Positive allosteric modulator of the metabotropic glutamate receptor subtype 2 receptor, synthesis and solid forms thereof

Abstract

Described herein are solid forms of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate and its pharmaceutical composition for the treatment of disease.

Description

WSGR Docket No.42256-608.601 POSITIVE ALLOSTERIC MODULATOR OF THE METABOTROPIC GLUTAMATE RECEPTOR SUBTYPE 2 RECEPTOR, SYNTHESIS AND SOLID FORMS THEREOF CROSS REFERENCE

[0001] This Application claims the benefit of U.S. Provisional Application No.63 / 514,767 filed on July 20, 2023, the content of which is incorporated by reference herein in its entirety. STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under U01 DA041731 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND

[0003] Metabotropic receptors belong to the family of G-protein-coupled receptors and are coupled to systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D, increases or decreases in cAMP formation, and changes in ion channel function. Metabotropic glutamate receptors (mGluRs) are divided into three groups based on amino acid sequence homology, transduction mechanism and binding selectivity: Group I, Group II and Group III. Glutamate receptors play a role in numerous neurological, neurodegenerative, psychiatric, and psychological disorders, and a variety of mammalian disease states are associated with aberrant activity of these receptors. Thus, modulators of mGluRs are promising targets for a variety of therapeutic indications including depression, schizophrenia and substance abuse such as cocaine addiction. SUMMARY

[0004] In one aspect, described herein is a solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1- oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate.

[0005] In one embodiment, solid form is polymorph Form I of sodium 4-chloro-3’-(((2- cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1’-biphenyl]-3-carboxylate.

[0006] Some embodiments provide a solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1- oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate having at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern, in terms of 2θ, substantially the same as shown in FIG.1; orWSGR Docket No.42256-608.601 (b) an X-ray powder diffraction (XRPD) pattern comprising at least two, three, four, five, six, seven, eight, nine or ten peaks, in terms of 2θ, selected from 5.8° ± 0.2°, 7.1° ± 0.2°, 8.5° ± 0.2°, 12.7° ± 0.2°, 14.3° ± 0.2°, 16.2° ± 0.2°, 17.1° ± 0.2°, 17.8°± 0.2°, 19.7°± 0.2°, 21.5°± 0.2°, 22.3°± 0.2°, 23.2°± 0.2°, 24.1°± 0.2°, 27.0°± 0.2°, 29.6°± 0.2° and 34.1°± 0.2°.

[0007] Some embodiments provide a solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1- oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate having at least one of the following properties: (a) a thermo-gravimetric analysis (TGA) profile substantially similar to the one set forth in FIG.2; or (b) a TGA profile showing 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0% or less weight loss, or a weight loss within a range defined by any of the preceding values out to about 147°C.

[0008] Some embodiments provide a solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1- oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate having at least one of the following properties: (a) a DSC thermogram substantially similar to the one set forth in FIG.3; (b) a DSC thermogram with an endotherm with an extrapolated onset temperature of 277°C, 278°C, 279°C, 280°C, 281°C, 282°C 283°C, 284°C, 285°C, 286°C, or 287°C, or an onset temperature within a range defined by any of the preceding values; or (c) a DSC thermogram with an endotherm having an extrapolated onset temperature of 277.5°C, 278.5°C, 279.5°C, 280.5°C, 281.5°C, 282.5°C 283.5°C, 284.5°C, 285.5°C, 286.5°C, or 287.5°C, or an extrapolated onset temperature within a range defined by any of the preceding values.

[0009] Some embodiments provide a process for preparing sodium 4-chloro-3'-(((2-cyclopentyl- 1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate (Compound I):comprising contacting Compound F:WSGR Docket No.42256-608.601or a salt thereof, with a first base in the presence of a first solvent, wherein R1is H or -C1-C6alkyl.

[0010] In some embodiments, the first base is selected from Na2CO3, NaHCO3, NaOH, NaOCH3, NaOCH2CH3, NaOCH2CH2CH3, NaOCH(CH3)2, and NaOC(CH3)3.

[0011] In some embodiments, the first solvent is selected from water, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, and any combination thereof.

[0012] Some embodiments provide a process for preparing Compound F by contacting Compound E:with Compound B:Compound B in the presence of a second base and a second solvent, wherein X is OS(O)2Y, Cl, Br, or I; and Y is CH3, CF3, 4-methylbenzene, or 4-bromobenzene.

[0013] In some embodiments, the second base comprises at least one species selected from the group consisting of NaH, KH, Cs2CO3, CsHCO3, CsOH, K2CO3, KHCO3, KOH, Na2CO3, NaHCO3and NaOH.

[0014] In some embodiments, the second solvent is isopropyl acetate, methyl tert-butyl ether, toluene, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetone, acetonitrile, 1,4- dioxane, or any combination thereof.

[0015] Some embodiments provide a process for preparing Compound B:WSGR Docket No.42256-608.601Compound B comprising demethylating Compound A:Compound A, or a salt thereof, in the presence of an acid.

[0016] In some embodiments, the acid is selected from HBr and BBr3.

[0017] In some embodiments, a solid dosage form comprises a dose of sodium 4-chloro-3'-(((2- cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate (Compound I).

[0018] In some embodiments, the solid dosage form comprises a capsule, tablet, dragée, powder, and / or granule.

[0019] Some embodiments provide a method of treating a disease, disorder or condition in a mammal that would benefit from positive allosteric modulation of the metabotropic glutamate receptor, comprising administering to the individual a therapeutically effective amount of a solid form of Compound I. INCORPORATION BY REFERENCE

[0020] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the extent applicable and relevant and to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] FIG. 1. Illustrates an X-ray powder diffraction (XRPD) pattern of crystalline sodium 4- chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate (Compound I), Form I.

[0022] FIG.2. Illustrates a thermogravimetric analysis (TGA) thermogram of crystalline sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate (Compound I), Form I.WSGR Docket No.42256-608.601

[0023] FIG. 3. Illustrates a differential scanning calorimetry (DSC) thermogram of sodium 4- chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate (Compound I), Form I. DETAILED DESCRIPTION

[0024] The disclosure provides synthesis of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin- 5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate, solid forms thereof, and methods of using these compounds and compositions as positive allosteric modulators of Group II metabotropic glutamate receptors (mGluII receptors). The compounds and compositions disclosed herein are useful, for example, for treating CNS disorders associated with mGluII receptors including schizophrenia, anxiety, addiction, e.g. cocaine addiction, nicotine addiction, and the like.

[0025] Good manufacturing practices are needed for large scale manufacture of clinically useful drug candidates. Provided herein are certain processes and methods for the manufacture of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate (Compound I).

[0026] Provided herein is a process useful for preparing a sodium 4-chloro-3'-(((2-cyclopentyl-1- oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate and its intermediates. In particular, provided herein is a process and method for the manufacture of sodium 4-chloro-3'-(((2- cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate (Compound I), for example as shown in scheme 1.WSGR Docket No.42256-608.601

[0027] In one aspect, described herein is a process for preparing sodium 4-chloro-3'-(((2- cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate (Compound I):comprising contacting Compound F:or a salt thereof, with a first base in the presence of a first solvent, wherein R1is H or -C1-C6alkyl.In some embodiments, R1is H. In some embodiments, R1is -CH3, -CH2CH3, - CH2CH2CH3, or -CH(CH3)2. In some embodiments, R1is -CH3 or -CH2CH3. In some embodiments, R1is-CH3. In some embodiments, R1is-CH2CH3.

[0028] In some embodiments, the first base is a sodium base. In some embodiments, the sodium base is an inorganic sodium base. In some embodiments, the sodium base is Na2CO3, NaHCO3 or NaOH. In some embodiments, the sodium base is Na2CO3. In some embodiments, the sodium base is NaOH. In some embodiments, the sodium base is an organic sodium base. In some embodiments, the organic sodium base is sodium 2-ethylhexanoate, sodium hexanoate, sodium dodecanoate, sodium myristate, sodium octanoate, sodium decanoate, sodium palmitate, sodium stearate, NaOCH3, NaOCH2CH3, NaOCH2CH2CH3, NaOCH(CH3)2, or NaOC(CH3)3. In some embodiments, the organic sodium base is sodium 2-ethylhexanoate, sodium hexanoate, sodium dodecanoate, sodium myristate, sodium octanoate, sodium decanoate, sodium palmitate, or sodium stearate. In some embodiments, the organic sodium base is sodium 2-ethylhexanoate, sodium hexanoate, or sodium dodecanoate. In some embodiments, the organic sodium base is sodium 2-ethylhexanoate. In some embodiments, the organic sodium base is NaOCH3, NaOCH2CH3, NaOCH2CH2CH3, NaOCH(CH3)2, or NaOC(CH3)3. In some embodiments, the organic sodium base is NaOCH3. In some embodiments, the first solvent is water. In some embodiments, the first solvent is 2-methyltetrahydrofuran, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, or any combination thereof.WSGR Docket No.42256-608.601

[0029] In some embodiments, the process further comprising (1) precipitating Compound I; and (2) isolating Compound I. In some embodiments, the isolating comprises removing the first solvent. In some embodiments, the isolating comprises removing the first solvent by filtration. In another aspect, described herein is the process further comprising preparing Compound F by contacting Compound E:with Compound B:Compound B in the presence of a second base and a second solvent, wherein X is OS(O)2Y, Cl, Br, or I; and Y is CH3, CF3, 4-methylbenzene, or 4-bromobenzene. In some embodiments, X is Cl, Br or OS(O)2Y. In some embodiments, X is Br. In some embodiments, the second base is an inorganic base, organic base, or combinations thereof. In some embodiments, the second base comprises at least one species selected from the group consisting of NaH, KH, Cs2CO3, CsHCO3, CsOH, K2CO3, KHCO3, KOH, Na2CO3, NaHCO3and NaOH. In some embodiments, the second base is K2CO3. In some embodiments, the second base is Na2CO3.

[0030] In some embodiments, the contacting Compound E takes place in the presence of a metal halide. In some embodiments, the metal halide comprises KI or NaI. In some embodiments, the metal halide is KI. In some embodiments, the metal halide is NaI.

[0031] In some embodiments, the second solvent comprises isopropyl acetate, methyl tert-butyl ether, toluene, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetone, acetonitrile or 1,4-dioxane. In some embodiments, the second solvent is isopropyl acetate, methyl tert-butyl ether, toluene, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetone, acetonitrile, 1,4-dioxane, or any combination thereof. In some embodiments, the second solvent is dimethylformamide. In some embodiments, the second solvent is dimethylsulfoxide. In some embodiments, the second solvent is acetonitrile.WSGR Docket No.42256-608.601

[0032] In some embodiments, described herein is the process for preparing the pharmaceutical composition, comprising admixing the solid Form I, and a pharmaceutically acceptable excipient.

[0033] In some embodiments, the process for preparing the pharmaceutical composition further comprising compressing and / or grinding the solid form to a bulk density of 0.10 g / mL, 0.15 g / mL, 0.20 g / mL, 0.25 g / mL, 0.30 g / mL, 0.35 g / mL, 0.40 g / mL, or more, or to a bulk density within a range defined by any of the preceding values. In some embodiments, the process for preparing the pharmaceutical composition comprising deagglomerating the solid form, thereby producing a flowable powder form of Compound I. In some embodiments, the pharmaceutically acceptable excipient comprises a binder, filler, and / or disintegrate. In some embodiments, the pharmaceutically acceptable excipient comprises a starch or a gelatin. In some embodiments, the method for preparing a pharmaceutical composition comprising admixing the solid form of compound I and a pharmaceutically acceptable excipient.

[0034] In some aspects, described herein is the process further comprising preparing Compound B:comprising demethylating Compound A:Compound A, or a salt thereof, in the presence of an acid. In some embodiments, the acid is an inorganic acid. In some embodiments, the inorganic acid is HBr or BBr3. In some embodiments, the inorganic acid is HBr. In some embodiments, the process further comprising a third solvent. In some embodiments, the third solvent is water or acetic acid. In some embodiments, the third solvent is dichloromethane.

[0035] Some embodiments provide a solid dosage form comprising the solid Form I, wherein the solid Form I comprises a dose of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5- yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate (Compound I). In some embodiments, the solid dosage form comprises a capsule, tablet, dragée, powder, and / or granule. In some embodiments, the solid dosage form comprises a capsule.WSGR Docket No.42256-608.601

[0036] In some embodiments, the solid dosage form comprises a dose of sodium 4-chloro-3'-(((2- cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate (Compound I) that is from about 60 mg to about 600 mg based on the weight of the free base. In some embodiments, the solid dosage form comprises a dose of sodium 4-chloro-3’-(((2-cyclopentyl-1-oxoisoindolin- 5-yl)oxy)methyl)-[1,1’-biphenyl]-3-carboxylate (Compound I) that is from about 75 mg to about 500 mg based on the weight of the free base.

[0037] In some embodiments, the solid dosage form comprises a dose of sodium 4-chloro-3’-(((2- cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1’-biphenyl]-3-carboxylate (Compound I) that is from about 150 mg to about 350 mg based on the weight of the free base. In some embodiments, the solid dosage form comprises a dose of sodium 4-chloro-3’-(((2-cyclopentyl-1-oxoisoindolin- 5-yl)oxy)methyl)-[1,1’-biphenyl]-3-carboxylate (Compound I) that is about 150 mg based on the weight of the free base. In some embodiments, the solid dosage form comprises a dose of sodium 4-chloro-3’-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1’-biphenyl]-3-carboxylate (Compound I) that is about 300 mg based on the weight of the free base.

[0038] In some embodiments, the solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1- oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate is characterized by having an X- ray powder diffraction (XRPD) pattern comprising characteristic peaks, in terms of 2θ, at 5.8°± 0.2°, 8.5°± 0.2°, and 19.7°± 0.2°. In some embodiments, the solid form of sodium 4-chloro-3'- (((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate is characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks, in terms of 2θ, at 7.1°± 0.2°, 17.1°± 0.2°, 21.5°± 0.2°, 23.2°± 0.2°, and 24.1°± 0.2°. In some embodiments, the solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'- biphenyl]-3-carboxylate has a bulk density of 0.10 g / mL, 0.15 g / mL, 0.20 g / mL, 0.25 g / mL, 0.30 g / mL, 0.35 g / mL, or 0.40 g / mL, or a bulk density within a range defined by any of the preceding values. In some embodiments, solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin- 5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate has a bulk density of 0.20 g / mL, 0.21 g / mL, 0.22 g / mL, 0.23 g / mL, 0.24 g / mL, 0.25 g / mL, 0.26 g / mL, or 0.27 g / mL, or a bulk density within a range defined by any of the preceding values.

[0039] In some embodiments, solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin- 5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate has a bulk density of 0.25 g / mL In some embodiments, the solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5- yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate has a tap density of 0.20 g / mL, 0.25 g / mL, 0.30 g / mL, 0.35 g / mL, 0.40 g / mL, 0.45 g / mL, or 0.50 g / mL, or a tap density within a range defined by any of the preceding values.WSGR Docket No.42256-608.601

[0040] In some embodiments, the solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1- oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate has an average particle size of 2.5 μm, 3.0 μm, 3.5 μm, 4.0 μm, 4.5 μm, 5.0 μm, 5.5 μm, 6.0 μm, 6.5 μm, 7.0 μm, 7.5 μm, 8.0 μm, or 8.5 μm, or an average particle size within a range defined by any of the preceding values. In some embodiments, the solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5- yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate has an average particle size of about 3.5 μm.

[0041] In some embodiments, the pharmaceutical composition is provided as a powder or as a capsule. In some embodiments, the pharmaceutical composition is provided as a powder-in-a- capsule (PIC).

[0042] In some embodiments, the pharmaceutical composition comprising no more than about 5% of total impurities. In some embodiments, the pharmaceutical composition comprising no more than 500 ppm, 100 ppm, 50 ppm, 40 ppm, 30 ppm, 20 ppm, 10 ppm, 5 ppm or 1 ppm, or ppm within a range defined by any of the preceding values, of methyl 3'-(bromomethyl)-4-chloro- [1,1'-biphenyl]-3-carboxylate, 2-cyclopentyl-5-hydroxyisoindolin-1-one, methyl 4-chloro-3'- (dibromomethyl)-[1,1'-biphenyl]-3-carboxylate, methyl 2-(bromomethyl)-4-methoxybenzoate, methyl bromide, methyl 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'- biphenyl]-3-carboxylate, sodium 3'-(bis((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-4- chloro-[1,1'-biphenyl]-3-carboxylate, methyl 3'-(bis((2-cyclopentyl-1-oxoisoindolin-5- yl)oxy)methyl)-4-chloro-[1,1'-biphenyl]-3-carboxylate or methyl 4′-chloro-2- (dibromomethyl)[1,1′-biphenyl]-4-carboxylate based on Compound I.

[0043] In some embodiments, the pharmaceutical composition comprising no more than 10000 ppm, 5000 ppm, 4000 ppm, 3000 ppm, 2000 ppm, 1000 ppm, 750 ppm or 500 ppm or ppm within a range defined by any of the preceding values, of isopropanol, ethanol, acetonitrile, dichloromethane, isopropyl acetate, n-heptane, dimethyl sulfoxide, ethyl acetate, methyl tert-butyl ether, or 2-methyltetrahydrofuran based on Compound I.

[0044] In some embodiments, the pharmaceutical composition comprising at least 100 ppm, 75 ppm, 50 ppm, 40 ppm, 30 ppm, 20 ppm, 10 ppm or 5 ppm, or ppm within a range defined by any of the preceding values, of isopropanol, ethanol, acetonitrile, dichloromethane, isopropyl acetate, n-heptane, dimethyl sulfoxide, ethyl acetate, methyl tert-butyl ether, or 2-methyltetrahydrofuran based on Compound I.

[0045] In some aspects, solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5- yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate (Compound I) is polymorph Form I.WSGR Docket No.42256-608.601

[0046] In some embodiments, the solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1- oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate has at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern, in terms of 2θ, substantially the same as shown in FIG.1; or (b) an X-ray powder diffraction (XRPD) pattern comprising at least two, three, four, five, six, seven, eight, nine or ten peaks, in terms of 2θ, selected from 5.8° ± 0.2°, 7.1° ± 0.2°, 8.5° ± 0.2°, 12.7° ± 0.2°, 14.3° ± 0.2°, 16.2° ± 0.2°, 17.1° ± 0.2°, 17.8°± 0.2°, 19.7°± 0.2°, 21.5°± 0.2°, 22.3°± 0.2°, 23.2°± 0.2°, 24.1°± 0.2°, 27.0°± 0.2°, 29.6°± 0.2° and 34.1°± 0.2°.

[0047] In some embodiments, the solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1- oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate has at least one of the following properties: (a) a thermo-gravimetric analysis (TGA) profile substantially similar to the one set forth in FIG.2; or (b) a TGA profile showing 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0% or less weight loss, or a weight loss within a range defined by any of the preceding values out to about 147°C.

[0048] In some embodiments, the solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1- oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate has at least one of the following properties: (a) a DSC thermogram substantially similar to the one set forth in FIG.3; (b) (b) a DSC thermogram with an endotherm with an extrapolated onset temperature of 277°C, 278°C, 279°C, 280°C, 281°C, 282°C 283°C, 284°C, 285°C, 286°C, or 287°C, or an onset temperature within a range defined by any of the preceding values; or (c) (c) a DSC thermogram with an endotherm having an extrapolated onset temperature of 277.5°C, 278.5°C, 279.5°C, 280.5°C, 281.5°C, 282.5°C 283.5°C, 284.5°C, 285.5°C, 286.5°C, or 287.5°C, or an extrapolated onset temperature within a range defined by any of the preceding values.

[0049] In some embodiments, the solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1- oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate has an X-ray powder diffraction (XRPD) pattern, in terms of 2θ, substantially the same as shown in FIG.1. In some embodiments,WSGR Docket No.42256-608.601 the solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'- biphenyl]-3-carboxylate having an X-ray powder diffraction (XRPD) pattern comprising 11, 12, 13, 14, or 15 peaks, in terms of 2θ, selected from 5.8° ± 0.2°, 7.1° ± 0.2°, 8.5° ± 0.2°, 12.7° ± 0.2°, 14.3° ± 0.2°, 16.2° ± 0.2°, 17.1° ± 0.2°, 17.8°± 0.2°, 19.7°± 0.2°, 21.5°± 0.2°, 22.3°± 0.2°, 23.2°± 0.2°, 24.1°± 0.2°, 27.0°± 0.2°, 29.6°± 0.2° and 34.1°± 0.2°.

[0050] In some embodiments, the solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1- oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate has a TGA profile showing 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or less weight loss, or a weight loss within a range defined by any of the preceding values out to about 147°C. In some embodiments, the solid form of sodium 4-chloro- 3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate has a DSC thermogram with an endotherm having an extrapolated onset temperature of 278°C, 279°C, 280°C, 281°C, 282°C, 283°C, or 284°C, or an extrapolated onset temperature within a range defined by any of the preceding values. In some embodiments, the solid form of sodium 4-chloro- 3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate has a DSC thermogram with an endotherm having an extrapolated onset temperature of 279°C, 280°C, 281°C, 282°C or 283°C, or an extrapolated onset temperature within a range defined by any of the preceding values.

[0051] In some embodiments, the solid form is a crystalline solid form. In some embodiments, the solid form is obtained from acetone, methyl ethyl ketone, acetonitrile, isopropyl acetate, ethyl acetate, anisole or acetone / water.

[0052] In some embodiments, the solid form is unsolvated. In some embodiments, the solid form is for use as a medicament. Some embodiments provide a pharmaceutical composition comprising the solid form and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for oral, intravenous, intramuscular, or subcutaneous administration.

[0053] Some embodiments provide a method of treating a disease, disorder or condition in a mammal that would benefit from positive allosteric modulation of the metabotropic glutamate receptor, comprising administering to the individual a therapeutically effective amount of a solid form. In some embodiments, the disease, disorder or condition in a mammal is a CNS disorder. In some embodiments, the CNS disorder is schizophrenia, anxiety, or addiction. In some embodiments, the mammal is a human.

[0054] In some embodiments, the therapeutically effective amount is administered orally.WSGR Docket No.42256-608.601

[0055] In some embodiments, the solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1- oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate meets at least one of the following criteria: (a) having an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks, in terms of 2θ, at 5.8°± 0.2°, 8.5°± 0.2°, and 19.7°± 0.2°; (b) having an X-ray powder diffraction (XRPD) pattern comprising peaks, in terms of 2θ, at 7.1°± 0.2°, 17.1°± 0.2°, 21.5°± 0.2°, 23.2°± 0.2°, and 24.1°± 0.2°; (c) having a bulk density of 0.21 g / mL, 0.22 g / mL, 0.23 g / mL, 0.24 g / mL, or 0.25 g / mL, or a bulk density within a range defined by any of the preceding values; (d) having an average particle size of 3.1 μm, 3.2 μm, 3.3 μm, 3.4 μm, 3.5 μm, 3.6 μm, 3.7 μm, 3.8 μm, or 3.9 μm or an average particle size within a range defined by any of the preceding value; (e) having a DSC thermogram with an endotherm having an extrapolated onset at 279°C, 280°C, 281°C, 282°C or 283°C, or an extrapolated onset temperature within a range defined by any of the preceding values; (f) having less than 3% total impurities after six months storage at 25°C ± 2°C / 60% ± 5% RH, preferably 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, or 1.3% total impurities after six months storage at 25°C ± 2°C / 60% ± 5% RH, or total impurities after six months storage at 25°C ± 2°C / 60% ± 5% RH within a range defined by any of the preceding values; and / or (g) having less than 3% total impurities after six months storage at 40°C ± 2°C / 75% ± 5% RH, preferably 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, or 1.3% total impurities after six months storage at 40°C ± 2°C / 75% ± 5% RH, or total impurities after six months storage at 40°C ± 2°C / 75% ± 5% RH within a range defined by any of the preceding values.

[0056] In some embodiments, the solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1- oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate meets at least one of the following criteria: (a) having less than 3% total impurities after twelve months storage at 25°C ± 2°C / 60% ± 5% RH, preferably 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, or 1.3% total impurities after twelve months storage at 25°C ±WSGR Docket No.42256-608.601 2°C / 60% ± 5% RH, or total impurities after twelve months storage at 25°C ± 2°C / 60% ± 5% RH within a range defined by any of the preceding values; (b) having less than 3% total impurities after 24 months storage at 25°C ± 2°C / 60% ± 5% RH, preferably 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, or 1.3% total impurities after 24 months storage at 25°C ± 2°C / 60% ± 5% RH, or total impurities after 24 months storage at 25°C ± 2°C / 60% ± 5% RH within a range defined by any of the preceding values; (c) having less than 3% total impurities after 36 months storage at 25°C ± 2°C / 60% ± 5% RH, preferably 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, or 1.3% total impurities after 36 months storage at 25°C ± 2°C / 60% ± 5% RH, or total impurities after 36 months storage at 25°C ± 2°C / 60% ± 5% RH within a range defined by any of the preceding values; and / or (d) having less than 3% total impurities after 48 months storage at 25°C ± 2°C / 60% ± 5% RH, preferably 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, or 1.3% total impurities after 48 months storage at 25°C ± 2°C / 60% ± 5% RH, or total impurities after 48 months storage at 25°C ± 2°C / 60% ± 5% RH within a range defined by any of the preceding values. Crystalline Forms

[0057] The identification and selection of a solid form of a pharmaceutical compound are complex, given that a change in solid form may affect a variety of physical and chemical properties, which may provide benefits or drawbacks in processing, formulation, stability, storage, and handling (e.g., shipping), among other important pharmaceutical characteristics. Useful pharmaceutical solids include crystalline solids and amorphous solids, depending on the product and its mode of administration. Amorphous solids are characterized by a lack of long-range structural order, whereas crystalline solids are characterized by structural periodicity. The desired class of pharmaceutical solid depends upon the specific application; amorphous solids are sometimes selected on the basis of, e.g., an enhanced dissolution profile, while crystalline solids may be desirable for properties such as, e.g., physical or chemical stability.

[0058] Whether crystalline or amorphous, solid forms of a pharmaceutical compound include single-component and multiple-component solids. Single-component solids consist essentially of the pharmaceutical compound or active ingredient in the absence of other compounds. Variety among single-component crystalline materials may potentially arise from the phenomenon ofWSGR Docket No.42256-608.601 polymorphism, wherein multiple three-dimensional arrangements exist for a particular pharmaceutical compound.

[0059] Notably, it is not possible to predict a priori if crystalline forms of a compound even exist, let alone how to successfully prepare them (see, e.g., Braga and Grepioni, 2005, “Making crystals from crystals: a green route to crystal engineering and polymorphism,” Chem. Commun.:3635- 3645 (with respect to crystal engineering, if instructions are not very precise and / or if other external factors affect the process, the result can be unpredictable); Jones et al., 2006, Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement,” MRS Bulletin 31:875-879 (At present it is not generally possible to computationally predict the number of observable polymorphs of even the simplest molecules); Price, 2004, “The computational prediction of pharmaceutical crystal structures and polymorphism,” Advanced Drug Delivery Reviews 56:301-319 (“Price”); and Bernstein, 2004, “Crystal Structure Prediction and Polymorphism,” ACA Transactions 39:14-23 (a great deal still needs to be learned and done before one can state with any degree of confidence the ability to predict a crystal structure, much less polymorphic forms)).

[0060] The variety of possible solid forms creates potential diversity in physical and chemical properties for a given pharmaceutical compound. The discovery and selection of solid forms can be of great importance in the development of an effective, stable, and marketable pharmaceutical product. Crystalline Compound I, Form I

[0061] In some embodiments, Compound I is crystalline. In some embodiments, Compound I is crystalline and anhydrous. In some embodiments, crystalline Compound I is Form I characterized as having at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern, in terms of 2θ, substantially the same as shown in FIG.1; or (b) an X-ray powder diffraction (XRPD) pattern comprising at least two, three, four, five, six, seven, eight, nine or ten peaks, in terms of 2θ, selected from 5.8° ± 0.2°, 7.1° ± 0.2°, 8.5° ± 0.2°, 12.7° ± 0.2°, 14.3° ± 0.2°, 16.2° ± 0.2°, 17.1° ± 0.2°, 17.8°± 0.2°, 19.7°± 0.2°, 21.5°± 0.2°, 22.3°± 0.2°, 23.2°± 0.2°, 24.1°± 0.2°, 27.0°± 0.2°, 29.6°± 0.2° and 34.1°± 0.2°.

[0062] In some embodiments, crystalline Compound I is Form I characterized as having at least one of the following properties: (a) a thermo-gravimetric analysis (TGA) profile substantially similar to the one set forth in FIG.2; orWSGR Docket No.42256-608.601 (b) a TGA profile showing 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0% or less weight loss, or a weight loss within a range defined by any of the preceding values out to about 147°C.

[0063] In some embodiments, crystalline Compound I is Form I characterized as having at least one of the following properties: (a) a DSC thermogram substantially similar to the one set forth in FIG.3; (b) a DSC thermogram with an endotherm with an extrapolated onset temperature of 277°C, 278°C, 279°C, 280°C, 281°C, 282°C 283°C, 284°C, 285°C, 286°C, or 287°C, or an onset temperature within a range defined by any of the preceding values; or (c) a DSC thermogram with an endotherm having an extrapolated onset temperature of 277.5°C, 278.5°C, 279.5°C, 280.5°C, 281.5°C, 282.5°C 283.5°C, 284.5°C, 285.5°C, 286.5°C, or 287.5°C, or an extrapolated onset temperature within a range defined by any of the preceding values.

[0064] In some embodiments, the crystalline form has an X-ray powder diffraction (XRPD) pattern, in terms of 2θ, substantially the same as shown in FIG.1.

[0065] In some embodiments, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising 11, 12, 13, 14, or 15 peaks, in terms of 2θ, selected from 5.8° ± 0.2°, 7.1° ± 0.2°, 8.5° ± 0.2°, 12.7° ± 0.2°, 14.3° ± 0.2°, 16.2° ± 0.2°, 17.1° ± 0.2°, 17.8°± 0.2°, 19.7°± 0.2°, 21.5°± 0.2°, 22.3°± 0.2°, 23.2°± 0.2°, 24.1°± 0.2°, 27.0°± 0.2°, 29.6°± 0.2° and 34.1°± 0.2°.

[0066] In some embodiments, the crystalline form having a TGA profile showing 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or less weight loss, or a weight loss within a range defined by any of the preceding values out to about 147°C.

[0067] In some embodiments, the crystalline form having a DSC thermogram with an endotherm having an extrapolated onset temperature of 278°C, 279°C, 280°C, 281°C, 282°C, 283°C, or 284°C, or an extrapolated onset temperature within a range defined by any of the preceding values.

[0068] In some embodiments, the crystalline form having a DSC thermogram with an endotherm having an extrapolated onset temperature of 279°C, 280°C, 281°C, 282°C or 283°C, or an extrapolated onset temperature within a range defined by any of the preceding values.

[0069] In some embodiments, the solid form is a crystalline solid form.

[0070] In some embodiments, the solid form is obtained from acetone, methyl ethyl ketone, acetonitrile, isopropyl acetate, ethyl acetate, anisole or acetone / water.

[0071] In some embodiments, the solid form is unsolvated.WSGR Docket No.42256-608.601

[0072] In some embodiments, the solid form is for use as a medicament.

[0073] In some embodiments, the pharmaceutical composition comprising the solid form and a pharmaceutically acceptable excipient.

[0074] In some embodiments, the pharmaceutical composition is formulated for oral, intravenous, intramuscular, or subcutaneous administration.

[0075] Some embodiments provide a method of treating a disease, disorder or condition in a mammal that would benefit from positive allosteric modulation of the metabotropic glutamate receptor, comprising administering to the individual a therapeutically effective amount of a solid form. In some embodiments, the disease, disorder or condition in a mammal is a CNS disorder. In some embodiments, the CNS disorder is schizophrenia, anxiety, or addiction. In some embodiments, the mammal is a human.

[0076] In some embodiments, the therapeutically effective amount is administered orally. Preparation of Crystalline Compound I

[0077] In some embodiments, crystalline forms of Compound I are prepared as outlined in the Examples. It is noted that solvents, temperatures, and other reaction conditions presented herein can vary.

[0078] In certain embodiments, provided herein are methods for making a solid form of Compound I, comprising 1) obtaining a saturated solution of Compound I in a solvent at a first temperature (e.g., about 50 °C); 2) adding an anti-solvent into the saturated solution at the first temperature; 3) cooling down to r.t.; and 4) collecting a solid if there is precipitation, and evaporating the solvent to collect a solid if there is no precipitation; and 5) optionally drying. In certain embodiments, the ratio by volume of solvent and anti-solvent is about 1:9. In certain embodiments, the ratio by volume of solvent and anti-solvent is about 1:5. In certain embodiments, the ratio by volume of solvent and anti-solvent is about 1:2. In certain embodiments, the ratio by volume of solvent and anti-solvent is about 1:1. In certain embodiments, the methods for making a solid form of Compound I are anti-solvent recrystallization experiments.

[0079] In another embodiment, crystalline Compound I, Form I, is substantially pure. In certain embodiments, the substantially pure crystalline Compound I, Form I, is substantially free of other solid forms, e.g., amorphous solid. In certain embodiments, the purity of the substantially pure crystalline Compound I, Form I, is no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%. In certain embodiments, the purity of the substantially pure crystalline Compound I, Form I, is no less than 95%, no less than 96%, no lessWSGR Docket No.42256-608.601 than 97%, no less than 98%, no less than 98.5%, no less than 99%, no less than 99.5%, or no less than 99.8%. In certain embodiments, the purity of the substantially pure crystalline Compound I, Form I, is less than about 98%, less than about 98.5%, less than about 99%, less than about 99.5%, or less than about 99.9%. In certain embodiments, the purity of the substantially pure crystalline Compound I, Form I, is less than 98%, less than 98.5%, less than 99%, less than 99.5%, or less than 99.9%.

[0080] In another embodiment, crystalline Compound I, Form 2, is substantially pure. In certain embodiments, the substantially pure crystalline Compound I, Form 2, is substantially free of other solid forms, e.g., amorphous solid. In certain embodiments, the purity of the substantially pure crystalline Compound I, Form 2, is no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%. In certain embodiments, the purity of the substantially pure crystalline Compound I, Form 2, is no less than 95%, no less than 96%, no less than 97%, no less than 98%, no less than 98.5%, no less than 99%, no less than 99.5%, or no less than 99.8%. In certain embodiments, the purity of the substantially pure crystalline Compound I, Form 2, is less than about 98%, less than about 98.5%, less than about 99%, less than about 99.5%, or less than about 99.9%. In certain embodiments, the purity of the substantially pure crystalline Compound I, Form 2, is less than 98%, less than 98.5%, less than 99%, less than 99.5%, or less than 99.9%. Suitable Solvents

[0081] In some embodiments, solvents disclosed herein are those that are suitable for use in GMP facilities and consistent with industrial safety concerns. Categories of solvents are defined in, for example, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), “Impurities: Guidelines for Residual Solvents Q3C(R6),” (October 2016). Solvents are categorized into three classes.

[0082] Class 1 solvents include: benzene; carbon tetrachloride; 1,2-dichloroethane; 1,1- dichloroethene; and 1,1,1-trichloroethane.

[0083] Class 2 solvents include: acetonitrile, chlorobenzene, chloroform, cumene, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N- dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutyl ketone, methylcyclohexane, methylisobutylketone, N- methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2- trichloroethene and xylene.WSGR Docket No.42256-608.601

[0084] Class 3 solvents include: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1- butanol, methylethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and triethylamine.

[0085] Residual solvents in solid forms originate from manufacturing. In some cases, the solvents are not completely removed by practical manufacturing techniques. Appropriate selection of the solvent for the synthesis can enhance the yield, or determine characteristics such as crystal form, purity, and solubility. Therefore, the solvent is a critical parameter in the synthetic process.

[0086] In some embodiments, compositions comprising Compound I comprise an organic solvent(s). In some embodiments, compositions comprising Compound I comprise a residual amount of an organic solvent(s). In some embodiments, compositions comprising Compound I comprise a residual amount of a Class 3 solvent. In some embodiments, the organic solvent is a Class 3 solvent. In some embodiments, the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methylethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and triethylamine. In some embodiments, the Class 3 solvent is selected from the group consisting of acetone, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, heptane, isopropanol, and ethanol.

[0087] In some embodiments, compositions comprising Compound I comprise a residual amount of a Class 2 solvent. In some embodiments, the organic solvent is a Class 2 solvent. In some embodiments, the Class 2 solvent is selected from the group consisting of acetonitrile, chlorobenzene, chloroform, cumene, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2- dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2- ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutyl ketone, methylcyclohexane, methylisobutylketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethene and xylene. In some embodiments, the Class 2 solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, and toluene. In some embodiments, the Class 2 solvent is acetonitrile.

[0088] In some embodiments, compositions comprising Compound I comprise a residual amount of a solvent for which no adequate toxicological data were found. In some embodiments, the organic solvent is a solvent for which no adequate toxicological data were found. In someWSGR Docket No.42256-608.601 embodiments, the solvent is selected from the group consisting of 2-butanone and 2- methyltetrahydrofuran. Certain Terminology

[0089] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may "consist of" or "consist essentially of" the described features. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the stated number or numerical range.

[0090] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, but not limited to, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety.

[0091] The term “acceptable” or “pharmaceutically acceptable”, with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated or does not abrogate the biological activity or properties of the compound, and is relatively nontoxic.

[0092] As used herein, “amelioration” of the symptoms of a particular disease, disorder, or condition by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.WSGR Docket No.42256-608.601

[0093] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition including a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms without undue adverse side effects. An appropriate “effective amount” in any individual case may be determined using techniques, such as a dose escalation study. An “effective amount” of a compound disclosed herein is an amount effective to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. It is understood that “an effect amount” or “a therapeutically effective amount” can vary from subject to subject, due to variation in metabolism of Compound I, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. By way of example only, therapeutically effective amounts may be determined by a dose escalation clinical trial.

[0094] The term “subject” as used herein, refers to an animal which is the object of treatment, observation or experiment. By way of example only, a subject may be, but is not limited to, a mammal including, but not limited to, a human.

[0095] The terms “treat,” “treating” or “treatment”, as used herein, include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. The terms “treat,” “treating” or “treatment”, include, but are not limited to, prophylactic and / or therapeutic treatments. Pharmaceutical Compositions / Formulations

[0096] Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein may be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker,WSGR Docket No.42256-608.601 New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference in their entirety.

[0097] A pharmaceutical composition, as used herein, refers to a mixture of sodium 4-chloro-3'- (((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate (Compound I) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. The pharmaceutical composition facilitates administration of the compound to a mammal. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of Compound I are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated. Preferably, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.

[0098] In some embodiments is a pharmaceutical composition comprising sodium 4-chloro-3'- (((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate (Compound I), and a pharmaceutically acceptable excipient. In some embodiments is a pharmaceutical composition comprising a crystalline form of Compound I, and a pharmaceutically acceptable excipient. In some embodiments is a pharmaceutical composition comprising a crystalline form of Compound I, Form I, and a pharmaceutically acceptable excipient. In some embodiments is a pharmaceutical composition comprising a crystalline form of Compound I, Form 2, and a pharmaceutically acceptable excipient.

[0099] Pharmaceutical compositions including a compound described herein may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes. Dosage Forms

[0100] The pharmaceutical compositions described herein can be formulated for administration to a mammal via any conventional means including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal, or transdermal administration routes. As used herein, the term “subject” or “individual” is used to mean a human. The terms individual, patient and subject may be used interchangeably.

[0101] Moreover, the pharmaceutical compositions described herein, which include Compound I can be formulated into any suitable dosage form, including but not limited to, solid oral dosage forms tablets, powders, and capsules.WSGR Docket No.42256-608.601

[0102] Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents may be added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0103] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. All formulations for oral administration should be in dosages suitable for such administration.

[0104] In some embodiments, the solid dosage forms disclosed herein may be in the form of a tablet, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder) a capsule multiparticulate dosage forms, pellets, or granules. In other embodiments, the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet. Additionally, pharmaceutical formulations described herein may be administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, or three, or four, capsules or tablets.

[0105] In some embodiments, solid dosage forms are prepared by mixing particles of Compound I with one or more pharmaceutical excipients to form a bulk blend composition. When referring to these bulk blend compositions as homogeneous, it is meant that the particles of Compound I are dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, and capsules. The individual unit dosages may also include film coatings, which disintegrate upon oral ingestion or upon contact with diluent. These formulations can be manufactured by conventional pharmacological techniques.

[0106] Conventional pharmacological techniques include, e.g., one or a combination of methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachman et al., The Theory and Practice of IndustrialWSGR Docket No.42256-608.601 Pharmacy (1986). Other methods include, e.g., spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extruding and the like.

[0107] The pharmaceutical solid dosage forms described herein can include Compound I, and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof. In still other aspects, using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000), a film coating is provided around the formulation of Compound I. In one embodiment, some or all of the particles of the Compound I are coated. In another embodiment, some or all of the particles of the Compound I are microencapsulated. In still another embodiment, the particles of the Compound I are not microencapsulated and are uncoated.

[0108] Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, and the like.

[0109] Suitable filling agents for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropylmethycellulose (HPMC), hydroxypropylmethycellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0110] In order to release the Compound I from a solid dosage form matrix as efficiently as possible, disintegrants are often used in the formulation, especially when the dosage forms are compressed with binder. In some embodiments provided herein, the disintegrating agent is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, and methylcrystalline cellulose

[0111] A capsule may be prepared, for example, by placing the bulk blend of the formulation of Compound I inside of a capsule. In some embodiments, the formulations re placed in a soft gelatinWSGR Docket No.42256-608.601 capsule. In some embodiments, the formulations are placed in a hard shell gelatin capsule. In other embodiments, the formulations are placed in standard gelatin capsules or non-gelatin capsules such as capsules comprising HPMC. In some embodiments, the entire dose of the formulation is delivered in a capsule form.

[0112] In some embodiments, pharmaceutical formulations are provided that include particles of Compound I and at least one dispersing agent or suspending agent for oral administration to a subject. Methods of Use, Dosing, and Treatment Regimens

[0113] In another aspect is a method of treating a disease, disorder or condition in a mammal that would benefit from mGlu receptor modulation comprising administering to the mammal a therapeutically effective amount of a crystalline form of Compound I described herein. In some embodiments, the mammal is a human.

[0114] In another embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from mGlu receptor modulation comprising administering to the mammal a therapeutically effective amount of a crystalline form of Compound I described herein; wherein the disease, disorder or condition in a mammal is selected from schizophrenia, anxiety, and addiction. In another embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from mGlu receptor modulation comprising administering to the mammal a therapeutically effective amount of a crystalline form of Compound I described herein; wherein the disease, disorder or condition in a mammal is schizophrenia. In another embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from mGlu receptor modulation comprising administering to the mammal a therapeutically effective amount of a crystalline form of Compound I described herein; wherein the disease, disorder or condition in a mammal is anxiety. In another embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from mGlu receptor modulation comprising administering to the mammal a therapeutically effective amount of a crystalline form of Compound I described herein; wherein the disease, disorder or condition in a mammal is addiction. In some embodiments, the mammal is a human.

[0115] In some embodiments, crystalline Compound I is used in the preparation of medicaments for the treatment of diseases or conditions that would benefit from mGlu receptor modulation. In addition, a method for treating any of the diseases or conditions described herein in an individual in need of such treatment, involves administration of pharmaceutical compositions containing crystalline Compound I, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said individual.WSGR Docket No.42256-608.601

[0116] In some embodiments, compositions containing crystalline Compound I are administered for prophylactic, therapeutic, or maintenance treatment. In some embodiments, compositions containing Compound I are administered for therapeutic applications. In some embodiments, compositions containing Compound I are administered for prophylactic applications. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.

[0117] The daily dosages appropriate for the compounds described herein are from about 0.01 mg / kg to about 20 mg / kg. In one embodiment, the daily dosages are from about 0.1 mg / kg to about 10 mg / kg. An indicated daily dosage in the larger mammal, including, but not limited to, humans, is in the range from about 0.5 mg to about 1000 mg, conveniently administered in a single dose or in divided doses, including, but not limited to, up to four times a day or in extended release form. Suitable unit dosage forms for oral administration include from about 1 to about 500 mg active ingredient. In one embodiment, the unit dosage is about 1 mg, about 5 mg, about, 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 400 mg, or about 500 mg. The foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon. Such dosages may be altered depending on a number of variables, not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner. EXAMPLES List of abbreviations As used throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: ACN acetonitrile DMSO dimethylsulfoxide eq or equiv equivalent(s) Et ethyl EtOH ethanol EtOAc ethyl acetateWSGR Docket No.42256-608.601 HPLC high performance liquid chromatography Me methyl MeOH methanol MTBE tert-butyl methyl ether h or hrs hour(s) IPA isopropyl alcohol IPAc isopropyl acetate MEK methyl ethyl ketone min or mins minutes MsOH methanesulfonic acid NMR nuclear magnetic resonance r / min or rpm revolutions per minute r.t. room temperature RH relative humidity THF tetrahydrofuran V volumes I. Chemical Synthesis

[0118] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and / or oxygen. Example 1: Synthesis of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5- yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate (Compound I)WSGR Docket No.42256-608.601 Compound I, particularly the sodium salt crystalline form of Pattern I, can be prepared as described herein. Example 1A: Preparation of 2-cyclopentyl-1-oxo-5-(oxo-l6-methyl)isoindoline (Compound A)

[0119] Compound A can be prepared from 4-methoxy-2-methylbenzoic acid in 3 steps, as described below:

[0120] Step 1: 4-Methoxy-2-methylbenzoic acid and methanol are mixed then treated with sulfuric acid. The mixture is heated for several hours, cooled, and concentrated. Methyl-t-butyl ether is added followed by water and sodium carbonate solution. After stirring, the organic layer is separated, filtered, washed with water, and concentrated to give the product as an orange oil.

[0121] Step 2: The product of Step 1, in dichloromethane containing N-bromosuccinimide, is passed slowly through a permeable, chemically inert perfluoroalkoxy tube irradiated with light. The solution is sequentially washed with aqueous sodium sulfite and water followed by removal of dichloromethane by distillation. Dichloromethane is added and the wash / distillation sequence is repeated. The final solvent removal yields crude solid product that also contains a dibrominated impurity. The dibrominated impurity is debrominated in the following process to maximize the yield of the mono-bromo product. The crude solid is dissolved in acetonitrile with diisopropylethylamine and diethyl phosphite. Following reaction completion, water is slowly added, the mixture is seeded with product crystals, and additional water is added. After aging theWSGR Docket No.42256-608.601 mixture, the product is isolated by filtration and washed with water. The wet cake is dissolved in dichloromethane and the organic layer is separated and concentrated. The purified product shown above is isolated and dried to give a light brown solid.

[0122] Step 3: The product of Step 2 is mixed with acetonitrile, cyclopentylamine, and potassium carbonate then heated. Reaction completion is confirmed by HPLC. The reaction mixture is cooled, filtered, and concentrated. Dichloromethane is added, and the pH is adjusted with dilute hydrochloric acid. The separated organic phase is washed with water and concentrated. Dichloromethane is added, and the mixture is concentrated. This process is repeated, if necessary, to give crude Compound A. Dichloromethane and water are then added, and the pH is adjusted to 2–5 with dilute hydrochloric acid. The separated water layer is extracted with dichloromethane and the combined organic layer is washed with water and concentrated. Methyl-t-butyl ether is added, and the mixture is heated then slowly cooled. n-Heptane is added, stirring is continued, and the product is subsequently isolated by filtration. The cake is washed with n-heptane and vacuum dried to give Compound A as a yellow solid. Example 1B: Preparation of 2-cyclopentyl-5-hydroxyisoindolin-1-one (Compound B):

[0123] Compound A (3.4 Kg) is mixed with 48% hydrobromic acid in water (23.8 L) and heated at 110-120 ºC for 18 h under stirring. The reaction mixture is cooled to 0-5 ºC and neutralized with 30% sodium hydroxide solution to adjust pH 5-6. The precipitated product is filtered and washed with water (13 Kg) followed by dichloromethane (6.8 Kg). After vacuum drying, crude product (3.015 Kg) is stirred with n-heptane, then filtered, and washed with n-heptane. The wet cake is vacuum dried to afford compound B as off white solid. Typical purity is > 99% by HPLC.1H NMR (400 MHz, DMSO-d6): δ 9.95 (1 H), 7.36 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 1.6 Hz, 1H), 6.75 (dd, J = 8.0, 1.6 Hz, 1H), 4.43 (m, 1H), 4.25 (s, 2H), 1.51-1.78 (m, 8H).WSGR Docket No.42256-608.601 Example 1C: Preparation of methyl 3'-(bromomethyl)-4-chloro-[1,1'-biphenyl]-3-carboxylate (Compound C)

[0124] Compound C can be prepared from 2-chloro-5-iodobenzoic acid and m-tolylboronic acid in 3 steps, as described below:

[0125] Step 1: 2-Chloro-5-iodobenzoic acid and m-tolylboronic acid are sequentially charged to an aqueous solution of sodium carbonate. The mixture is purged with nitrogen prior to addition of palladium (II) acetate. The warm mixture is stirred until the 2-chloro-5-iodobenzoic acid level is less than 5% by HPLC (any residual 2-chloro-5-iodobenzoic acid and m-tolylboronic acid are removed during workup). The reaction mixture is filtered through diatomite and the filtrate is acidified with hydrochloric acid. The product shown above is isolated by filtration and washed with water and n-heptane. Product is vacuum dried.

[0126] Step 2: The product of Step 1 and methanol are mixed then treated with sulfuric acid. The mixture is heated for several hours, cooled, and concentrated. Isopropyl acetate is added followed by sodium carbonate solution. After stirring, the organic layer is separated, washed with water, and concentrated. Isopropyl acetate is added, and the mixture is concentrated to give the product shown above as a white solid after filtration and drying.WSGR Docket No.42256-608.601

[0127] Step 3: The product of Step 2 in acetonitrile containing N-bromosuccinimide is passed slowly through a UV-permeable, chemically inert perfluoroalkoxy tube and irradiated with light. The resulting material is concentrated, and the solvent is exchanged to methyl t-butyl ether then washed sequentially with aqueous sodium sulfite and water. The organic layer is concentrated, heated, cooled, mixed with n-heptane, and the solid is isolated by filtration. The solid Compound C wet cake is resuspended in n-heptane, isolated by filtration, and dried. Typical purity is 93– 94%.

[0128] Example 1D: Preparation of methyl 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5- yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate (Compound D):

[0129] Compound C (2.1 Kg) and compound B (1.1 eq) are combined with ACN (10 V) followed by the addition of potassium carbonate (2 eq) and heated at 70-80 ºC for 18 h under stirring. Reaction completion is confirmed by HPLC. The reaction mixture is cooled to 30-40 ºC, diluted with dichloromethane (15 V) and stirred for 1.5 h. The resulting solid is washed with dichloromethane (4 L) and the filtrate is concentrated under vacuum. Isopropyl acetate is added, and the mixture is concentrated under vacuum. Isopropyl acetate is added, the mixture is heated and seeded. The mixture is cooled, stirred then filtered. The filter cake is washed with isopropyl acetate and dried under vacuum to afford compound D as a solid. Typical purity is 99% by HPLC.1H NMR (400 MHz, DMSO-d6): δ 8.07 (d, J = 2.4 Hz, 1H), 7.87 (m, 1H), 7.81 (m, 1H), 7.68 (m, 2H), 7.56 (d, J = 8.4 Hz, 1H), 7.52 (m, 2H), 7.23 (m, 1H), 7.18 (m, 2H), 5.26 (s, 2H), 4.51 (m, 1H), 4.38 (s, 2H), 3.88 (s, 3H), 1.58-1.82 (m, 8H).

[0130] An impurity of the coupling reaction of step 2 above is identified as Compound F:WSGR Docket No.42256-608.601Compound F Table 1: HPLC analysis of impurities associated with compound D

[0131] Example 1: Preparation of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5- yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate (Compound I):

[0132] Compound D (2.1 Kg) is mixed with methanol (6 V), aqueous sodium hydroxide solution (5 eq, 2 M), and then heated at 55-65 ºC for 1 h under stirring. Reaction completion is confirmed by HPLC. The mixture is concentrated under vacuum to 5 volumes and water is added (20 L). The mixture is acidified with aqueous hydrochloric acid (3 M) to adjust pH 0.8 and extracted with 2-methyltetrahydrofuran (70 L). The organic layer is washed with water (15 L) and concentrated under vacuum. 2-Methyltetrahydrofuran is added and removed by vacuum distillation several times. 2-Methyltetrahydrofuran is added followed by sodium 2-ethylhexanoate (1.1 eq) in 2-methyltetrahydrofuran. The mixture is heated until the conversion is complete by HPLC. The mixture is cooled and stirred. The solid is isolated by filtration and the cake is washed with 2-methyltetrahydrofuran. The wet cake is stirred with ethyl acetate and then filtered. The cake is washed with ethyl acetate and dried under vacuum to afford crude compound I. Typical crude yield is ~80%.

[0133] Crude compound I, dimethyl sulfoxide and methanol are mixed and then heated until the solid is dissolved. The warm solution is polish-filtered. Filtered ethyl acetate is added and seedWSGR Docket No.42256-608.601 crystals are introduced (seed crystals can be obtained according to procedure described in example 7). The warm solution is stirred then additional filtered ethyl acetate is added slowly over several hours. The mixture is cooled then filtered and the cake is washed with filtered ethyl acetate. The wet filter cake is tested for purity. The material can be reworked, if necessary, by repeating this process. The isolate is dried under vacuum at 55–65 °C affording compound I as off white solid. Typical yield is > 80% with a purity of > 99%.1H NMR (400 MHz, DMSO-d6): δ 8.04 (d, J = 2.4 Hz, 1H), 7.78 (m, 2H), 7.50-7.57 (m, 5H), 7.23 (m, 1H), 7.12 (m, 2H), 5.26 (s, 2H), 4.52 (m, 1H), 4.38 (s, 2H), 1.58-1.82 (m, 8H). Table 2: Headspace GC analysis of compound I for volatile impuritiesI I Example 1E: Alternative synthesis of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5- yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate (Compound I)WSGR Docket No.42256-608.601

[0134] Step 1: Preparation of 2-cyclopentyl-5-hydroxyisoindolin-1-one (Compound E):

[0135] Compound D (7.85 kg, 16.49 mol.) is mixed with methanol (43.2 kg) and aqueous sodium hydroxide solution (2 eq, 11.45 M, 4.2 kg) followed by addition of water (36 kg, 36 L), and then heated at 56-65 ºC for 1-3 h under stirring. The mixture was cooled to 20-40 ºC and then concentrated to 39-54 L keeping the inner temperature below 60 ºC. The mixture was then combined with water (69 kg, 69 L) and the resulting mixture stirred at 15-25 ºC for 1-3 h. The mixture was then combined with additional water (11 kg, 11 L). The stirring mixture was then slowly treated at 15-25 ºC with 2N HCl (31 kg, 30.1 L, 60.2 mol.) till pH 0.5-1.5. (Final pH = 0.85). The resulting mixture was stirred 0.5-1.5 h and then combined with 2- methyltetrahydrofuran (122 kg, 142 L). The mixture was then stirred at 40-50 ºC for 0.5-1 h and then allowed to stand at 40-50 ºC for 0.5-1 h to allow the layers to partition. The aqueous layer was removed and the remainder was combined with water (40 kg, 40 L). The mixture was then stirred at 40-50 ºC for 0.5-1 h and then allowed to stand at 40-50 ºC for 0.5-1 h to allow the layers to partition. The aqueous layer was removed and the remainder was combined with water (38 kg, 38 L). The mixture was then stirred at 40-50 ºC for 0.5-1 h and then allowed to stand at 40-50 ºC for 0.5-1 h to allow the layers to partition. The aqueous layer was removed and then concentrated to 62-77 L keeping the inner temperature below 55 ºC. The remainder was combined with 2- methyltetrahydrofuran (33.0 kg, 38.4 L) and then concentrated to 62-77 L keeping the inner temperature below 55 ºC. This procedure was repeated three more times (34 kg, 33 kg, 47 kg). The mixture was combined with two portions of 2-methyltetrahydrofuran (43.0 kg, 50.0 L, 46.5 kg, 54.1 L). The resulting mixture was refluxed at 72-82 ºC for 0.5-1.5 h and then the temperature was adjusted to 45-55 ºC to provide compound E in 2-methyltetrahydrofuran which was used immediately in the next step.WSGR Docket No.42256-608.601

[0136] Step 2: Preparation of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5- yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate (Compound I):

[0137] The stirring mixture of compound E in 2-methyltetrahydrofuran was then treated with 42.8 kg of a sodium 2-ethylhexanoate (3.5 kg, 21.06 mol.) in 2-methyltetrahydrofuran (48.0 kg, 55.8 L) solution maintaining the temperature at 45-55 ºC combing with additional 2- methyltetrahydrofuran (10.0 kg, 11.6 L). The resulting mixture was then stirred at 45-55 ºC for 2-3 h and then the temperature was adjusted to 15-25 ºC and stirred an additional 3-8 h. The solid material was collected by centrifuging. The vessel was rinsed with 2-methyltetrahydrofuran (27.0 kg, 31.4 L) and the rinse used to wash the solid material under nitrogen by centrifuging. The solid was then combined with EtOAc (70.4 kg, 78.0 L) and the resulting mixture was stirred at 15-25 ºC for 1-3 h. The solid was collected in portions by centrifuging. The vessel was rinsed with EtOAc (57.2 kg, 63.4 L) and the rinse used to wash the solid material under nitrogen by centrifuging. The solid material was then placed in a drying bag and heated to 50-60 °C for 18- 24 h then allowed to cool to r.t. affording compound I (6.60 kg). Table 3: Headspace GC analysis of compound I for volatile impuritiesI I II. Characterization of Polymorphs Example 2: X-ray Powder Diffraction (XRPD)

[0138] X-ray powder diffraction studies were performed using a Bruker D8 Advance with the following instrument parameters: Scan: 3o(2θ) to 40o(2θ) Increment: 0.02o(2θ) Scan speed: 0.3sec / stepWSGR Docket No.42256-608.601 Voltage: 40 KV Current: 40 mA Rotation: On Sample hold: Zero-background sample holder

[0139] XRPD analysis of Form I of Compound I (FIG. 1) showed to be crystalline with characteristic peaks, in terms of 2θ, at 5.8° ± 0.2°, 7.1° ± 0.2°, 8.5° ± 0.2°, 12.7° ± 0.2°, 14.3° ± 0.2°, 16.2° ± 0.2°, 17.1° ± 0.2°, 17.8°± 0.2°, 19.7°± 0.2°, 21.5°± 0.2°, 22.3°± 0.2°, 23.2°± 0.2°, 24.1°± 0.2°, 27.0°± 0.2°, 29.6°± 0.2° and 34.1°± 0.2° at 5.8° 2-Theta, 7.1° 2-Theta, 8.5° 2-Theta, 12.7° 2-Theta, 14.3° 2-Theta, 16.2° 2-Theta, 17.1° 2-Theta, 17.8° 2-Theta, 19.7° 2-Theta, 21.5° 2-Theta, 22.3° 2-Theta, 23.2° 2-Theta, 24.1° 2-Theta, 27.0° 2-Theta, 29.6° 2-Theta and 34.1° 2- Theta. Example 3: Polarized Light Microscopy (PLM)

[0140] Light microscopy studies were performed using a Nikon LV100 POL equipped with 5 megapixel CCD. The solid was placed on the glass slide and dispersed by cedar oil, then observed with suitable magnification. PLM analysis of Form I of Compound I showed needle-like crystals, sizes up to 100 ^m. Example 4: Thermogravimetric Analysis

[0141] Thermogravimetric analysis of solid was performed using TA Q5000IR or equivalent. The sample was placed in an open aluminum pan, the amount was weighed automatically. The sample was heated at the heating rate of 10 °C / min up to the final temperature. TGA of Form I of Compound I (FIG.2) showed no weight loss before decomposition with onset at about 147 °C. Example 5: Differential Scanning Calorimetry (DSC)

[0142] DSC studies were performed using a TA Q2000. The sample was weighed in pinhole aluminum pan and the accurate amount was recorded. The sample was heated at the heating rate of 10 °C / min with 50 mL / min nitrogen purge from 25 °C up to the final temperature. DSC analysis of Form I of Compound I (FIG.3) showed a sharp melting endotherm with onset at 281 °C (99 J / g). Example 6: Dynamic Vapor Sorption (DVS)

[0143] DVS studies were performed using a DVS Intrinsic (SMS, UK) or IGASORP (Hiden, UK). 10 to 50 mg of compound was transferred into the DVS and the weight change recorded with respect to a varying atmospheric humidity at 25 °C using the following parameters:WSGR Docket No.42256-608.601 Drying at 40°C until dm / dt<±0.002% / min Min time: 30 min, Max time: 120 min (for IGASORP) Equilibrium: 60 min Cycle: 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 80, 70, 60, 50, 40, 30, 20, 10, 5, 0 Characterize the sample after the DVS experiment by XRPD.

[0144] The DVS analysis of Form I of Compound I showed 7.5% moisture uptake between 0- 80% RH. Post-DVS analysis by XRPD showed no change. The material was hygroscopic. III. Polymorph Screen Example 7: Slurry Method

[0145] About 50 mg of Compound I was weighed in 2.0 mL glass vials and then 1.0 mL selected solvents were added. All the vials were placed on the hotplate stirring with the speed of 700 r / min at 25 °C and 50 °C. After 5 day’ slurry, suspensions were centrifuged (8000 r / min, 5 mins) and residual solids were dried in the vacuum oven at 30 °C for 4-5hrs. Then obtained dried solids were characterized by XRPD. The results are listed in Table 4. As shown in XRPD results of obtained solids after slurry experiment at 25 °C and 50 °C for 5 days, form I of compound I was found. Form I appeared in most of the systems, the melting point is about 272 °C. Table 4Example 8: Anti-Solvent Method

[0146] DMSO and MeOH were selected as solvents to dissolve the compounds because the compound showed relatively high solubility in these solvents, while MTBE was selected as anti-WSGR Docket No.42256-608.601 solvents, totally 2 different anti-solvent experiments were performed. Details of operation procedures were listed as below:

[0147] The compound I was weighed in 8.0 mL capacity glass vials and then 1.0-2.0 mL selected good solvents were added. All the vials were placed on the hotplate and stirred with the speed of 700 r / min at 50 °C. After stirring at 50 °C for 1-24 hrs, for the clear systems, selected anti-solvents were added stepwise until solids came out or the volume ratio of anti-solvent / good solvent reached 5:1. While for the systems which were still suspensions after heating, the suspensions were filtered into different clean 8.0 mL capacity glass vials, and then selected anti-solvents were added stepwise until solids came out or the volume ratio of anti-solvent / good solvent reached 5:1. After that, all the systems were holding at 50 °C for 2 hrs, and then cooled to 25 °C. After holding at 25 °C for 20-24 hrs, the suspensions were centrifuged at 8000 r / min for 5 mins. Wet solids were then dried in the vacuum oven at 30 °C for 18-20 hrs and then the obtained dry solids were characterized by XRPD. The results are listed in Table 5. Table 5Example 9: Heating-Cooling Method

[0148] About 150 mg, 30 mg of compound I was weighed in 8.0 mL glass vials and then different volume of solvents were added according to solubility. All the vials were placed on the hot-plate stirring with the speed of 700 r / min at 50 °C. After 22 hrs’ slurry, the suspensions were filtered into clean glass vials through 0.45 µm filter. Then the mother liquids were placed on the 5 °C stirrer. After stirring at 5 °C for 24 hrs, the obtained suspensions were then centrifuged at 8000 r / min for 5 mins and residual solids were characterized by XRPD after drying in the vacuum oven at 30 °C for 6 hrs. For those systems without precipitation, the samples were then placed in the fume hood at 25 °C for solvent evaporation. The results are listed in Table 6. As shown in XRPD results of obtained solids, Pattern I was obtained from Acetone / H2O (v / v, 9:1) system by heating-cooling method.WSGR Docket No.42256-608.601 Table 6Example 10: Grinding and wet granulation study

[0149] Dry and wet grinding was carried out to test physical stability of raw material in the milling process. For dry grinding experiment, about 50 mg compound (Form I) was added into mortar and grinded by pestle for 5 mins. The solids were then characterized by XRPD. For wet grinding experiment, about 50 mg compound (form I) was added into mortar and several drops of solvent EtOH or water were added until the solids were fully wetted. Wet solids were grinded by pestle for 5 mins manually and residual solids were characterized by XRPD after dried in the vacuum oven at 30 °C for 16 hrs. The results are listed in Table 7. As shown in XRPD results of obtained solids after grinding, the polymorph was not changed after dry grinding or wet granulation process. Table 7Example 11: Solubility test of Form I

[0150] About 20 mg of the compound (Form I) was weighed in a 2.0 mL glass vials and then different pH buffers were added to the vial. The samples were kept stirring at 700 rpm at 37 °C for 24 hours. After stirring for 24 hours, 100 µL of the samples was transferred into centrifuge tubes, and centrifuged twice at 14000 rpm for 5 mins. And then the supernatants were diluted by (ACN: water=70:30 (v / v)) and measured by HPLC for solubility determination. The pH was recorded after the solubility test. The results are listed in Table 8.WSGR Docket No.42256-608.601 Table 8*NS = not soluble by this method of determination Example 12: Competitive slurry experiment at 25 °C and 50 °C

[0151] A competitive slurry experiments were performed to investigate the relationship between Form I and Form II polymorphs. First, saturated solutions of the compound I were prepared.15~20 mg compound I were weighed in 4.0 mL capacity glass vials and then 1.0 mL selected solvents were added in the vials. All the vials were placed on the hot-plate and heated to 25 °C and 50 °C to make the saturation solution. Then 16~18 mg of different polymorph samples was weighed into 2 mL capacity glass vials. The above prepared saturated solutions were filtered through 0.45 µm filter into the 2 mL capacity glass vials with different polymorphs solids. Then all the 2 mL capacity glass vials were placed on the hotplate and heated to 25 °C and 50 °C. After stirring at 25 °C / 50 °C for about 3 days, some wet solids were collected and characterized by XRPD. According to XRPD results of competitive slurry experiments, residual solids were all Form I after slurry for 3 days at 25 °C and 50 °C, which indicated that Form 2 should be the metastable form of compound I, while Form I was thermodynamically stable at the range of 25 °C to ~50 °C. Table 9Example 13: Temperature and Moisture Stability Study

[0152] A stability study was conducted on the solid form of sodium 4-chloro-3'-(((2-cyclopentyl- 1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate (Compound I). Changes in theWSGR Docket No.42256-608.601 impurity profiles of the solid form of Compound I were monitored (e.g., using high performance liquid chromatography (HPLC)) upon exposure to various temperatures and / or humidity conditions. Briefly, each sample was placed in a closed container and exposed to two controlled environments: 1) 25°±2° C with 60%±5% relative humidity (RH), and 2) 40°±2° C with 75%±5% RH. Two samples (Batch 1, and Batch 2) were analyzed for each of the two controlled environments. Samples were analyzed for appearance, water content, impurities, XRPD, and bacterial / microbial presence (see Table 10-Table 13 below). Samples were analyzed at multiple time points starting from an initial measurement followed by measurements at 1 month (1M), 2 months (2M), 3 months (3M), 6 months (6M), 9 months (9M), 12 months (12M), 18 months (18M), 24 months (24M), 36 months (36M), and / or 48 months (48M). For the reversed-phase HPLC impurity profile method, reversed-phase HPLC analysis was conducted using a Waters Atlantis T3 column (100Å, 3 µm, 4.6 mm X 150 mm) and Agilent 1260 system, although analysis using a similar or equivalent column would be expected to yield similar results. The mobile phase components were 10 mmol ammonium acetate in water, v / v (Mobile Phase A) and acetonitrile (Mobile Phase B). The mobile phase composition was a gradient that increased from 15% to 95% B in 30 minutes, held at 95% B for three minutes, and then the system was re-equilibrated at 15% B for five minutes. The flow rate was 1.0 mL / minute, and the injection volume was 5 µL. The column temperature was maintained at 40° C. The retention time for Compound I, was approximately 13 minutes. The sample solution was prepared in mobile phase to a final concentration of 0.2 mg / mL. Stability study results for samples tested at 25°±2° C with 60%±5% RH are shown in Table 10 and Table 11. Stability study results for samples tested at 40°±2° C with 75%±5% RH are shown in Table 12 and Table 13. For XRPD results listed in Table 10-Table 13, “Consistent with reference” refers to an XRPD pattern comprising characteristic peaks, in terms of 2θ, at 5.8°± 0.2°, 8.5°± 0.2°, and 19.7°± 0.2°; and / or an XRPD pattern comprising peaks, in terms of 2θ, at 7.1°± 0.2°, 17.1°± 0.2°, 21.5°± 0.2°, 23.2°± 0.2°, and 24.1°± 0.2°. Table 10WSGR Docket No.42256-608.601Table 11Table 12WSGR Docket No.42256-608.601Table 13

[0153] While preferred embodiments of the present inventive concepts have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the inventive concepts. It should be understood that various alternatives to the embodiments of the inventive concepts described herein may be employed in practicing the inventive concepts. It is intended that the following claims define the scope of the inventive concepts and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

WSGR Docket No.42256-608.601 CLAIMS WHAT IS CLAIMED IS:

1. A solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)- [1,1'-biphenyl]-3-carboxylate (Compound I).

2. The solid form of claim 1, wherein the solid form is polymorph Form I.

3. The solid form of claim 1 or 2 having at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern, in terms of 2θ, substantially the same as shown in FIG.1; or (b) an XRPD pattern comprising at least two, three, four, five, six, seven, eight, nine or ten peaks, in terms of 2θ, selected from 5.8° ± 0.2°, 7.1° ± 0.2°, 8.5° ± 0.2°, 12.7° ± 0.2°, 14.3° ± 0.2°, 16.2° ± 0.2°, 17.1° ± 0.2°, 17.8°± 0.2°, 19.7°± 0.2°, 21.5°± 0.2°, 22.3°± 0.2°, 23.2°± 0.2°, 24.1°± 0.2°, 27.0°± 0.2°, 29.6°± 0.2° and 34.1°± 0.2°.

4. The solid form of any one of claims 1-3 having at least one of the following properties: (a) a thermo-gravimetric analysis (TGA) profile substantially similar to the one set forth in FIG.2; or (b) a TGA profile showing 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0% or less weight loss, or a weight loss within a range defined by any of the preceding values out to about 147°C.

5. The solid form of any one of claims 1 to 4 having at least one of the following properties: (a) a DSC thermogram substantially similar to the one set forth in FIG.3; (b) a DSC thermogram with an endotherm with an extrapolated onset temperature of 277°C, 278°C, 279°C, 280°C, 281°C, 282°C 283°C, 284°C, 285°C, 286°C, or 287°C, or an onset temperature within a range defined by any of the preceding values; or (c) a DSC thermogram with an endotherm having an extrapolated onset temperature of 277.5°C, 278.5°C, 279.5°C, 280.5°C, 281.5°C, 282.5°C 283.5°C, 284.5°C, 285.5°C, 286.5°C, or 287.5°C, or an extrapolated onset temperature within a range defined by any of the preceding values.

6. The solid form of any one of claims 1 to 5, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern, in terms of 2θ, substantially the same as shown in FIG.

1.

7. The solid form of any one of claims 1 to 5, having an X-ray powder diffraction (XRPD) pattern comprising 11, 12, 13, 14, or 15 peaks, in terms of 2θ, selected from 5.8° ± 0.2°, 7.1° ± 0.2°, 8.5° ± 0.2°, 12.7° ± 0.2°, 14.3° ± 0.2°, 16.2° ± 0.2°, 17.1° ± 0.2°, 17.8°± 0.2°,WSGR Docket No.42256-608.601 19.7°± 0.2°, 21.5°± 0.2°, 22.3°± 0.2°, 23.2°± 0.2°, 24.1°± 0.2°, 27.0°± 0.2°, 29.6°± 0.2° and 34.1°± 0.2°.

8. The solid form of any one of claims 1 to 7, having a TGA profile showing 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or less weight loss, or a weight loss within a range defined by any of the preceding values out to about 147°C.

9. The solid form of any one of claims 1 to 8, having a DSC thermogram with an endotherm having an extrapolated onset temperature of 278°C, 279°C, 280°C, 281°C, 282°C, 283°C, or 284°C, or an extrapolated onset temperature within a range defined by any of the preceding values.

10. The solid form of any one of claims 1 to 9, having a DSC thermogram with an endotherm having an extrapolated onset temperature of 279°C, 280°C, 281°C, 282°C or 283°C, or an extrapolated onset temperature within a range defined by any of the preceding values.

11. The solid form of any one of claims 1 to 10, wherein the solid form is a crystalline solid form.

12. The solid form of any one of claims 1-11, comprising up to 5% impurities selected from compound B, compound C, compound D, and compound E;13. The solid form of claim 12, comprising up to 0.2 area%, 0.3 area %, 0.4 area %, 0.5 area %, 0.6 area %, 0.7 area %, 0.8 area %, 0.9 area %, 1 area %, 1.5 area %, 2 area %, 2.5 areaWSGR Docket No.42256-608.601 %, 3 area %, 3.5 area %, 4 area %, or 4.5 area % impurities as determined by HPLC selected from compound B, compound C, compound D, and compound E, or impurities in an amount by area % as determined by HPLC within a range defined by any two of the preceding values.

14. The solid form of any one of claims 1-13, wherein the solid form contains one or more residual solvents selected from isopropanol, ethanol, dichloromethane, n-heptane, cyclohexane, dimethyl sulfoxide, methyl tert-butyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, acetone, methyl ethyl ketone, acetonitrile, isopropyl acetate, ethyl acetate, anisole and water.

15. The solid form of any one of claims 1-14, wherein the solid form is unsolvated.

16. The solid form of any one of claims 1-15, for use as a medicament.

17. A pharmaceutical composition comprising the solid form of any one of claims 1-15, and a pharmaceutically acceptable excipient.

18. The pharmaceutical composition of claim 17, formulated for oral, intravenous, intramuscular, or subcutaneous administration.

19. A method of treating a disease, disorder or condition in a mammal that would benefit from positive allosteric modulation of the metabotropic glutamate receptor, comprising administering to the individual a therapeutically effective amount of a solid form of any one of claims 1-15.

20. The method of claim 19, wherein the disease, disorder or condition in a mammal is a CNS disorder.

21. The method of claim 20, wherein the CNS disorder is schizophrenia, anxiety, or addiction.

22. The method of any one of claims 18-21, wherein the therapeutically effective amount is administered orally.

23. A process for preparing the pharmaceutical composition of claim 17, comprising admixing the solid form of any one of claims 1-17, and a pharmaceutically acceptable excipient.

24. The process of claim 23, further comprising compressing and / or grinding the solid form to a bulk density of 0.10 g / mL, 0.15 g / mL, 0.20 g / mL, 0.25 g / mL, 0.30 g / mL, 0.35 g / mL, 0.40 g / mL, or more, or to a bulk density within a range defined by any of the preceding values.

25. The process of claim 24, further comprising deagglomerating the solid form, thereby producing a flowable powder form of Compound I.

26. The process of any one of claims 23-25, wherein the pharmaceutically acceptable excipient comprises a binder, filler, and / or disintegrate.WSGR Docket No.42256-608.601 27. The process of any one of claims 23-26, wherein the pharmaceutically acceptable excipient comprises a starch or a gelatin.

28. The solid form of claim 1, wherein the solid form comprises up to 5% impurities selected from compound B, compound C, compound D, and compound E;29. The solid form of claim 28, comprising up to 0.2 area%, 0.3 area %, 0.4 area %, 0.5 area %, 0.6 area %, 0.7 area %, 0.8 area %, 0.9 area %, 1 area %, 1.5 area %, 2 area %, 2.5 area %, 3 area %, 3.5 area %, 4 area %, or 4.5 area % impurities as determined by HPLC selected from compound B, compound C, compound D, and compound E, or impurities in an amount by area % as determined by HPLC within a range defined by any two of the preceding values.

30. A method for preparing a pharmaceutical composition comprising admixing the solid form of any one of claims 1-17, and a pharmaceutically acceptable excipient.

31. A solid dosage form comprising the solid form of any one of claims 1-15, wherein the solid form comprises a dose of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5- yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate (Compound I).

32. The solid dosage form of claim 31, wherein the solid dosage form comprises a capsule, tablet, dragée, powder, and / or granule.

33. The solid dosage form of claim 31, wherein the solid dosage form comprises a capsule.

34. The solid dosage form of any one of claims 31-33, wherein the solid dosage form comprises a dose of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5-WSGR Docket No.42256-608.601 yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate (Compound I) that is from about 60 mg to about 600 mg based on the weight of the free base.

35. The solid dosage form of any one of claims 31-34, wherein the solid dosage form comprises a dose of sodium 4-chloro-3’-(((2-cyclopentyl-1-oxoisoindolin-5- yl)oxy)methyl)-[1,1’-biphenyl]-3-carboxylate (Compound I) that is from about 75 mg to about 500 mg based on the weight of the free base.

36. The solid dosage form of any one of claims 31-35, wherein the solid dosage form comprises a dose of sodium 4-chloro-3’-(((2-cyclopentyl-1-oxoisoindolin-5- yl)oxy)methyl)-[1,1’-biphenyl]-3-carboxylate (Compound I) that is from about 150 mg to about 350 mg based on the weight of the free base.

37. The solid dosage form of any one of claims 31-36, wherein the solid dosage form comprises a dose of sodium 4-chloro-3’-(((2-cyclopentyl-1-oxoisoindolin-5- yl)oxy)methyl)-[1,1’-biphenyl]-3-carboxylate (Compound I) that is about 150 mg based on the weight of the free base.

38. The solid dosage form of any one of claims 31-36, wherein the solid dosage form comprises a dose of sodium 4-chloro-3’-(((2-cyclopentyl-1-oxoisoindolin-5- yl)oxy)methyl)-[1,1’-biphenyl]-3-carboxylate (Compound I) that is about 300 mg based on the weight of the free base.

39. The pharmaceutical composition of claim 17, wherein the solid form of sodium 4-chloro- 3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate is characterized by having an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks, in terms of 2θ, at 5.8°± 0.2°, 8.5°± 0.2°, and 19.7°± 0.2°.

40. The pharmaceutical composition of claim 39, wherein the solid form of sodium 4-chloro- 3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate is characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks, in terms of 2θ, at 7.1°± 0.2°, 17.1°± 0.2°, 21.5°± 0.2°, 23.2°± 0.2°, and 24.1°± 0.2°.

41. The pharmaceutical composition of claim 39 or 40, wherein the solid form of sodium 4- chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate has a bulk density of 0.10 g / mL, 0.15 g / mL, 0.20 g / mL, 0.25 g / mL, 0.30 g / mL, 0.35 g / mL, or 0.40 g / mL, or a bulk density within a range defined by any of the preceding values.

42. The pharmaceutical composition of any one of claims 39-41, wherein solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3- carboxylate has a bulk density of 0.20 g / mL, 0.21 g / mL, 0.22 g / mL, 0.23 g / mL, 0.24 g / mL,WSGR Docket No.42256-608.601 0.25 g / mL, 0.26 g / mL, or 0.27 g / mL, or a bulk density within a range defined by any of the preceding values.

43. The pharmaceutical composition of any one of claims 39-42, wherein solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3- carboxylate has a bulk density of 0.25 g / mL.

44. The pharmaceutical composition of any one of claims 39-43, wherein the solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3- carboxylate has a tap density of 0.20 g / mL, 0.25 g / mL, 0.30 g / mL, 0.35 g / mL, 0.40 g / mL, 0.45 g / mL, or 0.50 g / mL, or a tap density within a range defined by any of the preceding values.

45. The pharmaceutical composition of any one of claims 39-44, wherein the solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3- carboxylate has an average particle size of 2.5 μm, 3.0 μm, 3.5 μm, 4.0 μm, 4.5 μm, 5.0 μm, 5.5 μm, 6.0 μm, 6.5 μm, 7.0 μm, 7.5 μm, 8.0 μm, or 8.5 μm, or an average particle size within a range defined by any of the preceding values.

46. The pharmaceutical composition of any one of claims 39-45, wherein the solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3- carboxylate has an average particle size of about 3.5 μm.

47. The pharmaceutical composition of any one of claims 39-46, wherein the pharmaceutical composition is provided as a powder or as a capsule.

48. The pharmaceutical composition of any one of claims 39-47, wherein the pharmaceutical composition is provided as a powder-in-a-capsule (PIC).

49. The pharmaceutical composition of any one of claims 39-48, comprising no more than about 5% of total impurities.

50. The pharmaceutical composition of any one of claims 39-49, comprising no more than 500 ppm, 100 ppm, 50 ppm, 40 ppm, 30 ppm, 20 ppm, 10 ppm, 5 ppm or 1 ppm, or ppm within a range defined by any of the preceding values, of methyl 3'-(bromomethyl)-4-chloro-[1,1'- biphenyl]-3-carboxylate, 2-cyclopentyl-5-hydroxyisoindolin-1-one, methyl 4-chloro-3'- (dibromomethyl)-[1,1'-biphenyl]-3-carboxylate, methyl 2-(bromomethyl)-4- methoxybenzoate, methyl bromide, methyl 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5- yl)oxy)methyl)-[1,1'-biphenyl]-3-carboxylate, sodium 3'-(bis((2-cyclopentyl-1- oxoisoindolin-5-yl)oxy)methyl)-4-chloro-[1,1'-biphenyl]-3-carboxylate, methyl 3'-(bis((2- cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-4-chloro-[1,1'-biphenyl]-3-carboxylate or methyl 4′-chloro-2-(dibromomethyl)[1,1′-biphenyl]-4-carboxylate based on Compound I.WSGR Docket No.42256-608.601 51. The pharmaceutical composition of any one of claims 39-50, comprising no more than 10000 ppm, 5000 ppm, 4000 ppm, 3000 ppm, 2000 ppm, 1000 ppm, 750 ppm or 500 ppm or ppm within a range defined by any of the preceding values, of isopropanol, ethanol, acetonitrile, dichloromethane, isopropyl acetate, n-heptane, dimethyl sulfoxide, ethyl acetate, methyl tert-butyl ether, or 2-methyltetrahydrofuran based on Compound I.

52. The pharmaceutical composition of claim 50 or 51, comprising at least 100 ppm, 75 ppm, 50 ppm, 40 ppm, 30 ppm, 20 ppm, 10 ppm or 5 ppm, or ppm within a range defined by any of the preceding values, of isopropanol, ethanol, acetonitrile, dichloromethane, isopropyl acetate, n-heptane, dimethyl sulfoxide, ethyl acetate, methyl tert-butyl ether, or 2- methyltetrahydrofuran based on Compound I.

53. The pharmaceutical composition of any one of claims 39-49, wherein the solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3- carboxylate meets at least one of the following criteria: (a) having an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks, in terms of 2θ, at 5.8°± 0.2°, 8.5°± 0.2°, and 19.7°± 0.2°; (b) having an X-ray powder diffraction (XRPD) pattern comprising peaks, in terms of 2θ, at 7.1°± 0.2°, 17.1°± 0.2°, 21.5°± 0.2°, 23.2°± 0.2°, and 24.1°± 0.2°; (c) having a bulk density of 0.21 g / mL, 0.22 g / mL, 0.23 g / mL, 0.24 g / mL, or 0.25 g / mL, or a bulk density within a range defined by any of the preceding values; (d) having an average particle size of 3.1 μm, 3.2 μm, 3.3 μm, 3.4 μm, 3.5 μm, 3.6 μm, 3.7 μm, 3.8 μm, or 3.9 μm or an average particle size within a range defined by any of the preceding values; (e) having a DSC thermogram with an endotherm having an extrapolated onset at 279°C, 280°C, 281°C, 282°C or 283°C, or an extrapolated onset temperature within a range defined by any of the preceding values; (f) having less than 3% total impurities after six months storage at 25°C ± 2°C / 60% ± 5% RH, preferably 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, or 1.3% total impurities after six months storage at 25°C ± 2°C / 60% ± 5% RH, or total impurities after six months storage at 25°C ± 2°C / 60% ± 5% RH within a range defined by any of the preceding values; and / or (g) having less than 3% total impurities after six months storage at 40°C ± 2°C / 75% ± 5% RH, preferably 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, or 1.3% total impurities after six months storage at 40°C ± 2°C / 75% ± 5% RH, or totalWSGR Docket No.42256-608.601 impurities after six months storage at 40°C ± 2°C / 75% ± 5% RH within a range defined by any of the preceding values.

54. The pharmaceutical composition of any one of claims 39-49, wherein the solid form of sodium 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3- carboxylate meets at least one of the following criteria: (a) having less than 3% total impurities after twelve months storage at 25°C ± 2°C / 60% ± 5% RH, preferably 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, or 1.3% total impurities after twelve months storage at 25°C ± 2°C / 60% ± 5% RH, or total impurities after twelve months storage at 25°C ± 2°C / 60% ± 5% RH within a range defined by any of the preceding values; (b) having less than 3% total impurities after 24 months storage at 25°C ± 2°C / 60% ± 5% RH, preferably 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, or 1.3% total impurities after 24 months storage at 25°C ± 2°C / 60% ± 5% RH, or total impurities after 24 months storage at 25°C ± 2°C / 60% ± 5% RH within a range defined by any of the preceding values; (c) having less than 3% total impurities after 36 months storage at 25°C ± 2°C / 60% ± 5% RH, preferably 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, or 1.3% total impurities after 36 months storage at 25°C ± 2°C / 60% ± 5% RH, or total impurities after 36 months storage at 25°C ± 2°C / 60% ± 5% RH within a range defined by any of the preceding values; and / or (d) having less than 3% total impurities after 48 months storage at 25°C ± 2°C / 60% ± 5% RH, preferably 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, or 1.3% total impurities after 48 months storage at 25°C ± 2°C / 60% ± 5% RH, or total impurities after 48 months storage at 25°C ± 2°C / 60% ± 5% RH within a range defined by any of the preceding values.

55. The solid form of claim 16 for use as a medicament, wherein the medicament comprises up to 5% impurities selected from compound B, compound C, compound D, and compoundWSGR Docket No.42256-608.60156. The solid form of claim 55 for use as a medicament, wherein the medicament comprises up to 0.2 area%, 0.3 area %, 0.4 area %, 0.5 area %, 0.6 area %, 0.7 area %, 0.8 area %, 0.9 area %, 1 area %, 1.5 area %, 2 area %, 2.5 area %, 3 area %, 3.5 area %, 4 area %, or 4.5 area % impurities as determined by HPLC selected from compound B, compound C, compound D, and compound E, or impurities in an amount by area % as determined by HPLC within a range defined by any two of the preceding values.

57. The solid form of claim 16 for use as a medicament, wherein the medicament comprises no more than 500 ppm, 100 ppm, 50 ppm, 40 ppm, 30 ppm, 20 ppm, 10 ppm, 5 ppm or 1 ppm, or ppm within a range defined by any of the preceding values, of methyl 3'- (bromomethyl)-4-chloro-[1,1'-biphenyl]-3-carboxylate, 2-cyclopentyl-5- hydroxyisoindolin-1-one, methyl 4-chloro-3'-(dibromomethyl)-[1,1'-biphenyl]-3- carboxylate, methyl 2-(bromomethyl)-4-methoxybenzoate, methyl bromide, methyl 4- chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3- carboxylate, sodium 3'-(bis((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-4-chloro- [1,1'-biphenyl]-3-carboxylate, methyl 3'-(bis((2-cyclopentyl-1-oxoisoindolin-5- yl)oxy)methyl)-4-chloro-[1,1'-biphenyl]-3-carboxylate or methyl 4′-chloro-2- (dibromomethyl)[1,1′-biphenyl]-4-carboxylate based on Compound I.

58. The solid form of claim 56 for use as a medicament, wherein the medicament comprises at least 0.5 ppm of methyl 3'-(bromomethyl)-4-chloro-[1,1'-biphenyl]-3-carboxylate, 2- cyclopentyl-5-hydroxyisoindolin-1-one, methyl 4-chloro-3'-(dibromomethyl)-[1,1'- biphenyl]-3-carboxylate, methyl 2-(bromomethyl)-4-methoxybenzoate, methyl bromide, methyl 4-chloro-3'-(((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-[1,1'-biphenyl]-3- carboxylate, sodium 3'-(bis((2-cyclopentyl-1-oxoisoindolin-5-yl)oxy)methyl)-4-chloro- [1,1'-biphenyl]-3-carboxylate, methyl 3'-(bis((2-cyclopentyl-1-oxoisoindolin-5- yl)oxy)methyl)-4-chloro-[1,1'-biphenyl]-3-carboxylate or methyl 4′-chloro-2- (dibromomethyl)[1,1′-biphenyl]-4-carboxylate based on Compound I.WSGR Docket No.42256-608.601 59. A method of treating a disease, disorder or condition in a mammal that would benefit from positive allosteric modulation of the metabotropic glutamate receptor, comprising administering to the individual a therapeutically effective amount of a solid form of any one of claims 31-38 or a pharmaceutical composition of one of claims 39-56.

60. The method of claim 59, wherein the disease, disorder or condition in a mammal is a CNS disorder.

61. The method of claim 60, wherein the CNS disorder is schizophrenia, anxiety, or addiction.

62. The method of any one of claims 59-61, wherein the therapeutically effective amount is administered orally.

Images