to an XRPD pattern comprising X-ray reflection positions as measured andobserved in X-

[0049] As used herein, the term “amorphous” refers to a solid material having no long-range order in the position of its molecules. Amorphous solids may be supercooled liquids in which the molecules are arranged in a random manner such that there is no well-defined arrangement, e.g., molecular packing, and no long-range order. For example, an amorphous material is a solid material with no sharp characteristic signal(s) in its X-ray power diffractogram (i.e., is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) may appear in its diffractogram.

[0050] As used herein, an X-ray powder diffractogram is “substantially similar to that in [a particular] Figure” when at least 90%, such as, for example, at least 95%, at least 98%, or atleast 99% of the signals in the two diffractograms overlap ± 0.2 2 . In determiningAttorney Docket No. 15496.0046-00304 “substantial similarity,” one of ordinary skill in the art will understand that there may be variation in the intensities and / or signal positions in the measurements of X-ray powder diffraction signal values even for the same crystalline form. As such, a person of ordinary skillin the art would appreciate that there may be variability of up to ± 0.2 2 in signal value forthe same signal in different samples. Additionally, it is well known to one of ordinary skill in the art that there can be variability in the measurements of relative signal intensities in X-ray powder diffraction experiments. Illustratively, non-limiting factors that can affect the relative signal intensities include sample thickness and preferred orientation (e.g., the crystalline particles are not distributed randomly).

[0051] As used herein, a crystalline form is “substantially pure” when it accounts for an amount by weight equal to or greater than 90% of the sum of all solid form(s) in a sample as determined by a method in accordance with the art, such as quantitative XRPD. In some embodiments, the solid form is “substantially pure” when it accounts for an amount by weight equal to or greater than 95% of the sum of all solid form(s) in a sample. In some embodiments, the solid form is “substantially pure” when it accounts for an amount by weight equal to or greater than 99% of the sum of all solid form(s) in a sample.

[0052] As used herein, the term “DSC” refers to the analytical method of differential scanning calorimetry.

[0053] As used herein, the term “TGA” refers to the analytical method of thermo gravimetric (or thermogravimetric) analysis.

[0054] As used herein, a “condition,” “disorder,” or “disease” relates to any unhealthy or abnormal state.

[0055] As used herein, an “effective amount” or a “therapeutically effective amount” refers to an amount of a molecule that treats, upon single or multiple dose administration, a patient suffering from a condition. An effective amount can be determined by the attending diagnostician through the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of patient; its size, age, and general health; the specific condition, disorder, or disease involved; the degree of or involvement or the severity of the condition, disorder, or disease, the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.Attorney Docket No. 15496.0046-00304

[0056] As used herein, the term “increase” refers to altering positively by at least 5%, including, but not limited to, altering positively by 5%, altering positively by 10%, altering positively by 25%, altering positively by 30% altering positively by 50%, altering positively by 75%, or altering positively by 100%.

[0057] As used herein, a “mammal” refers to domesticated animals (e.g., dogs, cats, and horses) and humans. In some embodiments, the mammal is a human.

[0058] As used herein, the term “modulate” refers to altering positively or negatively. Non-limiting example modulations include a 1% change, a 2% change, a 5% change, a 10% change, a 25% change, a 50% change, a 75% change, or a 100% change.

[0059] As used herein, the terms “patient” and “subject” are used interchangeably and refer to a mammal, such as, e.g., a human.

[0060] As used herein, a “pharmaceutically acceptable excipient” refers to a carrier or an excipient that is useful in preparing a pharmaceutical composition. For example, a pharmaceutically acceptable excipient is generally safe and includes carriers and excipients that are generally considered acceptable for mammalian pharmaceutical use. As a non-limiting example, pharmaceutically acceptable excipients may be solid, semi-solid, or liquid materials which in the aggregate can serve as a vehicle or medium for the active ingredient. Some examples of pharmaceutically acceptable excipients are found in Remington’s Pharmaceutical Sciences and the Handbook of Pharmaceutical Excipients and include diluents, vehicles, carriers, ointment bases, binders, disintegrates, lubricants, glidants, sweetening agents, flavoring agents, gel bases, sustained release matrices, stabilizing agents, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coating agents, and others.

[0061] As used herein, the term “reduce” refers to altering negatively by at least 5% including, but not limited to, altering negatively by 5%, altering negatively by 10%, altering negatively by 25%, altering negatively by 30%, altering negatively by 50%, altering negatively by 75%, or altering negatively by 100%.

[0062] As used herein, the term “treat,” “treating,” or “treatment,” when used in connection with a disorder or condition, includes any effect, e.g., lessening, reducing, modulating, ameliorating, or eliminating, that results in the improvement of the disorder or condition. Improvements in or lessening the severity of any symptom of the disorder or condition can be readily assessed according to standard methods and techniques known in the art. Non-Limiting Example Embodiments:

[0063] Without limitation, some embodiments of the disclosure include:Attorney Docket No. 15496.0046-00304 1. A co-crystal comprising Compound (I):co-crystal former. 2. The co-crystal according to Embodiment 1, wherein the co-crystal former is chosen from pamoic acid, benzoic acid, saccharin, hippuric acid, ascorbyl palmitate, (+)-camphoric acid, 4-acetamido-benzoic acid, and cholic acid. 3. The co-crystal according to Embodiment 1 or 2, wherein Compound (I) and the co- crystal former are present in a 1:1 stoichiometric ratio. 4. A co-crystal comprising Compound (I):and cholic acid. 5. The co-crystal according to Embodiment 4, wherein Compound (I) and cholic acid are present in a 1:1 stoichiometric ratio. 6. The co-crystal according to Embodiment 4 or 5, characterized by an X-ray powder diffractogram comprising a signal at at least two two-theta values chosen from 7.6 0.2, 9.0 0.2, 12.4 0.2, 13.2 0.2, 16.5 0.2, 18.6 0.2, and 21.9 0.2. 7. The co-crystal according to any one of Embodiments 4-6, characterized by an X-ray powder diffractogram comprising a signal at at least three two-theta values chosen from 7.6 0.2, 9.0 0.2, 12.4 0.2, 13.2 0.2, 16.5 0.2, 18.6 0.2, and 21.9 0.2.Attorney Docket No. 15496.0046-00304 8. The co-crystal according to any one of Embodiments 4-7, characterized by an X-ray powder diffractogram comprising a signal at at least four two-theta values chosen from 7.6 0.2, 9.0 0.2, 12.4 0.2, 13.2 0.2, 16.5 0.2, 18.6 0.2, and 21.9 0.2. 9. The co-crystal according to any one of Embodiments 4-8, characterized by an X-ray powder diffractogram comprising a signal at at least five two-theta values chosen from 7.6 0.2, 9.0 0.2, 12.4 0.2, 13.2 0.2, 16.5 0.2, 18.6 0.2, and 21.9 0.2. 10. The co-crystal according to any one of Embodiments 4-9, characterized by an X-ray powder diffractogram comprising a signal at at least six two-theta values chosen from 7.6 0.2, 9.0 0.2, 12.4 0.2, 13.2 0.2, 16.5 0.2, 18.6 0.2, and 21.9 0.2. 11. The co-crystal according to any one of Embodiments 4-10, characterized by an X-ray powder diffractogram substantially similar to that in FIG. 7. 12. The co-crystal according to any one of Embodiments 4-11, characterized by an DSC thermogram substantially similar to that in FIG. 6. 13. The co-crystal according to any one of Embodiments 4-12, characterized by a DSC thermogram comprising a peak endotherm (melting temperature) at a temperature between 96 °C and 101 °C. 14. The co-crystal according to any one of Embodiments 4-13, characterized by a mass loss of less than 1.5 wt. % between 25 °C and 125 °C by thermogravimetric analysis. 15. Crystalline Form (III) of Compound (I):.Attorney Docket No. 15496.0046-00304 16. Crystalline Form (III) according to Embodiment 15, characterized by an X-ray powder diffractogram comprising a signal at at least two two-theta values chosen from 4.7 0.2, 9.4 0.2, 14.1 0.2, and 18.9 0.2. 17. Crystalline Form (III) according to Embodiment 15 or 16, characterized by an X-ray powder diffractogram comprising a signal at at least three two-theta values chosen from 4.7 0.2, 9.4 0.2, 14.1 0.2, and 18.9 0.2. 18. Crystalline Form (III) according to any one of Embodiments 15-17, characterized by an X-ray powder diffractogram substantially similar to that in FIG. 8. 19. Crystalline Form (III) according to any one of Embodiments 15-18, characterized by a DSC thermogram comprising a peak endotherm (melting temperature) at about 111.9 ºC. 20. Crystalline Form (III) according to any one of Embodiments 15-18, characterized by a mass loss of less than 1.5 wt. % between 50 °C and 125 °C by thermogravimetric analysis. 21. A pharmaceutical composition comprising: at least one solid form of Compound (I) according to any one of Embodiments 1-20; and at least one pharmaceutically acceptable excipient. 22. A solid form of Compound (I) according to any one of Embodiments 1-20 or a pharmaceutical composition according to Embodiment 15 for use in prevention or treatment of depression, bipolar disorder, migraine, pain, or peripheral symptoms of dementia. 23. A method of antagonizing an NMDA receptor containing an NR2B subunit in a subject in need thereof, comprising administering a therapeutically effective amount of at least one solid form of Compound (I) according to any one of Embodiments 1-20 to the subject. 24. A method for preventing or treating depression, bipolar disorder, migraine, pain, or peripheral symptoms of dementia in a subject in need thereof, comprising administering a therapeutically effective amount of at least one solid form of Compound (I) according to any one of Embodiments 1-20 to the subject.Attorney Docket No. 15496.0046-00304 25. Use of at least one solid form of Compound (I) according to any one of Embodiments 1-20 in the manufacture of a prophylactic or therapeutic agent for depression, bipolar disorder, migraine, pain, or peripheral symptoms of dementia. 26. A process for preparing the co-crystal according to Embodiment 1, comprising: mixing Compound (I) and a co-crystal former to form a dry mixture, wherein the co-crystal former is chosen from pamoic acid, benzoic acid, saccharin, hippuric acid, ascorbyl palmitate, (+)-camphoric acid, 4-acetamido-benzoic acid, and cholic acid; dripping a solvent into the dry mixture to form a wet mixture; and grinding the wet mixture. 27. The process according to Embodiment 26, wherein Compound (I) and the co-crystal former are present in the dry mixture in a 1:1 stoichiometric ratio. 28. The process according to Embodiment 26 or 27, wherein the solvent is water. 29. The process according to any one of Embodiments 26-28, wherein the wet mixture is ground for 2 minutes. 30. A process for preparing the co-crystal according to Embodiment 1, comprising: slurrying Compound (I) and a co-crystal former in a solvent to form a slurry, wherein the co-crystal former is chosen from pamoic acid, benzoic acid, saccharin, hippuric acid, ascorbyl palmitate, (+)-camphoric acid, 4-acetamido-benzoic acid, and cholic acid; and equilibrating the slurry. 31. The process according to Embodiment 30, wherein Compound (I) and the co-crystal former are present in the slurry in a 1:1 or 1:2 stoichiometric ratio. 32. The process according to Embodiment 30 or 31, wherein the solvent is water. 33. The process according to Embodiment 30 or 31, wherein the solvent is chosen from organic solvents.Attorney Docket No. 15496.0046-00304 34. The process according to any one of Embodiments 30-33, wherein the slurry is equilibrated at a temperature between 20 ºC and 25 ºC. 35. The process according to any one of Embodiments 30-34, wherein the slurry is equilibrated for 2 weeks. 36. The process according to any one of Embodiments 30-33, wherein the slurry is equilibrated at an elevated temperature. 37. The process according to Embodiment 36, further comprising slowly cooling the slurry to a temperature between 20 ºC and 25 ºC. 38. The process according to any one of Embodiments 26-37, further comprising isolating the co-crystal according to Embodiment 1. 39. A process for preparing crystalline Form (III) of Compound (I), comprising: dissolving Compound (I) in 1,2-dimethoxyethane to form a first solution; heating the first solution to an elevated temperature; adding an anti-solvent to the first solution to form a second solution; and cooling the second solution.

[0064] Some embodiments of this disclosure relate to a co-crystal comprising Compound (I):co-crystal former.

[0065] In some embodiments, the co-crystal former is chosen from pamoic acid, benzoic acid, saccharin, hippuric acid, ascorbyl palmitate, (+)-camphoric acid, 4-acetamido-benzoic acid, and cholic acid. In some embodiments, the co-crystal former is pamoic acid. In some embodiments, the co-crystal former is benzoic acid. In some embodiments, the co-crystal former is saccharin. In some embodiments, the co-crystal former is chosen from hippuric acid. In some embodiments, the co-crystal former is ascorbyl palmitate. In some embodiments, the co-crystal former is (+)-camphoric acid. In some embodiments, the co-crystal former is 4-acetamido-benzoic acid. In some embodiments, the co-crystal former is cholic acid.Attorney Docket No. 15496.0046-00304

[0066] In some embodiments, Compound (I) and the co-crystal former are present in a 1:1 stoichiometric ratio.

[0067] Some embodiments of this disclosure relate to a co-crystal comprising Compound (I):cholic acid.

[0068] In some embodiments, Compound (I) and cholic acid are present in a 1:1 stoichiometric ratio in the co-crystal.

[0069] FIG. 7 shows an X-ray powder diffractogram for a co-crystal comprising Compound (I) and cholic acid.

[0070] FIG. 6 shows a DSC thermogram of a co-crystal comprising Compound (I) and cholic acid.

[0071] In some embodiments, the co-crystal is characterized by a DSC thermogram having a peak endotherm (melting temperature) between 96 °C and 101 °C. In some embodiments, the -55 J / g). In some embodiments, the -crystal is further characterized by a DSC thermogram having a peak endotherm (melting temperature) between 170 °C and 180 °C.

[0072] In some embodiments, the co-crystal is characterized by a DSC thermogram substantially similar to that in FIG. 6.

[0073] FIG. 6 also shows a TGA thermal curve for a co-crystal comprising Compound (I) and cholic acid.

[0074] In some embodiments, the co-crystal is characterized by a mass loss of less than 2 wt. % between 25 °C and 125 °C by thermogravimetric analysis. In some embodiments, the co- crystal is characterized by a mass loss of less than 1.75 wt. % between 25 °C and 125 °C by thermogravimetric analysis. In some embodiments, the co-crystal is characterized by a mass loss of less than 1.5 wt. % between 25 °C and 125 °C by thermogravimetric analysis. In some embodiments, the co-crystal is characterized by a mass loss of less than 1.4 wt. % between 25 °C and 125 °C by thermogravimetric analysis.

[0075] In some embodiments, the co-crystal is characterized by a mass loss of less than 1 wt. % between 125 °C and 200 °C by thermogravimetric analysis. In some embodiments, the co- crystal is characterized by a mass loss of less than 0.9 wt. % between 125 °C and 200 °C byAttorney Docket No. 15496.0046-00304 thermogravimetric analysis. In some embodiments, the co-crystal is characterized by a mass loss of less than 0.8 wt. % between 125 °C and 200 °C by thermogravimetric analysis. In some embodiments, the co-crystal is characterized by a mass loss of less than 0.7 wt. % between 125 °C and 200 °C by thermogravimetric analysis. In some embodiments, the co-crystal is characterized by a mass loss of less than 0.6 wt. % between 125 °C and 200 °C by thermogravimetric analysis.

[0076] In some embodiments, the co-crystal is characterized by an X-ray powder diffractogram comprising a signal at 7.6 ± 0.2 degrees two-theta. In some embodiments, the co-crystal is characterized by an X-ray powder diffractogram comprising a signal at 9.0 ± 0.2 degrees two- theta. In some embodiments, the co-crystal is characterized by an X-ray powder diffractogram comprising a signal at 12.4 ± 0.2 degrees two-theta. In some embodiments, the co-crystal is characterized by an X-ray powder diffractogram comprising a signal at 13.2 ± 0.2 degrees two- theta. In some embodiments, the co-crystal is characterized by an X-ray powder diffractogram comprising a signal at 16.5 ± 0.2 degrees two-theta. In some embodiments, the co-crystal is characterized by an X-ray powder diffractogram comprising a signal at 18.6 ± 0.2 degrees two- theta. In some embodiments, the co-crystal is characterized by an X-ray powder diffractogram comprising a signal at 21.9 ± 0.2 degrees two-theta.

[0077] In some embodiments, the co-crystal is characterized by an X-ray powder diffractogram comprising a signal at two-theta values of 7.6 0.2, 9.0 0.2, 12.4 0.2, 13.2 0.2, 16.5 0.2, 18.6 0.2, and 21.9 0.2. In some embodiments, the co-crystal is characterized by an X-ray powder diffractogram comprising a signal at at least six two-theta values chosen from 7.6 0.2, 9.0 0.2, 12.4 0.2, 13.2 0.2, 16.5 0.2, 18.6 0.2, and 21.9 0.2. In some embodiments, the co-crystal is characterized by an X-ray powder diffractogram comprising a signal at at least five two-theta values chosen from 7.6 0.2, 9.0 0.2, 12.4 0.2, 13.2 0.2, 16.5 0.2, 18.6 0.2, and 21.9 0.2. In some embodiments, the co-crystal is characterized by an X-ray powder diffractogram comprising a signal at at least four two-theta values chosen from 7.6 0.2, 9.0 0.2, 12.4 0.2, 13.2 0.2, 16.5 0.2, 18.6 0.2, and 21.9 0.2. In some embodiments, the co-crystal is characterized by an X-ray powder diffractogram comprising a signal at at least three two-theta values chosen from 7.6 0.2, 9.0 0.2, 12.4 0.2, 13.2 0.2, 16.5 0.2, 18.6 0.2, and 21.9 0.2. In some embodiments, the co-crystal is characterized by an X-ray powder diffractogram comprising a signal at at least two two-theta values chosen from 7.6 0.2, 9.0 0.2, 12.4 0.2, 13.2 0.2, 16.5 0.2, 18.6 0.2, and 21.9 0.2. In some embodiments, the co-crystal is characterized by an X-ray powder diffractogram comprising aAttorney Docket No. 15496.0046-00304 signal at at least one two-theta value chosen from 7.6 0.2, 9.0 0.2, 12.4 0.2, 13.2 0.2, 16.5 0.2, 18.6 0.2, and 21.9 0.2.

[0078] In some embodiments, the co-crystal is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 7.

[0079] Some embodiments of the present disclosure provide a process for preparing a co-crystal comprising Compound (I):co-crystal former.

[0080] In some embodiments, the process comprises: mixing Compound (I) and a co-crystal former to form a dry mixture; dripping a solvent into the dry mixture to form a wet mixture; and grinding the wet mixture.

[0081] In some embodiments, the co-crystal former is chosen from pamoic acid, benzoic acid, saccharin, hippuric acid, ascorbyl palmitate, (+)-camphoric acid, 4-acetamido-benzoic acid, and cholic acid. In some embodiments, the co-crystal former is pamoic acid. In some embodiments, the co-crystal former is benzoic acid. In some embodiments, the co-crystal former is saccharin. In some embodiments, the co-crystal former is chosen from hippuric acid. In some embodiments, the co-crystal former is ascorbyl palmitate. In some embodiments, the co-crystal former is (+)-camphoric acid. In some embodiments, the co-crystal former is 4-acetamido-benzoic acid. In some embodiments, the co-crystal former is cholic acid.

[0082] In some embodiments, Compound (I) and the co-crystal former are present in the dry mixture in a 1:1 or 1:2 stoichiometric ratio. In some embodiments, Compound (I) and the co-crystal former are present in the dry mixture in a 1:1 stoichiometric ratio. In some embodiments, Compound (I) and the co-crystal former are present in the dry mixture in a 1:2 stoichiometric ratio.

[0083] In some embodiments, the solvent is an aqueous solvent. In some embodiments, the solvent is water.

[0084] In some embodiments, the solvent is an organic solvent. In some embodiments, the solvent is chosen from isopropyl alcohol, isopropyl acetate, toluene, and methyltertbutyl ether. In some embodiments, the solvent is toluene.Attorney Docket No. 15496.0046-00304

[0085] In some embodiments, the wet mixture is ground for at least 2 minutes. In some embodiments, the wet mixture is ground for 2 minutes. In some embodiments, the wet mixture is ground for less than 2 minutes.

[0086] In some embodiments, the process comprises: slurrying Compound (I) and a co-crystal former in a solvent to form a slurry, wherein the co-crystal former is chosen from pamoic acid, benzoic acid, saccharin, hippuric acid, ascorbyl palmitate, (+)-camphoric acid, 4-acetamido-benzoic acid, and cholic acid; and equilibrating the slurry.

[0087] In some embodiments, the co-crystal former is chosen from pamoic acid, benzoic acid, saccharin, hippuric acid, ascorbyl palmitate, (+)-camphoric acid, 4-acetamido-benzoic acid, and cholic acid. In some embodiments, the co-crystal former is pamoic acid. In some embodiments, the co-crystal former is benzoic acid. In some embodiments, the co-crystal former is saccharin. In some embodiments, the co-crystal former is chosen from hippuric acid. In some embodiments, the co-crystal former is ascorbyl palmitate. In some embodiments, the co-crystal former is (+)-camphoric acid. In some embodiments, the co-crystal former is 4-acetamido-benzoic acid. In some embodiments, the co-crystal former is cholic acid.

[0088] In some embodiments, Compound (I) and the co-crystal former are present in the slurry in a 1:1 or 1:2 stoichiometric ratio. In some embodiments, Compound (I) and the co-crystal former are present in the slurry in a 1:1 stoichiometric ratio. In some embodiments, Compound (I) and the co-crystal former are present in the slurry in a 1:2 stoichiometric ratio.

[0089] In some embodiments, the solvent is an aqueous solvent. In some embodiments, the solvent is water.

[0090] In some embodiments, the solvent is an organic solvent. In some embodiments, the solvent is chosen from isopropyl alcohol, isopropyl acetate, toluene, and methyltertbutyl ether. In some embodiments, the solvent is toluene.

[0091] In some embodiments, the slurry is equilibrated at a temperature between 20 ºC and 25 ºC. In some embodiments, the slurry is equilibrated at a temperature between 20 ºC and 25 ºC for less than 2 weeks. In some embodiments, the slurry is equilibrated at a temperature between 20 ºC and 25 ºC for 2 weeks. In some embodiments, the slurry is equilibrated at a temperature between 20 ºC and 25 ºC for more than 2 weeks.

[0092] In some embodiments, the slurry is equilibrated at an elevated temperature. In some embodiments, the elevated temperature is greater than 60 ºC. In some embodiments, the elevated temperature is between 60 ºC and 80 ºC. In some embodiments, the elevatedAttorney Docket No. 15496.0046-00304 temperature is between 65 ºC and 75 ºC. In some embodiments, the elevated temperature is 65 ºC. In some embodiments, the elevated temperature is 70 ºC.

[0093] In some embodiments, the slurry is equilibrated at an elevated temperature for less than 2 days. In some embodiments, the slurry is equilibrated at an elevated temperature for 2 days. In some embodiments, the slurry is equilibrated at an elevated temperature for more than 2 days.

[0094] In some embodiments, the process further comprises slowly cooling the slurry to a temperature between 20 ºC and 25 ºC.

[0095] In some embodiments, the process further comprises isolating the co-crystal.

[0096] Some embodiments of this disclosure relate to crystalline Form (III) of Compound (I):.

[0097] FIG. 8 shows an X-ray powder diffractogram for a crystalline material comprising crystalline Form (III) of Compound (I).

[0098] FIG. 9 shows a DSC thermogram of a crystalline material comprising crystalline Form (III) of Compound (I).

[0099] In some embodiments, crystalline Form (III) of Compound (I) is characterized by a DSC thermogram having a peak endotherm (melting temperature) between 110 °C and 115 °C. In some embodiments, crystalline Form (III) of Compound (I) is characterized by a DSC thermogram having a peak endotherm (melting temperature) at about 111.9 ºC. In some -85 J / g). In some 9.8 J / g).

[0100] In some embodiments, crystalline Form (III) of Compound (I) is characterized by a DSC thermogram substantially similar to that in FIG. 9.

[0101] FIG. 9 also shows a TGA thermal curve for a crystalline material comprising crystalline Form (III) of Compound (I).

[0102] In some embodiments, crystalline Form (III) of Compound (I) is characterized by a mass loss of less than 2 wt. % between 25 °C and 125 °C by thermogravimetric analysis. In some embodiments, crystalline Form (III) of Compound (I) is characterized by a mass loss of less than 1.75 wt. % between 25 °C and 125 °C by thermogravimetric analysis. In some embodiments, crystalline Form (III) of Compound (I) is characterized by a mass loss of less than 1.5 wt. % between 25 °C and 125 °C by thermogravimetric analysis. In someAttorney Docket No. 15496.0046-00304 embodiments, crystalline Form (III) of Compound (I) is characterized by a mass loss of less than 1.4 wt. % between 25 °C and 125 °C by thermogravimetric analysis. In some embodiments, crystalline Form (III) of Compound (I) is characterized by a mass loss of less than 1.3 wt. % between 25 °C and 125 °C by thermogravimetric analysis. In some embodiments, crystalline Form (III) of Compound (I) is characterized by a mass loss of less than 1.25 wt. % between 25 °C and 125 °C by thermogravimetric analysis. In some embodiments, crystalline Form (III) of Compound (I) is characterized by a mass loss of less than 1.2 wt. % between 25 °C and 125 °C by thermogravimetric analysis.

[0103] In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram comprising a signal at 4.7 0.2 degrees two-theta. In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram comprising a signal at 9.4 0.2 degrees two-theta. In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram comprising a signal at 14.1 0.2 degrees two-theta. In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram comprising a signal at 18.9 0.2 degrees two-theta.

[0104] In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram comprising a signal at two-theta values of 4.7 0.2, 9.4 0.2, 14.1 0.2, and 18.9 0.2. In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram comprising a signal at at least three two-theta values chosen from 4.7 0.2, 9.4 0.2, 14.1 0.2, and 18.9 0.2. In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram comprising a signal at at least two two-theta values chosen from 4.7 0.2, 9.4 0.2, 14.1 0.2, and 18.9 0.2. In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram comprising a signal at at least one two-theta values chosen from 4.7 0.2, 9.4 0.2, 14.1 0.2, and 18.9 0.2.

[0105] In some embodiments, crystalline Form (III) of Compound (I) is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 8.

[0106] Some embodiments of the present disclosure provide a process for preparing crystalline Form (III) of Compound (I):Attorney Docket No. 15496.0046-00304.

[0107] In some embodiments, the process comprises: dissolving Compound (I) in 1,2-dimethoxyethane to form a first solution; heating the first solution to an elevated temperature; adding an anti-solvent to the first solution to form a second solution; and cooling the second solution.

[0108] In some embodiments, the elevated temperature is between 50 ºC and 60 ºC. In some embodiments, the elevated temperature is 55 ºC.

[0109] In some embodiments, the anti-solvent is water.

[0110] In some embodiments, the anti-solvent is added to the first solution at a 1:1 ratio. In some embodiments, water is added to the first solution at a 1:1 ratio.

[0111] In some embodiments, the mixture is cooled to a temperature between 0 ºC and 10 ºC. In some embodiments, the mixture is cooled to 5 ºC.

[0112] In some embodiments, the process further comprises isolating crystalline Form (III) of Compound (I).

[0113] Claims or descriptions that include “or” or “and / or” between at least one 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 context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all the group members are present in, employed in, or otherwise relevant to a given product or process.

[0114] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which at least one limitation, element, clause, and descriptive term from at least one of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include at least one limitation found in any other claim that is dependent on the same base claim. Where elements are presented as lists, such as, 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 be understood that, in general, where the disclosure, or aspects of the disclosure, is / are referred to as comprising particular elements and / or features, embodiments of the disclosure or aspects of the disclosure consist, or consistAttorney Docket No. 15496.0046-00304 essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. Where ranges are given (such as, e.g., from [X] to [Y]), endpoints (such as, e.g., [X] and [Y] in the phrase “from [X] to [Y]”) are included unless otherwise indicated. 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 disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0115] Those of ordinary skill in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described herein. Such equivalents are intended to be encompassed by the following claims. EXAMPLES

[0116] The following examples are intended to be illustrative and are not meant in any way to limit the scope of the disclosure. Example 1: Preparation of Compound (I) A) Methyl 6-(2-fluoro-4-formylphenoxy)nicotinate

[0117] A mixture of methyl 6-fluoronicotinate (12.2 g), 3-fluoro-4-hydroxybenzaldehyde (11.0 g), potassium carbonate (16.3 g), and NMP (75 mL) was stirred for 16 hours at 90°C in a nitrogen atmosphere.

[0118] The mixture was diluted with ethyl acetate and water, and it was extracted with ethyl acetate. The organic layer was washed with 10% aqueous potassium carbonate solution and saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and crystallized from hexane to give the title compound (17.4 g).

[0119] MS: [M+H]+276.0. B) Methyl 6-(4-(difluoromethyl)-2-fluorophenoxy)nicotinate

[0120] (Diethylamino)sulfur trifluoride (11.5 mL) was added to a solution of methyl 6-(2- fluoro-4-formylphenoxy)nicotinate (8.00 g) in toluene (90 mL) at 0°C, and the mixture was stirred for one day at room temperature. After adding MeOH (10 mL) to stop the reaction, the mixture was diluted with 10% potassium carbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, passed through an NH silica gel pad, and concentrated under reduced pressure. The residueAttorney Docket No. 15496.0046-00304 was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (8.14 g).

[0121] MS: [M+H]+298.0. C) (6-(4-(difluoromethyl)-2-fluorophenoxy)pyridine-3-yl)methanol

[0122] Sodium borohydride (4.14 g) was added to a THF (60 mL) / MeOH (15 mL) suspension of methyl 6-(4-(difluoromethyl)-2-fluorophenoxy)nicotinate (8.14 g) at room temperature, and the mixture was stirred for 1 hour at 60°C. Sodium borohydride (4.14 g) was added at room temperature, and the mixture was stirred for an additional hour at 60°C. The mixture was diluted with water, and it was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (5.33 g).

[0123] MS: [M+H]+270.0.

[0124] Phosphorus tribromide (0.357 mL) was added to a mixture of (6-(4-difluoromethyl)-2- fluorophenoxy)pyridine-3-yl)methanol (920 mg) and THF (10 mL) at 0°C, and this was stirred for 16 hours at room temperature. After diluting the mixture with ethyl acetate, the solution was washed with sodium hydrogen carbonate aqueous solution and a saturated saline solution and dried over sodium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (977 mg).

[0125] MS: [M+H]+332.0. E) (4S,5S)-4-((tert-butyldimethylsilyl)oxy)-1-((6-(4-(difluoromethyl)-2- fluorophenoxy)pyridine-3-yl)methyl)-5-methylpyrrolidine-2-one

[0126] 1.6 M butyllithium-hexane solution (4.50 mL) was added dropwise to a mixture of (4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-methylpyrrolidine-2-one (1.65 g) and THF (24 mL) at -78°C, and this was stirred for 30 minutes at 0°C. 5-(bromomethyl)-2-(4-(difluoromethyl)- 2-fluorophenoxy)pyridine (2.39 g) was added to the mixture, and this was stirred for 20 minutes at room temperature. Afterward, this was stirred for 22 hours at 50°C and stirred for 48 hours at 40°C. The mixture was diluted with ethyl acetate and water and afterward it was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), to give the title compound (2.15 g).

[0127] MS: [M+H]+481.2.Attorney Docket No. 15496.0046-00304 F) (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5- methylpyrrolidine-2-one

[0128] A mixture of (4S,5S)-4-((tert-butyldimethylsilyl)oxy)-1-((6-(4-(difluoromethyl)-2- fluorophenoxy)pyridine-3-yl)methyl)-5-methylpyrrolidine-2-one (2.14 g) and 2 M hydrogen chloride-ethanol solution (40 mL) was stirred for 18 hours at room temperature. The mixture was concentrated, then the residue was diluted with sodium hydrogen carbonate aqueous solution. Afterward, this was extracted with ethyl acetate. The organic layer was washed with saturated saline solution. Afterward, this was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane and ethyl acetate / methanol), and a crude product (1.61 g) was obtained. The crude product was dissolved in warm ethyl acetate (5 mL), to the solution was added heptane (8 mL) dropwise at room temperature, and the mixture was stirred for 15 minutes. Heptane (16 mL) was added dropwise to the obtained mixture at room temperature, and the mixture was stirred for an additional 30 minutes. Heptane (16 mL) was added dropwise to the obtained mixture at room temperature, and the mixture was stirred for an additional 72 hours. The precipitate was collected by filtration and dried under reduced pressure to give the title compound (1.52 g) as crystals.

[0129] 1H NMR (300 MHz, DMSO-d6) Hz), 2.52-2.61 (1H, m), 3.45-3.55 (1H, m), 4.06-7.61 (1

[0130] X-ray powder diffraction patterns were generated using a Rigaku Ultima IV (Rigaku, Tokyo, Japan) with Copper K-alpha radiation.

[0131] The obtained crystal was characterized by having specific peaks at the two thetas of 5.1°±0.2°, 10.3°±0.2°,14.3°±0.2°, 16.5°±0.2°, 17.6°±0.2°, 22.3°±0.2° and 25.2°±0.2° degrees in a powder X-ray diffraction pattern. Example 2: Alternative Preparation of Compound (I)

[0132] After adding 2 M hydrogen chloride-ethanol solution (240 mL) dropwise to an ethanol (100 mL) solution of the (4S,5S)-4-((tert-butyldimethylsilyl)oxy)-1-((6-(4-(difluoromethyl)-2- fluorophenoxy)pyridin-3-yl)methyl)-5-methylpyrrolidine-2-one (140 g) obtained by steps A) to E) in example 2 at 0°C, 5% hydrogen chloride-methanol solution (218 mL) was added, the resultant mixture was slowly returned to room temperature and stirred overnight (using grained silica gel tube). The mixture was concentrated, ethyl acetate (500 mL) was then added to theAttorney Docket No. 15496.0046-00304 residue and cooled to 0°C, then aqueous sodium carbonate solution (500 mL) was slowly added, and the organic layer and the aqueous layer were isolated. The aqueous layer was washed with ethyl acetate (1000 mL), and the organic layer was isolated. The obtained organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. After dissolving the residue in ethyl acetate (500 mL), it was then filtered through NH silica gel pad (eluted with ethyl acetate (2000 mL)) and concentrated under reduced pressure. Toluene / ethyl acetate (1:0.5) was added to the residue and heated to 50°C while stirring, then filtered to obtain a crude product (90.5 g). After further concentrating the filtrate, the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (6.37 g).

[0133] All steps to this point were repeated 7 times to finally obtain 525g of the title compound.

[0134] Ethyl acetate (1630 mL) was added to the title compound (523 g) thus obtained, heated to 50°C, and stirred until dissolved. The solution was filtered and cooled to room temperature, then heptane (2120 mL) was added dropwise while stirring. After stirring the mixture for 1 hour, heptane (4230 mL) was added dropwise. Heptane (4230 mL) was added dropwise to the mixture, and the mixture was further stirred overnight. The precipitate was collected by filtration and washed with heptane, then dried under reduced pressure at 50°C to obtain the title compound (500 g) as crystals.

[0135] 1H NMR (300 MHz, DMSO-d6) Hz) 2.52-2.60 (1H, m) 3.45-3.54 (1H, m) 4.07- -

[0136] X-ray powder diffraction patterns were generated using a Rigaku Ultima IV (Rigaku, Tokyo, Japan) with Copper K-alpha radiation.

[0137] The obtained crystal was characterized by having specific peaks at the two thetas of 8.5°±0.2°, 11.2°±0.2°,13.5°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, 21.5°±0.2° and 22.5°±0.2° degrees in a powder X-ray diffraction pattern. Example 3: X-Ray Powder Diffraction (XRPD) Measurements

[0138] XRPD analysis for samples described in Examples 5-7 was performed on a Rigaku Powder X-Ray Diffractometer Miniflex Plus Serial Number ZD01936. For analysis, about 1 to 5 mg of sample was added to a XRPD zero-background sample holder. The powder was pressed down gently with a piece of weigh paper, and the sample holder was placed in the sample changer.Attorney Docket No. 15496.0046-00304

[0139] Run Parameters: Miniflex Counter Detector, Kb Filter, Scan Axis Theta / 2-Theta, Mode Continuous, Start (deg) 3.0, Stop (deg) 45.0, Step (deg) 0.020, Speed (deg / min) 1.0, Spin-yes, Voltage (kV) 30, Current (mA) 15. Example 4: Differential Scanning Calorimetry (DSC) and Thermal Gravimetric Analysis (TGA):

[0140] DSC and TGA analysis for samples described in Examples 5-7 was performed on TA Instruments Discovery 2500 calorimeter with serial number: 2500-00547 (DSC) and Discovery5500 with serial number: 5500-0126 (TGA). For DSC analysis, the weight of a Tzero pan and aTzerolid were recorded. About 1 to 3 mg of sample was weighed into the TzeroPan, and the Tzerolid was pressed on with tweezers. The pan was transferred to the DSC autosampler for analysis. The method for analysis was a ramp at 10 °C / min to about 350 °C or just under the degradation temperature as determined by TGA analysis. The reference pan was prepared with the same procedures, absent the sample.

[0141] For TGA analysis, a standard aluminum sample pan was placed into the platinum TGA pan, and the blank was tared with the instrument. About 1 to 5 mg of sample was added to the standard aluminum pan and analyzed at 10 °C / min up to about 400 °C, or until fully degraded. Example 5: Co-Crystal Screening

[0142] Samples were prepared by combining a 1:1 stoichiometric amount of crystalline Compound (I) starting material substantially similar to that produced by the process of Example 2 (FIGs. 1, 2) and a Generally Regarded as Safe (GRAS) co-crystal former. Collected solids were initially analyzed using XRPD and further characterized upon identification of a new solid form.

[0143] Five methods were used to screen for co-crystal formation. A) Water-Mediated Drip Grinding Method

[0144] In a water-mediated drip grinding method, Compound (I) and a co-crystal former were mixed in a mortar at a 1:1 stoichiometric ratio. About 0.5 mL of water was dripped into the mortar, and the components were firmly ground for about 2 minutes.

[0145] The following co-formers were tested: L-aspartic; adipic acid; gluconic acid (sodium salt); D-glucuronic acid; pamoic acid; tromethamine; L-malic acid; maleic acid; succinic acid; L-tartaric acid; fumaric acid; citric acid; benzoic acid; lactamide; nicotinamide; urea; saccharin; ethyl maltol; hippuric acid; benzamide; glycolamide; 4-acetamidobenzoic acid; ascorbylAttorney Docket No. 15496.0046-00304 palmitate; (+)-camphoric acid; betaine; L-alanine; calcium chloride; L-carnitine; cholic acid; 4-(2-hydroxyethyl)morpholine; meglumine; acesulfame K; and lactitol monohydrate.

[0146] Resulting samples were analyzed by XRPD. Relative to the crystalline Compound (I) starting material, new peaks associated with the presence of the co-crystal former, as a mixture and not a new solid form, were observed in samples prepared with: L-aspartic; adipic acid; gluconic acid (sodium salt); pamoic acid; tromethamine; maleic acid; succinic acid; fumaric acid; benzoic acid; lactamide; nicotinamide; saccharin; ethyl maltol; hippuric acid; benzamide; 4-acetamidobenzoic acid; ascorbyl palmitate; (+)-camphoric acid; L-alanine; cholic acid; and acesulfame K. B) Slurry Method

[0147] In a slurry method, Compound (I) and a co-crystal former were slurried in neat water or a neat organic solvent at a 1:1 stoichiometric ratio and equilibrated at 25 ºC for about 2 weeks.

[0148] The following co-formers were tested using neat water as the solvent: L-aspartic; adipic acid; gluconic acid (sodium salt); D-glucuronic acid; pamoic acid; tromethamine; L-malic acid; maleic acid; succinic acid; L-tartaric acid; fumaric acid; citric acid; benzoic acid; lactamide; nicotinamide; urea; saccharin; ethyl maltol; hippuric acid; benzamide; glycolamide; 4-acetamidobenzoic acid; ascorbyl palmitate; (+)-camphoric acid; betaine; L-alanine; calcium chloride; L-carnitine; cholic acid; 4-(2-hydroxyethyl)morpholine; meglumine; acesulfame K; and lactitol monohydrate.

[0149] Resulting samples were analyzed by XRPD. Relative to the crystalline Compound (I) starting material, new peaks associated with the presence of the co-crystal former, as a mixture and not a new solid form, were observed in samples prepared with: pamoic acid; benzoic acid; saccharin; hippuric acid; ascorbyl palmitate; and cholic acid.

[0150] Compound (I) and cholic acid were also slurried at a 1:1 stoichiometric ratio in the following neat organic solvents: isopropyl alcohol; isopropyl acetate; toluene; and methyltertbutyl ether. No solids precipitated when isopropyl alcohol was used as a solvent. In isopropyl acetate, only cholic acid was detected in the final XRPD form. In methyltertbutyl ether, cholic acid was the dominant presence in the final form, but peaks associated with Compound (I) were also observed. New peaks were observed when toluene was used as the solvent. C) Heated Slurry (Heat Cycle) Method

[0151] In a heated solvent (heat cycle) slurry method, Compound (I) and cholic acid were slurried in neat water at a 1:1 or 1:2 stoichiometric ratio, heated to 70 ºC and held at elevatedAttorney Docket No. 15496.0046-00304 temperature for about 2 days, and slowly cooled to 25 ºC. A ripened co-crystal pattern was observed at a 1:1 stoichiometric ratio of Compound (I) to cholic acid. A weakened co-crystal pattern was observed at a 1:2 stoichiometric ratio of Compound (I) to cholic acid. D) DSC Thermal Method

[0152] In a DSC thermal method, Compound (I) and cholic acid were mixed in a DSC pan at a 1:1 stoichiometric ratio, heated past the melting point of Compound (I), cooled to 25 ºC, and reheated. Although a new melt was observed at 191 ºC, isolation suggested the sample was converting to pure cholic acid. Example 6: Characterization of Co-Crystals Comprising Cholic Acid

[0153] Samples prepared in Example 5 by slurrying Compound (I) and cholic acid (1:1) in neat water and equilibrating for 2 weeks (A), slurrying Compound (I) and cholic acid in neat water and heat cycling at a 1:1 (B) or 1:2 (C) stoichiometric ratio, or slurrying Compound (I) and cholic acid (1:1) in neat toluene and equilibrating for 2 weeks (D) produced a novel co-crystal form. Consistent XRPD patterns were observed for Samples A, B, and C (FIGs. 3A, 3B), with the first two unique peaks being minimal in size but detectable in Sample C. A similar XRPD pattern was also observed for Sample D that was heated up to 70 ºC in a water slurry and then cooled to room temperature (D’) (FIG. 4).

[0154] The cholic acid co-crystal (Samples A-D’) was characterized by having specific peaks at the two thetas of 7.6°±0.2°, 9.0°±0.2°,12.4°±0.2°, 13.2°±0.2°, 16.5°±0.2°, 18.6°±0.2°, and 21.9°±0.2° degrees in a powder X-ray diffraction pattern.

[0155] DSC analysis of Samples C and D’ showed a similar onset melt of 96-100°C in both samples, followed by exothermic events likely associated with the recrystallization of cholic acid, which later melts around its expected melting temperature (about 200 °C) (FIG.5).

[0156] 1H NMR characterization of Sample C confirmed co-crystal formation with cholic acid at a 1:1 stoichiometric ratio.

[0157] Cholic acid 1H NMR (400 MHz, DMSO-d6 - 1.00 (m, 7H),1.12 - 1.47 (m, 11H), 1.60 - 1.84 (m, 6H), 1.98 (td, J - 2.27 (m, 4H),3.12 - 3.23 (m, 1H), 3.61 (br s, 1H), 3.78 (br d, J J(d, J J

[0158] Compound (I) starting material 1H NMR (400 MHz, DMSO-d6 JHz, 3H), 2.15 (dd, J J - 3.59 (m,1H), 4.11 (d, J - 4.20 (m, 1H), 4.60 (d, J JAttorney Docket No. 15496.0046-00304Hz, 1H), 7.07 (t, J - 7.17 (m, 1H), 7.40 - 7.55 (m, 2H), 7.61 (d, JHz, 1H), 7.74 (dd, J J

[0159] Co-crystal1H NMR (400 MHz, DMSO-d6d, J J J J7.07 (t, J J J JHz, 1H), 7.74 (dd, J JExample 7: Preparation of Crystalline Form (III)

[0160] Crystalline Compound (I) starting material substantially similar to that produced by the process of Example 2 (FIGs. 1, 2) was added to an HPLC vial comprising 200-500 μL of 1,2-dimethoxyethane (DME). Compound (I) was freely soluble in 1,2-DME, with an observed solubility of at least 363.2 mg / mL.

[0161] Vials were placed in ReactiTherm aluminum blocks with stir bars. Temperature was set to 55 ºC, with continuous stirring at a medium rate for approximately1 hour. Water was added in a 1:1 ratio by volume to the 1,2-DME, and the mixture was cooled to 5 ºC. The resulting precipitate was filtered and dried with 0.22 μm centrifuge filters. The collected solid comprising crystalline Form (III) of Compound (I) was analyzed using XRPD, DSC, and TGA (FIGs. 8, 9).

Claims

Attorney Docket No. 15496.0046-00304 What is claimed is:

1. A co-crystal comprising Compound (I):co-crystal former.

2. The co-crystal according to claim 1, wherein the co-crystal former is chosen from pamoic acid, benzoic acid, saccharin, hippuric acid, ascorbyl palmitate, (+)-camphoric acid, 4-acetamido-benzoic acid, and cholic acid.

3. The co-crystal according to claim 1 or 2, wherein Compound (I) and the co-crystal former are present in a 1:1 stoichiometric ratio.

4. A co-crystal comprising Compound (I):and cholic acid.

5. The co-crystal according to claim 4, wherein Compound (I) and cholic acid are present in a 1:1 stoichiometric ratio.

6. The co-crystal according to claim 4 or 5, characterized by an X-ray powder diffractogram comprising a signal at at least two two-theta values chosen from 7.6 0.2, 9.0 0.2, 12.4 0.2, 13.2 0.2, 16.5 0.2, 18.6 0.2, and 21.9 0.

2.

7. The co-crystal according to any one of claims 4-6, characterized by an X-ray powder diffractogram comprising a signal at at least three two-theta values chosen from 7.6 0.2, 9.0 0.2, 12.4 0.2, 13.2 0.2, 16.5 0.2, 18.6 0.2, and 21.9 0.2.Attorney Docket No. 15496.0046-00304 8. The co-crystal according to any one of claims 4-7, characterized by an X-ray powder diffractogram comprising a signal at at least four two-theta values chosen from 7.6 0.2, 9.0 0.2, 12.4 0.2, 13.2 0.2, 16.5 0.2, 18.6 0.2, and 21.9 0.

2.

9. The co-crystal according to any one of claims 4-8, characterized by an X-ray powder diffractogram comprising a signal at at least five two-theta values chosen from 7.6 0.2, 9.0 0.2, 12.4 0.2, 13.2 0.2, 16.5 0.2, 18.6 0.2, and 21.9 0.

2.

10. The co-crystal according to any one of claims 4-9, characterized by an X-ray powder diffractogram comprising a signal at at least six two-theta values chosen from 7.6 0.2, 9.0 0.2, 12.4 0.2, 13.2 0.2, 16.5 0.2, 18.6 0.2, and 21.9 0.

2.

11. The co-crystal according to any one of claims 4-10, characterized by an X-ray powder diffractogram substantially similar to that in FIG.

7.

12. The co-crystal according to any one of claims 4-11, characterized by an DSC thermogram substantially similar to that in FIG.

6.

13. The co-crystal according to any one of claims 4-12, characterized by a DSC thermogram comprising a peak endotherm (melting temperature) at a temperature between 96 °C and 101 °C.

14. The co-crystal according to any one of claims 4-13, characterized by a mass loss of less than 1.5 wt. % between 25 °C and 125 °C by thermogravimetric analysis.

15. Crystalline Form (III) of Compound (I):.Attorney Docket No. 15496.0046-00304 16. Crystalline Form (III) according to claim 15, characterized by an X-ray powder diffractogram comprising a signal at at least two two-theta values chosen from 4.7 0.2, 9.4 0.2, 14.1 0.2, and 18.9 0.

2.

17. Crystalline Form (III) according to claim 15 or 16, characterized by an X-ray powder diffractogram comprising a signal at at least three two-theta values chosen from 4.7 0.2, 9.4 0.2, 14.1 0.2, and 18.9 0.

2.

18. Crystalline Form (III) according to any one of claims 15-17, characterized by an X-ray powder diffractogram substantially similar to that in FIG.

8.

19. Crystalline Form (III) according to any one of claims 15-18, characterized by a DSC thermogram comprising a peak endotherm (melting temperature) at about 111.9 ºC.

20. Crystalline Form (III) according to any one of claims 15-18, characterized by a mass loss of less than 1.5 wt. % between 50 °C and 125 °C by thermogravimetric analysis.

21. A pharmaceutical composition comprising: at least one solid form of Compound (I) according to any one of claims 1-20; and at least one pharmaceutically acceptable excipient.

22. A solid form of Compound (I) according to any one of claims 1-20 or a pharmaceutical composition according to claim 15 for use in prevention or treatment of depression, bipolar disorder, migraine, pain, or peripheral symptoms of dementia.

23. A method of antagonizing an NMDA receptor containing an NR2B subunit in a subject in need thereof, comprising administering a therapeutically effective amount of at least one solid form of Compound (I) according to any one of claims 1-20 to the subject.

24. A method for preventing or treating depression, bipolar disorder, migraine, pain, or peripheral symptoms of dementia in a subject in need thereof, comprising administering a therapeutically effective amount of at least one solid form of Compound (I) according to any one of claims 1-20 to the subject.Attorney Docket No. 15496.0046-00304 25. Use of at least one solid form of Compound (I) according to any one of claims 1-20 in the manufacture of a prophylactic or therapeutic agent for depression, bipolar disorder, migraine, pain, or peripheral symptoms of dementia.

26. A process for preparing the co-crystal according to claim 1, comprising: mixing Compound (I) and a co-crystal former to form a dry mixture, wherein the co-crystal former is chosen from pamoic acid, benzoic acid, saccharin, hippuric acid, ascorbyl palmitate, (+)-camphoric acid, 4-acetamido-benzoic acid, and cholic acid; dripping a solvent into the dry mixture to form a wet mixture; and grinding the wet mixture.

27. The process according to claim 26, wherein Compound (I) and the co-crystal former are present in the dry mixture in a 1:1 stoichiometric ratio.

28. The process according to claim 26 or 27, wherein the solvent is water.

29. The process according to any one of claims 26-28, wherein the wet mixture is ground for 2 minutes.

30. A process for preparing the co-crystal according to claim 1, comprising: slurrying Compound (I) and a co-crystal former in a solvent to form a slurry, wherein the co-crystal former is chosen from pamoic acid, benzoic acid, saccharin, hippuric acid, ascorbyl palmitate, (+)-camphoric acid, 4-acetamido-benzoic acid, and cholic acid; and equilibrating the slurry.

31. The process according to claim 30, wherein Compound (I) and the co-crystal former are present in the slurry in a 1:1 or 1:2 stoichiometric ratio.

32. The process according to claim 30 or 31, wherein the solvent is water.

33. The process according to claim 30 or 31, wherein the solvent is chosen from organic solvents.Attorney Docket No. 15496.0046-00304 34. The process according to any one of claims 30-33, wherein the slurry is equilibrated at a temperature between 20 ºC and 25 ºC.

35. The process according to any one of claims 30-34, wherein the slurry is equilibrated for 2 weeks.

36. The process according to any one of claims 30-33, wherein the slurry is equilibrated at an elevated temperature.

37. The process according to claim 36, further comprising slowly cooling the slurry to a temperature between 20 ºC and 25 ºC.

38. The process according to any one of claims 26-37, further comprising isolating the co-crystal according to claim 1.

39. A process for preparing crystalline Form (III) of Compound (I), comprising: dissolving Compound (I) in 1,2-dimethoxyethane to form a first solution; heating the first solution to an elevated temperature; adding an anti-solvent to the first solution to form a second solution; and cooling the second solution.

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