Gabaa positive allosteric modulator compounds, and methods of making and using the same

Abstract

To provide compounds for use in methods of treating a disease or disorder associated with α2 / α3 GABAA receptor.SOLUTION: Provided herein are crystalline polymorphs or co-crystals of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with phosphoric acid.SELECTED DRAWING: Figure 19

Description

[Technical Field]

[0001] cross reference

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 659,226, filed April 18, 2018, which is incorporated by reference in its entirety herein. Summary of the Invention

[0002] This disclosure generally relates to salts and polymorphs of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile (referred to herein as TPA023B), including the salt of TPA023B with phosphoric acid:

[0003] [ka]

[0004] This invention relates to salts and polymorphs, including but not limited to stable polymorphs of:

[0003] Polymorphs of the free base compound are also described that are suitable for use as active pharmaceutical ingredients in products intended for therapeutic use in either humans or animals, and also as chemical intermediates in the synthesis of active pharmaceutical ingredients.

[0005] In one aspect, disclosed herein is a crystalline salt or co-crystal of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with phosphoric acid, wherein the crystalline salt or co-crystal has at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as the XRPD pattern shown in FIG. 19, when measured using the parameters set forth in Table 1; (b) an XRPD pattern substantially the same as the XRPD pattern shown in FIG. 1, when measured using the parameters set forth in Table 1; (c) a densitometric value of about 6.4, 7.5, 10.2, 12.7, 13.3, 14.5, 15.0, 16.0, 17.5, 18.0, 19.0, 20.0, 21.0, 22.0, 23.0, 24.0, 25.0, 26.0, 27.0, 28.0, 29.0, 30.0, 31.0, 32.0, 33.0, 34.0, 35.0, 36.0, 37.0, 38.0, 39.0, 40.0, 41.0, 42.0, 43.0, 44.0, 45.0, 46.0, 47.0, 48.0, 49.0, 50.0, 51.0, 52.0, 53.0, 54.0, 55.0, 56.0, 57.0, 58.0, 59.0, 60.0, 61.0, 62.0 (d) an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of 6.0, 17.1, 17.4, 17.9, 18.5, 19.1, 19.7, 20.3, 20.9, 21.5, 22.6, 23.7, 26.2, 26.7, 26.9, 27.5, 28.4, 30.2, and 32.1±0.2 degrees two-theta; and (d) an XRPD pattern having characteristic peak positions of about 6.4, 7.5, 12.7, 13.3, 17.1, 17. (e) a differential scanning calorimetry (DSC) thermogram substantially identical to the DSC thermogram shown in FIG. 2A ; (f) a DSC thermogram having an endothermic peak at about 205° C.; (g) stable at about 40° C. for at least one week; and (h) stable at about 25° C. for at least one week. In certain embodiments, the crystalline salt or co-crystal provides an XRPD pattern substantially identical to the XRPD pattern shown in FIG. 19 when measured using the parameters set forth in Table 1. In certain embodiments, the crystalline salt or co-crystal provides an XRPD pattern substantially identical to the XRPD pattern shown in FIG. 1 when measured using the parameters set forth in Table 1. In certain embodiments, the crystalline salt or co-crystal provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.4, 7.5, 10.2, 12.7, 13.3, 14.5, 16.0, 17.1, 17.4, 17.9, 18.5, 19.1, 19.7, 20.3, 20.9, 21.5, 22.6, 23.7, 26.2, 26.7, 26.9, 27.5, 28.4, 30.2, and 32.1±0.2 degrees two-theta, when measured using the parameters set forth in Table 1.In certain embodiments, the crystalline salt or co-crystal provides an XRPD pattern having characteristic peak positions of at least six values ​​selected from the group consisting of about 6.4, 7.5, 10.2, 12.7, 13.3, 14.5, 16.0, 17.1, 17.4, 17.9, 18.5, 19.1, 19.7, 20.3, 20.9, 21.5, 22.6, 23.7, 26.2, 26.7, 26.9, 27.5, 28.4, 30.2, and 32.1±0.2 degrees two-theta, when measured using the parameters set forth in Table 1. In certain embodiments, the crystalline salt or co-crystal provides an XRPD pattern having characteristic peak positions at at least three values ​​selected from the group consisting of about 6.4, 7.5, 12.7, 13.3, 17.1, 17.4, 18.5, 19.1, 19.7, 26.7, 30.2, and 32.1±0.2 degrees two-theta, when measured using the parameters set forth in Table 1. In certain embodiments, the crystalline salt or co-crystal provides a DSC thermogram substantially identical to the DSC thermogram shown in FIG. 2A. In certain embodiments, the crystalline salt or co-crystal provides a DSC thermogram having an endothermic peak at about 205° C. In certain embodiments, the crystalline salt or co-crystal is stable at about 40° C. for at least one month. In certain embodiments, the crystalline salt or co-crystal is stable at about 25° C. for at least one month. In certain embodiments, the crystalline salt or co-crystal provides substantially the same XRPD pattern after storage at 40° C. and 75% RH for at least one week. In certain embodiments, the crystalline salt or co-crystal provides substantially the same XRPD pattern after at least two weeks of storage at 40° C. and 75% RH. In certain embodiments, the crystalline salt or co-crystal is a salt. In certain embodiments, the crystalline salt or co-crystal is a co-crystal.

[0006] In another aspect, provided herein is a crystalline polymorph of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile of Form C, having a molecular weight of about 5.4, 10.8, 12.3, 12.5, 13.0, 14.0, 15.0, 16.0, 17.0, 18.0, 19.0, 20.0, 21.0, 22.0, 23.0, 24.0, 25.0, 26.0, 27.0, 28.0, 30.0, 31.0, 32.0, 33.0, 34.0, 35.0, 36.0, 37.0, 38.0, 40.0, 41.0, 42.0, 43.0, 44.0, 45.0, 46.0, 47.0, 48.0, 50.0, 51.0, 52.0, 53.0, 54.0, 55.0, 56.0, 57.0, 58.0, 59.0, 60.0, 61.0, 62.0, 63.0, 64.0, 65.0, 66.0, 67.0, 68.0, 69.0, 70.0, 71.0, 72.0, 73.0, 74.0, 75.0, 76.0, 77.0, 78.0, 79.0, 80.0, 81.0, 82.0, 83. Selected from the group consisting of 0.6, 13.5, 14.8, 15.9, 16.3, 16.4, 17.3, 17.8, 19.3, 20.4, 21.5, 21.7, 22.7, 23.4, 24.4, 24.7, 25.0, 26.1, 26.6, 27.0, 27.2, 27.5, 28.4, 28.7, 29.0, 29.6, 30.2 and 32.3 ± 0.2 degrees 2-theta Disclosed are crystalline polymorphs that provide an X-ray powder diffraction (XRPD) pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 5.4, 10.8, 12.3, 12.6, 13.5, 14.8, 16.2, 17.3, 19.3, 20.4, 21.7, 22.7, 23.4, 24.4, 25.0, 27.2, 29.6, and 32.2±0.2 degrees two-theta when measured using the parameters set forth in Table 1. In some embodiments, the crystalline polymorph provides an XRPD pattern substantially identical to the XRPD pattern labeled Form C in Figure 12. In some embodiments, the crystalline polymorph has a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 210°C. In certain embodiments, the crystalline polymorph has a DSC thermogram substantially the same as the DSC thermogram shown in Figure 13. The crystalline polymorph of Form B of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile provides an X-ray powder diffraction (XRPD) pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 7.4, 7.7, 10.0, 13.2, 17.2, 20.4, and 29.9±0.2 degrees two-theta, when measured using the parameters set forth in Table 1. In certain embodiments, the crystalline polymorph provides an XRPD pattern substantially the same as the XRPD pattern shown in Figure 11. In certain embodiments, the crystalline polymorph is an ethanol solvate.

[0007] In another aspect, disclosed herein is a crystalline salt or co-crystal of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with toluenesulfonic acid, which provides an X-ray powder diffraction (XRPD) pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 7.0, 12.4, 12.6, 13.0, 14.1, 15.4, 15.7, 16.3, 17.5, 18.3, 19.0, 21.0, 22.3, 23.0, and 24.9±0.2 degrees two-theta, when measured using the parameters set forth in Table 1. In certain embodiments, the crystalline salt or co-crystal provides an XRPD pattern substantially the same as the XRPD pattern shown in FIG. In certain embodiments, the crystalline salt or co-crystal is a hydrate or solvate. In certain embodiments, the crystalline salt or co-crystal provides a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 170° C. In certain embodiments, the crystalline salt or co-crystal provides a DSC thermogram substantially the same as the DSC thermogram shown in FIG.

[0008] In one aspect, disclosed herein are therapeutic or prophylactic compositions comprising the compounds described herein.

[0008] In another aspect, disclosed herein is a method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or composition described herein. In some embodiments, the disease or disorder is associated with α2 / α3 GABAA receptors. In some embodiments, the disease or disorder is selected from the following diseases or disorders: pain, anxiety, epilepsy, muscle spasms, pruritus, itching, cognitive impairment, alcoholism, drug addition, schizophrenia, depression, autism, panic disorder, and generalized anxiety disorder. In some embodiments, the disease or disorder is pain. In some embodiments, the pain is fibromyalgia, inflammatory pain, neuropathic pain, peripheral diabetic neuropathy, chemotherapy-induced pain, HIV-associated neuropathy, postherpetic neuralgia, musculoskeletal pain, rheumatoid arthritis, osteoarthritis, post-surgical pain, burn pain, sunburn pain, or phantom limb pain. In some embodiments, the disease or disorder is itch. In some embodiments, the itch is chronic itch, neurogenic itch, uremic itch, neurodermatitis, atopic dermatitis, prurigo nodularis, paresthesia back pain (Notalgia P) In some embodiments, the disease or disorder is epilepsy. In some embodiments, the epilepsy is selected from the group consisting of focal epilepsy, generalized epilepsy, Dravet syndrome, childhood absence epilepsy (CEA), juvenile absence epilepsy, juvenile myoclonic epilepsy (JME), West syndrome, Lennox-Gastaut syndrome (LGS), sunflower syndrome, status epilepticus, and the like. epilepticus), nerve agent-induced seizures, alcohol withdrawal-related tremors, traumatic brain injury, tuberous sclerosis, Doss syndrome, Rasmussen syndrome, early myoclonic encephalopathy, malignant migratory partial seizures of infancy, epilepsy with continuous spikes and waves during slow-wave sleep, Landau-Kleffner syndrome, benign epilepsy with centrotemporal spikes, benign familial neonatal infantile seizures, cortical dysplasia, focal epilepsy syndrome, generalized epilepsy with febrile seizures plus (GEFS+), myoclonic atonic epilepsy, malignant migratory partial seizures of infancy, Ohtahara syndrome (also known as early infantile epileptic encephalopathy), or partial epilepsy and febrile seizures plus. In some embodiments, the disease or disorder is autism. In some embodiments, the autism is autism resulting from an SCN2a mutation, fragile X syndrome, or autism associated with ion channel dysfunction.

[0009] In one aspect, disclosed herein is a method for preparing a crystalline salt or co-crystal of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with phosphoric acid, the method comprising crystallizing 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile phosphate from a solution comprising one or more of ethyl acetate, methyl ethyl ketone, 2-methylbutanone, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, acetone, water, tetrahydrofuran (THF), 2-methyl-THF, isopropyl acetate (IPAC), acetonitrile, and dichloromethane, wherein the crystalline salt or co-crystal has a pH measured using the parameters listed in Table 1. and providing an X-ray powder diffraction (XRPD) pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.4, 7.5, 10.2, 12.7, 13.3, 14.5, 16.0, 17.1, 17.4, 17.9, 18.5, 19.1, 19.7, 20.3, 20.9, 21.5, 22.6, 23.7, 26.2, 26.7, 26.9, 27.5, 28.4, 30.2, and 32.1±0.2 degrees two-theta. In certain embodiments, the crystalline salt or co-crystal provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.4, 7.5, 12.7, 13.3, 17.1, 17.4, 18.5, 19.1, 19.7, 26.7, 30.2, and 32.1±0.2 degrees two-theta, when measured using the parameters set forth in Table 1. In certain embodiments, the crystalline salt or co-crystal provides an XRPD pattern substantially the same as the XRPD pattern shown in Figure 19, when measured using the parameters set forth in Table 1. [Brief explanation of the drawings]

[0010] [Figure 1] FIG. 1 illustrates the XRPD pattern for TPA023B phosphate Form A. [Figure 2A]

[0011] Figure 2A illustrates the DSC / TGA thermogram for TPA023B phosphate Form A (Figure 2A); [Figure 2B] Figure 2B illustrates the NMR spectrum of TPA023B phosphate Form A (Figure 2B); and [Figure 2C] FIG. 2C illustrates an additional DSC / TGA thermogram for TPA023B phosphate Form A (FIG. 2C). [Figure 3]

[0012] FIG. 3 illustrates the XRPD pattern for TPA023B phosphate pattern B. [Figure 4]

[0013] FIG. 4 illustrates the DSC / TGA thermogram for TPA023B phosphate pattern B. [Figure 5]

[0014] FIG. 5 illustrates the XRPD pattern for TPA023B free base form C. [Figure 6]

[0015] FIG. 6 illustrates the DSC / TGA thermogram for TPA023B free base form C. [Figure 7]

[0016] FIG. 7 illustrates the XRPD pattern for a TPA023B phosphate mixture containing TPA023B phosphate Form A. [Figure 8]

[0017] FIG. 8 illustrates the DSC / TGA thermogram for TPA023B phosphate mixtures containing TPA023B phosphate Form A. [Figure 9]

[0018] FIG. 9 illustrates the XRPD pattern for TPA023B free base form A. [Figure 10A]

[0019] FIG. 10A illustrates the DSC / TGA thermogram for TPA023B free base form A (FIG. 10A); and [Figure 10B]FIG. 10B illustrates the NMR spectrum for TPA023B free base form A (FIG. 10B). [Figure 11]

[0020] FIG. 11 illustrates the XRPD pattern for TPA023B free base form B. [Figure 12]

[0021] FIG. 12 illustrates the XRPD pattern for TPA023B free base form C. [Figure 13]

[0022] FIG. 13 illustrates the DSC thermogram for TPA023B free base form C. [Figure 14]

[0023] FIG. 14 illustrates the XRPD pattern for the TPA023B free base mixture containing free base Form A. [Figure 15]

[0024] FIG. 15 illustrates the XRPD pattern for TPA023B chloride Pattern A. [Figure 16]

[0025] FIG. 16 illustrates the DSC / TGA thermogram for TPA023B chloride Pattern A. [Figure 17A]

[0026] Figure 17A shows the XRPD pattern for TPA023B tosylate Form A (Figure 17A); and [Figure 17B] FIG. 17B illustrates the NMR spectrum for TPA023B tosylate Form A (FIG. 18B). [Figure 18]

[0027] FIG. 18 illustrates the DSC / TGA thermogram for TPA023B tosylate Form A. [Figure 19]

[0028] FIG. 19 illustrates the XRPD pattern for TPA023B phosphate Form A. [Figure 20]

[0029] FIG. 20 illustrates the XRPD pattern of the TPA023B HCl salt screen. [Figure 21]

[0030] FIG. 21 illustrates the XRPD pattern of the TPA023B sulfate screen. [Figure 22]

[0031] FIG. 22 illustrates the XRPD pattern of the TPA023B phosphate screen. [Figure 23]

[0032] FIG. 23 illustrates the XRPD pattern of the TPA023B tosylate screen. [Figure 24]

[0033] FIG. 24 illustrates the XRPD pattern of the TPA023B methanesulfonate salt screen. [Figure 25]

[0034] FIG. 25 illustrates the TGA and DSC results of TPA023B HCl salt in an acetone system (a mixture containing TPA023B free base form C and TPA023B chloride pattern A). [Figure 26]

[0035] FIG. 26 illustrates the TGA and DSC results of TPA023B phosphate in an ACN system (TPA023B phosphate form A). [Figure 27]

[0036] FIG. 27 illustrates an overlay of the XRPD profiles of TPA023B slurries in solvent (I). [Figure 28]

[0037] FIG. 28 illustrates an overlay of the XRPD profiles of TPA023B slurries in solvent (II). [Figure 29]

[0038] FIG. 29 illustrates the XRPD pattern of TPA023B phosphate solids obtained by polymorph screening using the slurry method. [Figure 30]

[0039] FIG. 30 illustrates the XRPD pattern of TPA023B phosphate solid obtained by polymorph screening using the heat-cool method. [Figure 31]

[0040] FIG. 31 illustrates the DSC / TGA thermogram for TPA023B phosphate pattern D. [Figure 32]

[0041] FIG. 32 illustrates the XRPD pattern of TPA023B phosphate solid obtained by polymorph screening using the anti-solvent method. [Figure 33]

[0042] FIG. 33 illustrates additional XRPD patterns of TPA23B polymorph screening by the heat-cool method. [Figure 34]

[0043] FIG. 34 illustrates additional DSC / TGA thermograms of TPA023B polymorph screening in IPA by the heat-cool method. DETAILED DESCRIPTION OF THE INVENTION

[0011]

[0044] Described herein are novel free base polymorphs, pharmaceutical salts, and cocrystals with beneficial properties, including improved solubility, improved oral bioavailability, more consistent oral bioavailability, improved stability, improved manufacturability, and corresponding improved formulations. Described herein are salts, cocrystals, polymorphs, salt polymorphs, and cocrystal polymorphs of TPA023B, which are useful for treating several disorders in addition to itch. Those skilled in the art will appreciate that such compounds may find use in treating any disorder reported to be treatable by α2 / α3 GABAA-positive allosteric modulators, as well as disorders treatable by non-selective GABAA-positive allosteric modulators. These include, but are not limited to, pain, anxiety, epilepsy, muscle spasms, pruritus, itching, cognitive impairment, alcoholism, schizophrenia, depression, autism, and the like.

[0012] phosphate Phosphate Form A

[0045] In one or more embodiments, the present disclosure introduces a novel stable polymorph of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile, a salt or co-crystal with phosphoric acid. In one or more embodiments, protonated 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile has a pKa of 2.19 as measured in Example 23. Phosphoric acid is reported to have a pKa of 2.16. It has been surprisingly discovered that 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile can form a stable crystalline polymorph with phosphoric acid due to similar pKa values. In one or more embodiments, the crystalline form is a salt. In one or more embodiments, the crystalline form is a co-crystal. This crystalline polymorph, designated "Phosphate Polymorph Form A" (i.e., Phosphate Form A), has a pH of approximately 6.4, 7.5, 12.7, 13.3, 17.1, 17.4, 18.5, 19.1, 19.7, 26.7, 30.2, and 32.1±0.2 degrees, 2 seams, as measured using the parameters set forth in Table 1. In one or more embodiments, phosphate polymorph Form A exhibits an X-ray powder diffraction (XRPD) pattern having characteristic peak positions for at least 3, at least 6, at least 9, at least 12, or all values ​​selected from the group consisting of: phosphate polymorph Form A, phosphate polymorph Form B, phosphate polymorph Form C, phosphate polymorph Form D, phosphate polymorph Form E, phosphate polymorph Form F ... In certain embodiments, phosphate polymorph Form A provides an XRPD pattern having characteristic peak positions of at least 3, at least 6, at least 9, at least 12, at least 15, or all values ​​selected from the group consisting of about 6.4, 7.5, 10.2, 12.7, 13.3, 14.5, 16.0, 17.1, 17.4, 17.9, 18.5, 19.1, 19.7, 20.3, 20.9, 21.5, 22.6, 23.7, 26.2, 26.7, 26.9, 27.5, 28.4, 30.2, and 32.1±0.2 degrees two-theta when measured using the parameters set forth in Table 1. In certain embodiments, phosphate polymorph Form A exhibits an XRPD pattern having a characteristic peak located at about 6.4±0.2 degrees two-theta. In certain embodiments, phosphate polymorph Form A exhibits an XRPD pattern with a characteristic peak located at about 7.5±0.2 degrees 2-theta. In certain embodiments, phosphate polymorph Form A exhibits an XRPD pattern with a characteristic peak located at about 13.3±0.2 degrees 2-theta. In certain embodiments, phosphate polymorph Form A exhibits an XRPD pattern with a characteristic peak located at about 17.4±0.2 degrees 2-theta. In certain embodiments, phosphate polymorph Form A exhibits an XRPD pattern with a characteristic peak located at about 18.5±0.2 degrees 2-theta. In certain embodiments, phosphate polymorph Form A exhibits an XRPD pattern with a characteristic peak located at about 19.1±0.2 degrees 2-theta. In certain embodiments, phosphate polymorph Form A exhibits an XRPD pattern with a characteristic peak located at about 26.7±0.2 degrees 2-theta. In certain embodiments, phosphate polymorph Form A exhibits an XRPD pattern with a characteristic peak located at about 30.2±0.2 degrees 2-theta.In one or more embodiments, phosphate polymorph Form A exhibits an XRPD pattern substantially the same as the XRPD pattern labeled Phosphate Form A in FIG.

[0013] [Table 1]

[0014]

[0046] In some embodiments, phosphate polymorph Form A is a stable form. In some embodiments, phosphate polymorph Form A can be stored at various temperatures and relative humidity. For example, phosphate polymorph Form A can be stored at about -20°C, about -10°C, about 0°C, about 5°C, about 15°C, about 25°C, about 40°C, about 60°C, and about 80°C. As another example, phosphate polymorph Form A can be stored at 10% RH, 20% RH, 30% RH, 40% RH, 50% RH, 60% RH, 75% RH, 90% RH, or 95% RH. In some embodiments, phosphate polymorph Form A can be stored at about 25°C for at least 7 days, at least 14 days, at least 21 days, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, or at least 1 month. In some embodiments, phosphate polymorph Form A is stable for at least 12 months or at least 24 months at about 25° C. In some embodiments, phosphate polymorph Form A is stable for at least 36 months, at least 48 months, or at least 60 months at about 25° C. In some embodiments, phosphate polymorph Form A is stable for at least 3 days, at least 7 days, at least 14 days, at least 21 days, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, or at least 24 months at about 40° C. In some embodiments, phosphate polymorph Form A is stable for at least 3 days, at least 7 days, at least 14 days, at least 21 days, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, or at least 24 months at about 60° C. In some embodiments, stable phosphate polymorph Form A has about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more w / w of the initial amount of phosphate at the end of a given storage period. In some embodiments, stable phosphate polymorph Form A has about 20%, 15%, 10%, 5%, 2%, 1% or less w / w of total impurities or related substances at the end of a given storage period. In some embodiments, phosphate polymorph Form A provides substantially the same XRPD pattern after at least one week of storage at about 40°C and 75% RH. In some embodiments, phosphate polymorph Form A provides substantially the same XRPD pattern after at least two weeks of storage at about 40°C and 75% RH. In some embodiments, phosphate polymorph Form A provides substantially the same XRPD pattern after at least one month of storage at about 40°C and 75% RH. In some embodiments, phosphate polymorph Form A provides substantially the same XRPD pattern after at least 3 months of storage at about 40° C. and 75% RH. In some embodiments, phosphate polymorph Form A provides substantially the same XRPD pattern after at least 6 months of storage at about 40° C. and 75% RH. In some embodiments, phosphate polymorph Form A provides substantially the same XRPD pattern after at least 9 months of storage at about 40° C. and 75% RH.In certain embodiments, phosphate polymorph Form A provides substantially the same XRPD pattern after storage at about 40° C. and 75% RH for at least 12 months.

[0015]

[0047] In one or more embodiments, phosphate polymorph Form A has a melting range of about 199°C to about 209°C. In one or more embodiments, phosphate polymorph Form A exhibits a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 205°C. In one or more embodiments, phosphate polymorph Form A provides a DSC thermogram comprising an endothermic peak at about 206°C. In some embodiments, phosphate polymorph Form A provides a DSC thermogram comprising a single endothermic peak with an onset temperature of 203°C. In some embodiments, phosphate polymorph Form A provides a DSC thermogram comprising a single endothermic peak with an onset temperature of 204°C. In some embodiments, phosphate polymorph Form A provides a DSC thermogram comprising a single endothermic peak with an onset temperature of 205°C. In one or more embodiments, phosphate polymorph Form A exhibits a DSC thermogram substantially the same as the DSC thermogram shown in Figure 2A. In certain embodiments, phosphate polymorph Form A provides a DSC thermogram substantially the same as that shown in Figure 2C. In one or more embodiments, phosphate polymorph Form A exhibits a DSC thermogram substantially the same as that shown in Figure 26. This melting point is obtained using DSC at a heating rate of 10°C / min. In certain embodiments, phosphate polymorph Form A exhibits birefringence under polarized light. Phosphate polymorph Form A can be synthesized using the method of Example 5. In one or more embodiments, pharmaceutical compositions comprising phosphate polymorph Form A are described. In one or more embodiments, the present disclosure includes purified forms of crystalline phosphate polymorph Form A.

[0016]

[0048] In one or more embodiments, the phosphate polymorph Form A described herein has a solubility of at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85% as measured by HPLC as described herein. , at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% pure. In certain embodiments, phosphate polymorph Form A described herein contains impurities. In certain embodiments, the impurities in phosphate polymorph Form A are at most 0.1%, at most 0.5%, at most 1%, at most 2%, at most 3%, at most 4%, at most 5%, at most 6%, at most 7%, at most 8%, at most 9%, at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 40%, or at most 50% pure, as measured by HPLC as described herein.

[0017]

[0049] In some embodiments, phosphate polymorph Form A has a plasma half-life in rat plasma of at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 13 hours, at least 14 hours, or at least 15 hours. In some embodiments, phosphate polymorph Form A has a plasma half-life in rat plasma of at most 5 hours, at most 6 hours, at most 7 hours, at most 8 hours, at most 9 hours, at most 10 hours, at most 11 hours, at most 12 hours, at most 13 hours, at most 14 hours, at most 15 hours, at most 20 hours, or at most 40 hours. In some embodiments, phosphate polymorph Form A has a plasma half-life in rat plasma of from about 8 hours to about 15 hours. In certain embodiments, phosphate polymorph Form A has a plasma half-life of about 10 hours to about 13 hours in rat plasma.

[0018]

[0050] Phosphate polymorph Form A can have a higher solubility than the free base form of TPA023B. For example, solubility can be determined as described in Example 15. In some embodiments, the solubility of phosphate polymorph Form A is at least 1.1-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, or 8-fold higher in simulated gastric fluid (SGF) than the solubility of free base Form A. In some embodiments, the solubility of phosphate polymorph Form A is at least 1.1-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, or 8-fold higher in fasted-state simulated intestinal fluid (FaSSIF) than the solubility of free base Form A. In some embodiments, the solubility of phosphate polymorph Form A is at least 1.1-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, or 8-fold greater than the solubility of free base polymorph Form A in fed-state simulated intestinal fluid (FeSSIF).

[0019] Phosphate Pattern

[0051] In certain embodiments, described herein are mixtures containing crystalline polymorphs of salts or co-crystals of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with phosphoric acid. This crystalline polymorphic mixture is designated "phosphate polymorph pattern B" (i.e., phosphate pattern B) and exhibits an XRPD pattern having characteristic peak positions of at least 3, at least 6, at least 9, at least 12, at least 15, or all values ​​selected from the group consisting of about 6.3, 7.0, 8.0, 9.4, 10.9, 12.7, 13.2, 14.0, 14.7, 16.1, 17.3, 19.4, 19.7, 22.1, 24.1, 24.3, 26.6, 27.0, and 28.2±0.2 degrees two-theta, as measured using the parameters set forth in Table 1. TPA023B phosphate polymorph pattern B can comprise TPA023B phosphate Form A. Phosphate polymorph pattern B can also comprise phosphate pattern G. In one or more embodiments, phosphate polymorph pattern B exhibits an XRPD pattern substantially the same as the XRPD pattern shown in Figure 3. In one or more embodiments, phosphate polymorph pattern B has a melting / dehydration / desolvation range of about 80°C to about 205°C. In one or more embodiments, phosphate polymorph pattern B exhibits a DSC thermogram comprising endothermic peaks at about 193° C. and about 203° C. In one or more embodiments, phosphate polymorph pattern B exhibits a DSC thermogram substantially the same as the DSC thermogram shown in FIG. 4A. In one or more embodiments, phosphate polymorph pattern B can be synthesized using the method of Example 6. In one or more embodiments, pharmaceutical compositions comprising phosphate polymorph pattern B are described.

[0020]

[0052] In certain embodiments, described herein are other mixtures containing crystalline polymorphs of salts or co-crystals of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with phosphoric acid. This crystalline polymorphic mixture is designated "phosphate polymorph pattern D" (i.e., phosphate pattern D) and exhibits an XRPD pattern having characteristic peak positions of at least 3, at least 6, at least 9, at least 12, at least 15, or all values ​​selected from the group consisting of about 5.3, 6.3, 7.4, 10.8, 12.2, 12.6, 13.1, 13.3, 14.6, 15.8, 16.0, 16.9, 17.1, 18.9, 19.0, 19.4, 20.1, 22.5, 23.1, 24.3, 24.9, 26.0, 26.5, 27.2, 29.5, and 30.0±0.2 degrees two-theta when measured using the parameters set forth in Table 1. TPA023B phosphate polymorph pattern D can comprise TPA023B phosphate Form A. TPA023B phosphate polymorph pattern D can also include TPA023B free base form C. In one or more embodiments, phosphate polymorph pattern D exhibits an XRPD pattern substantially the same as the XRPD pattern labeled phosphate pattern D, as shown in Figure 30. In one or more embodiments, phosphate polymorph pattern D has a melting / dehydration / desolvation range of about 190 to about 210°C. In one or more embodiments, phosphate polymorph pattern D exhibits a DSC thermogram including an endothermic peak at about 202°C. In one or more embodiments, phosphate polymorph pattern D exhibits a DSC thermogram substantially the same as the DSC thermogram shown in Figure 31. In one or more embodiments, phosphate polymorph pattern D can be synthesized using the methods described in Example 27. In one or more embodiments, pharmaceutical compositions comprising phosphate polymorph pattern D are described.

[0021]

[0053] In one or more embodiments, a mixture containing a crystalline polymorph of a salt or co-crystal of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with phosphoric acid is described. This crystalline polymorphic mixture exhibits an XRPD pattern designated "Phosphate Polymorph Pattern E" having characteristic peak positions of at least three, at least six, at least nine, at least twelve, or all values ​​selected from the group consisting of about 6.4, 7.6, 13.0, 13.3, 15.5, 15.8, 17.0, 17.4, 19.1, 19.5, 20.3, 20.7, 26.8, and 30.1±0.2 degrees two-theta, as measured using the parameters set forth in Table 1. TPA023B phosphate polymorph pattern E is likely a mixture containing TPA023B phosphate form A. In one or more embodiments, phosphate polymorph pattern E exhibits an XRPD pattern substantially the same as the XRPD pattern shown in Figure 7. In one or more embodiments, phosphate polymorph pattern E has a melting / dehydration / desolvation range of about 60°C to about 95°C. In one or more embodiments, phosphate polymorph pattern E exhibits a DSC thermogram including an endothermic peak at about 191°C. In one or more embodiments, phosphate polymorph pattern E exhibits a DSC thermogram including an endothermic peak at about 199°C. In one or more embodiments, phosphate polymorph pattern E exhibits a DSC thermogram substantially the same as the DSC thermogram shown in Figure 8. This melting point is obtained using a DSC with a heating rate of 10°C / min. In one or more embodiments, phosphate polymorph pattern E is synthesized using the method of Example 8. In one or more embodiments, pharmaceutical compositions comprising phosphate polymorph pattern E are described.

[0022] Tosylate

[0054] In one or more embodiments, a crystalline polymorph of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile salt with p-toluenesulfonic acid is also described. This crystalline polymorph is designated "tosylate polymorph Form A" (i.e., Tosylate Form A), and exhibits an XRPD pattern having characteristic peak positions of at least 3, at least 6, at least 9, at least 12, at least 15, or all values ​​selected from the group consisting of about 7.0, 12.4, 12.6, 13.0, 14.1, 15.4, 15.7, 16.3, 17.5, 18.3, 19.0, 21.0, 22.3, 23.0, 24.9, and ±0.2 degrees two-theta, when measured using the parameters set forth in Table 1. In one or more embodiments, tosylate polymorph Form A exhibits an XRPD pattern substantially identical to the XRPD pattern shown in Figure 17A. In one or more embodiments, tosylate polymorph Form A has a melting range of about 155°C to about 175°C. In one or more embodiments, tosylate polymorph Form A exhibits a DSC thermogram comprising an endothermic peak at about 170°C. In one or more embodiments, tosylate polymorph Form A exhibits a DSC thermogram substantially identical to the DSC thermogram shown in Figure 18. This melting point is obtained using a DSC with a heating rate of 10°C / min. In certain embodiments, tosylate polymorph Form A can be synthesized using the method of Example 9. In one or more embodiments, pharmaceutical compositions comprising tosylate polymorph Form A are described. In one or more embodiments, the present disclosure provides purified forms of crystalline tosylate polymorph Form A.

[0023] Free base

[0055] In one or more embodiments, a crystalline polymorph of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile has also been identified. This crystalline polymorph is designated "Free Base Polymorph Form A" and exhibits an XRPD pattern having characteristic peak positions of at least 3, at least 6, at least 9, at least 12, at least 15, or all values ​​selected from the group consisting of about 5.5, 11.0, 12.0, 12.5, 14.7, 16.5, 17.1, 18.1, 18.4, 19.3, 20.6, 22.1, 23.5, 24.6, 25.3, 26.8, 27.7, 28.1, 29.3, and 30.5±0.2 degrees two-theta, when measured using the parameters set forth in Table 1. In one or more embodiments, free base polymorph Form A exhibits an XRPD pattern substantially the same as the XRPD pattern shown in Figure 9. In one or more embodiments, free base polymorph Form A has a melting range of about 195°C to about 210°C. In one or more embodiments, free base polymorph Form A exhibits a DSC thermogram comprising an endothermic peak at about 206°C. In one or more embodiments, free base polymorph Form A exhibits a DSC thermogram substantially the same as the DSC thermogram shown in Figure 10A. This melting point is obtained using a DSC with a heating rate of 10°C / min. In certain embodiments, free base polymorph Form A exhibits birefringence under polarized light. In certain embodiments, free base polymorph Form A is anhydrous. In certain embodiments, free base polymorph Form A can be synthesized using the method of Example 10. In one or more embodiments, pharmaceutical compositions comprising free base polymorph Form A are described. In one or more embodiments, the present disclosure includes purified forms of crystalline free base polymorph Form A.

[0024]

[0056] In one or more embodiments, the present disclosure further provides a crystalline polymorph of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile. This crystalline polymorph is designated "Free Base Polymorph Form B" and is determined using the parameters set forth in Table 1. 11. In one or more embodiments, the free base polymorph Form B exhibits an XRPD pattern having characteristic peak positions of at least 3, at least 6, at least 9, at least 12, at least 15, or all values ​​selected from the group consisting of about 6.3, 7.4, 7.7, 10.0, 13.2, 15.6, 15.8, 16.7, 17.2, 19.1, 19.4, 20.0, 20.4, 26.0, 26.7, 27.9, and 29.9±0.2 degrees two-theta, as measured at 200° C. In one or more embodiments, the free base polymorph Form B exhibits an XRPD pattern substantially the same as the XRPD pattern shown in FIG. 11. In one or more embodiments, the free base polymorph Form B has a melting / desolvation range of about 40° C. to about 150° C. In one or more embodiments, the free base polymorph Form B is synthesized using the method of Example 11. In one or more embodiments, pharmaceutical compositions comprising the free base polymorph Form B are described. In one or more embodiments, the present disclosure provides an ethanol solvate. In one or more embodiments, the present disclosure provides a purified form of the crystalline free base polymorph Form B.

[0025]

[0057] In one or more embodiments, yet another crystalline polymorph of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile is described herein. This crystalline polymorph is designated "free base polymorph Form C" (i.e., free base Form C), and exhibits an XRPD pattern having characteristic peak positions of at least 3, at least 6, at least 9, at least 12, at least 15, or all values ​​selected from the group consisting of about 5.4, 10.8, 12.3, 12.6, 13.5, 14.8, 16.2, 17.3, 19.3, 20.4, 21.7, 22.7, 23.4, 24.4, 25.0, 27.2, 29.6, and 32.2±0.2 degrees two-theta, when measured using the parameters set forth in Table 1. In certain embodiments, the free base polymorph Form C provides an XRPD pattern having characteristic peak positions of at least 3, at least 6, at least 9, at least 12, at least 15, or all values ​​selected from the group consisting of about 5.4, 10.8, 12.3, 12.6, 13.5, 14.8, 15.9, 16.3, 16.4, 17.3, 17.8, 19.3, 20.4, 21.5, 21.7, 22.7, 23.4, 24.4, 24.7, 25.0, 26.1, 26.6, 27.0, 27.2, 27.5, 28.4, 28.7, 29.0, 29.6, 30.2, and 32.3±0.2 degrees two-theta when measured using the parameters set forth in Table 1. In one or more embodiments, TPA023B free base polymorph Form C exhibits an XRPD pattern substantially the same as the XRPD pattern shown in Figure 5. In one or more embodiments, free base polymorph Form C exhibits an XRPD pattern substantially the same as the XRPD pattern shown in Figure 12.

[0026]

[0058] In one or more embodiments, free base polymorph Form C has a melting range of about 205°C to about 215°C. In one or more embodiments, free base polymorph Form C has a melting range of about 195°C to about 215°C. In one or more embodiments, free base polymorph Form C exhibits a DSC thermogram comprising an endothermic peak at about 209-211°C. In one or more embodiments, free base polymorph Form C exhibits a DSC thermogram comprising an endothermic peak at about 209°C. In one or more embodiments, free base polymorph Form C exhibits a DSC thermogram comprising an endothermic peak at about 210°C. In one or more embodiments, free base polymorph Form C exhibits a DSC thermogram comprising an endothermic peak at about 211°C. In one or more embodiments, free base polymorph Form C exhibits a DSC thermogram comprising an endothermic peak with an onset temperature at about 209°C. In one or more embodiments, free base polymorph Form C exhibits a DSC thermogram substantially the same as FIG. 13. In one or more embodiments, the free base polymorph Form C exhibits a DSC thermogram substantially the same as that shown in Figure 6. This melting point is obtained using a DSC with a heating rate of 10°C / min. In certain embodiments, the free base polymorph Form C exhibits birefringence under polarized light. In one or more embodiments, the free base polymorph Form C can be synthesized using the method of Example 12. In certain embodiments, the free base polymorph Form C is anhydrous. In US Pat. No. 6,299,499, a pharmaceutical composition is described comprising the free base polymorph Form C. In one or more embodiments, the present disclosure provides a purified form of the crystalline free base polymorph Form C.

[0027]

[0059] In some embodiments, the free base polymorph Form C is a stable form. In some embodiments, the free base polymorph Form C can be stored at various temperatures and relative humidities. For example, the free base polymorph Form C can be stored at about -20°C, about -10°C, about 0°C, about 5°C, about 15°C, about 25°C, about 40°C, and about 60°C. As another example, the free base polymorph Form C can be stored at 10% RH, 20% RH, 30% RH, 40% RH, 50% RH, 60% RH, 75% RH, 90% RH, or 95% RH. In some embodiments, the free base polymorph Form C is stable at about 25°C for at least 7 days, at least 14 days, at least 21 days, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 24 months, at least 36 months, at least 48 months, or at least 60 months. In some embodiments, the free base polymorph Form C is stable for at least 3 days, at least 7 days, at least 14 days, at least 21 days, at least 1 month, at least 3 months, at least 6 months, at least 9 months, at least 12 months, or at least 24 months at about 40° C. In some embodiments, the free base polymorph Form C is stable for at least 3 days, at least 7 days, at least 14 days, at least 21 days, at least 1 month, at least 3 months, at least 6 months, at least 9 months, at least 12 months, or at least 24 months at about 60° C. In some embodiments, a stable TPA023B free base polymorph form, such as free base Form C, has about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% w / w or more of the initial amount of free base at the end of a given storage period. In certain embodiments, a stable TPA023B free base polymorphic form, such as free base Form C, has about 20%, 15%, 10%, 5%, 2%, 1% w / w or less of total impurities or related substances at the end of a given storage period. In certain embodiments, free base polymorph Form C provides substantially the same XRPD pattern after at least 1 week of storage at about 40° C. and 75% RH.In certain embodiments, the free base polymorph Form C provides substantially the same XRPD pattern after storage at about 40° C. and 75% RH for at least 2 weeks, at least 1 month, at least 3 months, at least 6 months, at least 9 months, at least 12 months, or at least 24 months.

[0028]

[0060] In one or more embodiments, the free base polymorphic form described herein, e.g., free base Form C, is at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% pure as measured by HPLC as described herein. In some embodiments, the free base polymorphic form, e.g., free base Form C, contains impurities. In some embodiments, impurities in the free base form, e.g., free base Form C, are at most 0.1%, at most 0.5%, at most 1%, at most 2%, at most 3%, at most 4%, at most 5%, at most 6%, at most 7%, at most 8%, at most 9%, at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 40%, or at most 50%, as measured by HPLC as described herein.

[0029]

[0061] In one or more embodiments, a crystalline polymorphic mixture of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile is described. This crystalline polymorphic mixture is designated "Free Base Polymorph Pattern D" and has the following molecular weights as measured using the parameters set forth in Table 1: approximately 5.4, 10.8, 11.0, 12.0, 12.4, 13.5, 14.7, 15.8, 16.2, 16.5, 17.2, 18.0, 19.3, 20. 14. 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 13 Free base polymorphic pattern D can be synthesized using the method of Example 13. In one or more embodiments, pharmaceutical compositions comprising free base polymorphic pattern D are described. In one or more embodiments, the present disclosure provides purified forms of crystalline free base polymorphic pattern D.

[0030] chloride

[0062] In one or more embodiments, a mixture containing crystalline polymorphs of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile is described. This crystalline polymorphic mixture is designated "Chloride Polymorph Pattern A" (i.e., Chloride Pattern A) and exhibits an XRPD pattern having characteristic peak positions of at least three or all values ​​selected from the group consisting of about 7.0, 7.7, 8.2, 14.0, and 14.3±0.2 degrees two-theta, when measured using the parameters set forth in Table 1. Chloride Pattern A can comprise free base Form C. Chloride Pattern A can comprise free base Form F. In one or more embodiments, chloride Polymorph Pattern A exhibits an XRPD pattern substantially the same as the XRPD pattern shown in FIG. 15. In one or more embodiments, chloride polymorph Pattern A has a melting / desolvation range of about 150°C to about 210°C. In one or more embodiments, chloride polymorph Pattern A has a DSC thermogram substantially the same as Figure 16. Chloride polymorph Pattern A can be synthesized using the method of Example 1. In one or more embodiments, pharmaceutical compositions comprising chloride polymorph Pattern A are described. In one or more embodiments, the present disclosure provides purified forms of crystalline chloride polymorph Pattern A.

[0031]

[0063] In one or more embodiments, additional anhydrous, hydrated, or solvated crystalline polymorphs of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile are described, including, but not limited to, acetic acid, benzoic acid, benzenesulfonic acid, carbonic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, glucuranoic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, isethionic acid, lactic acid, laurylsulfonic acid, malic acid, maleic acid, malonic acid, methanesulfonic acid, 1-naphthylenesulfonic acid, 2-naphthylenesulfonic acid, oleic acid, oxalic acid, pamoic acid, phosphoric acid, succinic acid, sulfuric acid, stearic acid, and the like. acid), tartaric acid, or para-toluenesulfonic acid. Additional crystalline polymorphic forms are synthesized using the method of Example 19 or any other method known to one of skill in the art. In one or more embodiments, pharmaceutical compositions comprising the polymorphic forms are described. In one or more embodiments, the present disclosure provides purified forms of the crystalline polymorphic forms.

[0032]

[0064] In one or more embodiments, additional anhydrous, hydrated, or solvated crystalline polymorphs of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile are described. Additional crystalline polymorphic forms are synthesized using the method of Example 20. In one or more embodiments, pharmaceutical compositions comprising the polymorphic forms are described. In one or more embodiments, the present disclosure The figures provide purified forms of the crystalline polymorphic forms.

[0033] salts

[0065] In one aspect, disclosed herein are salts of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile. In some embodiments, the disclosed salts are formed with TPA023B and an acid. The acid can be an organic acid or an inorganic acid. In some embodiments, the acid comprises one or more of acetic acid, benzoic acid, benzenesulfonic acid, carbonic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, glucuronic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, isethionic acid, lactic acid, laurylsulfonic acid, malic acid, maleic acid, malonic acid, methanesulfonic acid, 1-naphthylenesulfonic acid, 2-naphthylenesulfonic acid, oleic acid, oxalic acid, pamoic acid, phosphoric acid, succinic acid, sulfuric acid, steric acid, tartaric acid, para-toluenesulfonic acid, etc. In some embodiments, the acid is a pharmaceutically acceptable acid. In some embodiments, the salt comprises TPA023B free base and an acid in a specific ratio, for example, a molar ratio of TPA023B free base to acid of 5:1, 4:1, 3:1, 2:1, or 1:1. In some embodiments, the ratio between TPA023B free base and acid can be any molar ratio, for example, from 1:10 to 10:1. In some embodiments, the salt is in an anhydrous form. In some embodiments, the salt is in a hydrate form. In some embodiments, the salt is in a solvate form, such as an ethanol, dioxane, THF, methanol, or acetone solvate. In some embodiments, the salt is free of any solvent. In some embodiments, the salt is in a crystalline form. In some embodiments, the salt is partially crystalline. In some embodiments, the salt is in an amorphous form.

[0034]

[0066] In some embodiments, the salt is TPA023B phosphate. In some embodiments, the salt is TPA023B tosylate. In some embodiments, the salt is TPA023B carboxylate. In some embodiments, the salt is TPA023B gluconate. In some embodiments, the salt is TPA023B maleate. In some embodiments, the salt is TPA023B benzoate.

[0035]

[0067] In one aspect, disclosed herein are mixtures comprising TPA023B or a salt thereof. In certain embodiments, the disclosed mixtures comprise TPA023B free base. In certain embodiments, the mixtures comprise one or more TPA023B free base forms, such as free base form C, free base form A, or a combination of form C and form A. In certain embodiments, the mixtures comprise a salt of TPA023B, such as TPA023B phosphate. In certain embodiments, the mixtures comprise one or more TPA023 salt forms, such as TPA023B phosphate form A and TPA023B phosphate form E. In certain embodiments, the mixtures comprise TPA023B free base and a TPA023B salt, such as free base form C and phosphate form A.

[0036]

[0068] In one or more embodiments, the TPA023B salts described herein are at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% pure as measured by HPLC as described herein. In certain embodiments, the TPA023B salts described herein include impurities. In certain embodiments, impurities in the TPA023B salt are at most 0.1%, at most 0.5%, at most 1%, at most 2%, at most 3%, at most 4%, at most 5%, at most 6%, at most 7%, at most 8%, at most 9%, at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 40% or less when measured by HPLC as described herein. is at most 50%.

[0037] Cocrystals

[0069] In one aspect, disclosed herein is a co-crystal of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile. In some embodiments, the disclosed co-crystal is formed with TPA023B and an acid. The acid can be an organic acid or an inorganic acid. In some embodiments, the acid includes one or more of acetic acid, benzoic acid, benzenesulfonic acid, carbonic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, glucuronic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, isethionic acid, lactic acid, laurylsulfonic acid, malic acid, maleic acid, malonic acid, methanesulfonic acid, 1-naphthylenesulfonic acid, 2-naphthylenesulfonic acid, oleic acid, oxalic acid, pamoic acid, phosphoric acid, succinic acid, sulfuric acid, steric acid, tartaric acid, para-toluenesulfonic acid, etc. In some embodiments, the acid is a pharmaceutically acceptable acid. In some embodiments, the cocrystal includes TPA023B free base and an acid in a specific ratio, for example, a molar ratio of TPA023B free base to acid of 5:1, 4:1, 3:1, 2:1, or 1:1. In some embodiments, the ratio between TPA023B free base and acid can be any molar ratio, for example, from 1:10 to 10:1. In some embodiments, the co-crystal is in an anhydrous form. In some embodiments, the co-crystal is in a hydrate form. In some embodiments, the co-crystal is in a solvate form, such as an ethanol, dioxane, THF, methanol, ethyl acetate, or acetone solvate. In some embodiments, the co-crystal is free of any solvent. In some embodiments, the co-crystal is in a crystalline form. In some embodiments, the co-crystal is partially crystalline.

[0038]

[0070] In some embodiments, the co-crystal is TPA023B phosphate. In some embodiments, the co-crystal is TPA023B gluconate. In some embodiments, the co-crystal is TPA023B maleate. In some embodiments, the co-crystal is TPA023B benzoate.

[0039]

[0071] In one aspect, disclosed herein are mixtures comprising TPA023B or a co-crystal thereof. In certain embodiments, the disclosed mixtures comprise TPA023B free base. In certain embodiments, the mixtures comprise one or more TPA023B free base forms, such as free base form C, free base form A, or a combination of form C and form A. In certain embodiments, the mixtures comprise a co-crystal of TPA023B, such as TPA023B phosphate. In certain embodiments, the mixtures comprise one or more TPA023 co-crystal forms. In certain embodiments, the mixtures comprise TPA023B free base and a TPA023B co-crystal, such as a co-crystal of free base form C and phosphate form A.

[0040]

[0072] In one or more embodiments, the TPA023B co-crystals described herein are at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% pure as measured by HPLC as described herein. In certain embodiments, the TPA023B co-crystals described herein include impurities. In certain embodiments, impurities in the TPA023B co-crystal are at most 0.1%, at most 0.5%, at most 1%, at most 2%, at most 3%, at most 4%, at most 5%, at most 6%, at most 7%, at most 8%, at most 9%, at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 40%, or at most 50%, as measured by HPLC as described herein.

[0041]

[0073] In some embodiments, a salt or co-crystal of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with an acid can have a higher solubility than the free base form of TPA023b. For example, solubility can be determined as described in Example 15. In some embodiments, the solubility of the salt or co-crystal is at least 1.1-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, or 8-fold higher than the solubility of free base Form A in simulated gastric fluid (SGF). In some embodiments, the solubility of the salt or co-crystal is at least 1.1-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, or 8-fold higher than the solubility of free base Form A in fasted-state simulated intestinal fluid (FaSSIF). In certain embodiments, the solubility of the salt or co-crystal is at least 1.1-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, or 8-fold greater than the solubility of free base Form A in fed-state simulated intestinal fluid (FeSSIF) than the solubility of free base polymorph Form A.

[0042]

[0074] In the context of this application, a "polymorph" is a particular crystalline arrangement or crystalline "form" of a chemical compound in the solid state. A crystalline form or polymorph of a chemical compound contains constituent molecules arranged in a regularly repeating three-dimensional pattern. Some chemical compounds can form multiple polymorphs, each with a different arrangement of atoms and / or molecules in the crystalline structure. When a compound is a biologically active compound, such as an active pharmaceutical ingredient, differences in crystalline structure can result in each polymorph having different chemical, physical, and biological properties. Properties that can be affected include crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspendability, dissolution rate, and bioavailability. Thus, a particular polymorph may have properties that make it unexpectedly advantageous in a particular application compared to another polymorph of the same parent compound. In particular, the physical, chemical, and biological properties listed above can have a significant impact on manufacturing processes and formulation development, as well as the quality and efficacy of active pharmaceutical ingredients. Some chemical compounds and molecular complexes (e.g., solvates, cocrystals, coordination compounds) can exist in multiple polymorphs, each exhibiting different physical characteristics. In addition, less stable polymorphs can be converted or partially converted into more stable polymorphs under appropriate conditions.For these reasons, when developing products that will be used for therapeutic benefit in humans or animals, it is necessary to control the specific crystalline form of active pharmaceutical ingredients.It should be noted that it is impossible to predict whether the solid state of a compound can form one or more polymorphs, and it is also impossible to predict the properties of any of these crystalline forms.

[0043]

[0075] In one or more embodiments, the crystalline polymorphs described herein are at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% pure as measured by HPLC as described herein. In some embodiments, the crystalline polymorphs described herein contain impurities. In certain embodiments, the impurities in the crystalline polymorph are at most 0.1%, at most 0.5%, at most 1%, at most 2%, at most 3%, at most 4%, at most 5%, at most 6%, at most 7%, at most 8%, at most 9%, at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 40% or at most 50% as measured by HPLC as described herein.

[0044]

[0076] The assay of solid phase for the presence of crystals can be carried out by conventional methods known in the art.For example, it is convenient and routine to use powder X-ray diffraction technique.Other techniques that can be used include differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and Raman or infrared spectroscopy, NMR, gas chromatography or HPLC.

[0045]

[0077] In one or more embodiments, the present disclosure provides a pharmaceutical composition dispersed in a pharmaceutically acceptable carrier. Prophylactic and / or therapeutic compositions comprising one or more of the compounds described herein are provided. The term "carrier" is used herein to refer to a diluent, excipient, vehicle, etc., in which a compound can be dispersed for administration. A suitable carrier will be pharmaceutically acceptable. As used herein, the term "pharmaceutically acceptable" means that the carrier can be administered to a subject without excessive toxicity, irritation, or allergic response, and is not biologically or otherwise undesirable, in that it does not cause unacceptable biological effects or interact in a deleterious manner with any of the other components of the composition in which it is contained. A pharmaceutically acceptable carrier would, of course, be selected to minimize any degradation of the compound or other agent and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art. Pharmaceutically acceptable components include components acceptable for veterinary use as well as human pharmaceutical use, and will depend on the route of administration. For example, a composition suitable for administration by injection is typically a solution in sterile isotonic aqueous buffer. Typical carriers include aqueous solutions such as normal (n.) saline (about 0.9% NaCl), phosphate buffered saline (PBS), sterile water / distilled autoclaved water (DAW), other acceptable vehicles, etc. Other ingredients, such as adjuvants, other active agents, preservatives, buffers, salts, other pharmaceutically acceptable ingredients, can be included in the composition. The composition can comprise a therapeutically effective amount of the compound dispersed in the carrier.

[0046]

[0078] In one or more embodiments, the present disclosure provides methods for treating a disease or disorder in a subject in need thereof, generally comprising administering a therapeutically effective amount of one or more of the compounds described herein. As used herein, a "therapeutically effective" amount refers to an amount that will elicit the biological or medical response in a tissue, system, or subject sought by a researcher or clinician, and will particularly elicit some desired therapeutic or preventative effect against a targeted disease or condition. Those skilled in the art will recognize that an amount may be considered therapeutically "effective" when the condition or its symptoms and / or effects are partially improved or alleviated in a subject, even if the condition is not completely eradicated or prevented. It will be understood that, in the case of a particular salt or cocrystal, the formulation may be administered in an amount that provides sufficient levels of the active compound.

[0047]

[0079] In some embodiments, the disease or disorder is associated with α2 / α3 GABAA receptors, hi some embodiments, the disease or disorder is pain, anxiety, epilepsy, muscle spasms, pruritus, itching, cognitive impairment, alcoholism, drug addition, schizophrenia, depression, autism, panic disorder, or generalized anxiety disorder.

[0048]

[0080] In some embodiments, the disease or disorder is pain. In some embodiments, the pain is fibromyalgia, inflammatory pain, neuropathic pain, pain resulting from peripheral diabetic neuropathy, chemotherapy-induced pain, pain resulting from HIV-associated neuropathy, pain resulting from postherpetic neuralgia, musculoskeletal pain, pain resulting from rheumatoid arthritis, pain resulting from osteoarthritis, post-operative pain, burn pain, sunburn pain, or phantom limb pain. In some embodiments, the pain is acute pain, chronic pain, neuropathic pain, nociceptive (including inflammatory) pain, somatic pain, visceral pain, or dysfunctional pain. In some embodiments, there is a brain or spinal cord disease underlying the pain. In some embodiments, the pain is neuropathic, nociceptive, and / or inflammatory in nature. In some embodiments, the pain can affect either a somatic system or a visceral system, or it can affect multiple systems. In some embodiments, the pain is physiological pain. In some embodiments, the pain is acute pain. In some embodiments, the pain is associated with a defined injury, such as surgery, dental work, a strain, or a sprain. In some embodiments, the pain is chronic pain. In some embodiments, chronic pain is neuropathic pain (e.g., painful diabetic neuropathy or postherpetic neuralgia), carpal tunnel syndrome, back pain, or other conditions. The pain may be pain, headache, cancer pain, arthritis pain, or chronic postoperative pain. In some embodiments, the pain is a chronic pain condition affecting all systems. In some embodiments, the neuropathic pain is associated with pain associated with disease or trauma, such as peripheral neuropathy, postherpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, cancer neuropathy, HIV neuropathy, phantom limb pain, back pain, carpal tunnel syndrome, central post-stroke pain, and pain associated with chronic alcoholism, hypothyroidism, uremia, spinal cord injury, multiple sclerosis, Parkinson's disease, epilepsy, and vitamin deficiency. In some embodiments, the disease or disorder is fibromyalgia or chronic regional pain syndrome. In some embodiments, the pain is moderate to severe acute nociceptive pain, which may be associated with postoperative pain, posttraumatic pain, cancer pain, back pain, pain associated with gout, or pain from a muscle strain, sprain, burn, myocardial infarction, or acute pancreatitis. In some embodiments, the cancer pain is chronic pain, such as tumor-related bone pain, headache, facial pain, or visceral pain. In some embodiments, the cancer pain is pain associated with cancer therapy, such as pain in response to chemotherapy, immunotherapy, hormonal therapy, or radiation therapy. In some embodiments, the pain is back pain. In some embodiments, the pain is associated with arthritis, such as rheumatoid arthritis.

[0049]

[0081] In some embodiments, the disease or disorder is drug addiction or alcoholism. In some embodiments, the disease or disorder is panic disorder, generalized anxiety disorder, anxiety, or schizophrenia. In some embodiments, the disease or disorder is a stress disorder, such as post-traumatic stress disorder, acute stress disorder, or substance-induced stress disorder. In some embodiments, the disease or disorder is a phobia (e.g., agoraphobia, social phobia, or animal phobia). In some embodiments, the disease or disorder is obsessive-compulsive disorder. In some embodiments, the anxiety is separation anxiety or childhood anxiety disorder.

[0050]

[0082] In some embodiments, the disease or disorder is itch, such as chronic or acute itch. In some embodiments, the disease or disorder is chronic itch, neurogenic itch, uremic itch, neurodermatitis, atopic dermatitis, paresthesia, prurigo nodularis, psoriasis, psychogenic itch, or water-related itch. In some embodiments, the itch is pruritic itch. Pruritic itch can be caused by an allergic reaction, inflammation, dryness, or other skin damage. Pruritic itch can be associated with atopic dermatitis (eczema), urticaria (hives), psoriasis, a drug reaction, mites, or dry skin. In some embodiments, the itch is neuropathic itch. Neuropathic itch can be caused by damage to the nervous system and is often accompanied by numbness and tingling sensations. Neuropathic itch can be seen after shingles, stroke, or burns, and in notalgia parasthetica (an area of ​​itchy skin, usually on the back). Neurogenic itch can be associated with chronic liver and kidney disease in response to opioid neuropeptides. Neuropathic itch, psychogenic itch. Psychogenic itch can be triggered in response to the chemicals serotonin or norepinephrine, which influence stress, depression, and delusional parasitosis (a false belief in parasitic infestation). In some embodiments, the disease or disorder is cholestatic pruritus, uremic pruritus, neurodermatitis, notalgia parasitosis, atopic dermatitis, contact dermatitis, prurigo nodularis, psoriasis, insect bites, parasites, fungal infections, water-related itch, urticaria, allergic itch, or delusional parasitosis.

[0051]

[0083] In some embodiments, the disease or disorder is chronic cough or irritable bowel syndrome. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the epilepsy is selected from the group consisting of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), focal epilepsy, generalized epilepsy, Dravet syndrome, childhood absence epilepsy (CEA), juvenile absence epilepsy, juvenile myoclonic epilepsy (JME), West syndrome, Lennox-Gastaut syndrome (LGS), sunflower syndrome, status epilepticus, nerve agent-induced seizures, alcohol withdrawal-related tremors, traumatic brain injury, tuberous sclerosis complex, Doze syndrome, Rasmussen syndrome, early myoclonic encephalopathy, malignant migratory partial seizures of infancy, and continuous spike and wave activity during slow-wave sleep. The disease or disorder may be epilepsy with cerebrospinal fluid (CSF), Landau-Kleffner syndrome, benign epilepsy with centrotemporal spikes, benign familial neonatal infantile seizures, benign central-temporal lobe epilepsy of childhood, benign occipital lobe epilepsy of childhood (BOEC), cortical dysplasia, focal epilepsy syndrome, generalized epilepsy with febrile seizures plus (GEFS+), myoclonic atonic epilepsy, malignant migratory partial seizures of infancy, Ohtahara syndrome (also known as early infantile epileptic encephalopathy), primary reading epilepsy, symptomatic localization-related epilepsy, temporal lobe epilepsy (TLE), Rasmussen's encephalitis, progressive myoclonic or partial epilepsy, and febrile seizures plus. In some embodiments, the disease or disorder is spasticity (e.g., post-stroke spasticity or generalized and focal spasticity), muscle spasms, essential tremor, dystonia, or premature ejaculation. In some embodiments, the disease or disorder is autism. In some embodiments, the disease or disorder is autism resulting from SCN2a mutation, fragile X syndrome, or any form of autism associated with ion channel dysfunction. In some embodiments, the disease or disorder is a depressive disorder (e.g., depression), bipolar disorder, or cyclothymic disorder. In some embodiments, the disease or disorder is schizophrenia, such as paranoid, disorganized, catatonic, undifferentiated, residual schizophrenia, post-schizophrenic depression, and simple schizophrenia.

[0052]

[0084] In some embodiments, the compounds and compositions described herein can be used as antiemetics, for example, for chemotherapy- or radiation-induced emesis, postoperative nausea and vomiting, or motion sickness. In some embodiments, the compounds and compositions described herein can be used as cognitive enhancers.

[0053]

[0085] In some embodiments, the subject is afflicted with or suffering from a condition (e.g., an infection, disease, or disorder) before the compound is administered, and the methods described herein are useful for treating the condition and / or ameliorating the effects of the condition. In one or more embodiments, the methods are useful for reversing the progression of a disease or condition. In other embodiments, the subject is free of the given condition before the compound is administered, and the methods described herein are useful for preventing the onset or onset of the condition and / or preventing the observable effects of the condition. The disclosed embodiments can be formulated for various routes of administration, depending on the particular carrier and other components used. For example, prophylactic and / or therapeutic compounds or compositions can be injected intramuscularly, subcutaneously, intradermally, or intravenously. They can also be administered via mucosal membranes, such as intranasally or orally. The compounds or compositions can also be administered through the skin via a transdermal patch or microneedle. Suspensions, powders, tablets, gelcaps, and the like are contemplated herein.

[0054]

[0086] In some embodiments, the compound or composition can be provided in a unit dosage form in a suitable container. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human or animal use. Each unit dosage form can contain a predetermined amount of a compound of the present invention (and / or other active agent) in a carrier calculated to produce a desired effect. In other embodiments, the compound can be provided separately from the carrier (e.g., in its own vial, ampoule, sachet, or other suitable container) for on-site mixing prior to administration to a subject. Kits containing the compound(s) are also disclosed herein. The kits further include instructions for administering the compound to a subject. The compound(s) can be provided as part of a dosage unit already dispersed in a pharmaceutically acceptable carrier, or it can be provided separately from the carrier. The kit can further include instructions for preparing the compound for administration to a subject, including, for example, instructions for dispersing the compound in a suitable carrier.

[0055]

[0087] The therapeutic and prophylactic methods described herein are useful in humans and in any suitable animal. It will be understood that the methods are applicable to a variety of animals, including but not limited to dogs, cats and other pets as well as rodents, primates, horses, cattle, pigs, etc. The methods may also be applied in clinical research and / or clinical trials.

[0056]

[0088] In yet another aspect, the present invention describes a method for preparing the crystalline form of the compound described herein.The method generally comprises one or more of the following techniques: slurrying the compound in one or more solvents for a period of time, with or without heating; dissolving the compound in one or more solvents, with or without heating, and then removing some or all of the solvent(s) by methods such as evaporation or distillation; dissolving the compound in one or more solvents, and adding anti-solvent, anti-solvent combinations, or a mixture of solvent and anti-solvent; dissolving the compound in one or more solvents, with or without heating, and then allowing the solution to cool, or actively cooling any solution; heating the compound in the absence of solvent; heating the compound under atmospheric pressure or reduced pressure until it sublimes, and collecting it on a cooled surface; melting the solid and allowing it to cool; exposing the compound to water vapor or solvent vapor; adding a small amount of seed material; any other method known to those skilled in the art; and any or all combinations of the above process.

[0057]

[0089] In yet another aspect, the present disclosure relates to the use of compounds according to various embodiments described herein for the preparation of a therapeutic or prophylactic medicament for the treatment or prevention of diseases or conditions treatable by α2 / α3 GABAA positive allosteric modulators and disorders treatable by non-selective GABAA positive allosteric modulators in both animals and humans.

[0058]

[0090] Additional advantages of various aspects of the present disclosure will become apparent to those skilled in the art upon review of the disclosure herein and the examples below. It will be understood that the various aspects described herein are not necessarily mutually exclusive, unless otherwise indicated herein. For example, features described or depicted in one aspect may, but are not necessarily, included in other aspects. Accordingly, the present disclosure encompasses various combinations and / or integrations of the specific aspects described and claimed herein.

[0059]

[0091] As used herein, the phrase "and / or," when used in connection with a list of two or more items, means that any one of the listed items can be utilized by itself, or any combination of two or more of the listed items can be utilized. For example, if a composition is described as containing or excluding components A, B, and / or C, the composition can contain or exclude A alone; B alone; C alone; a combination of A and B; a combination of A and C; a combination of B and C; or a combination of A, B, and C.

[0060]

[0092] As used herein, the term "about" when used in connection with a measurement or to modify a value, unit, constant, or range of values, refers to a variation of + / -3%.

[0061]

[0093] The term "substantially the same," as used herein to define a figure, is intended to mean that the figure would be considered the same as the reference figure by one of ordinary skill in the art, taking into account deviations acceptable in the art. Such deviations may be caused by factors related to equipment, operating conditions, and human factors, etc., as known in the art. For example, one of ordinary skill in the art will appreciate that endothermic onset and peak temperatures measured by differential scanning calorimetry (DSC) can vary significantly from experiment to experiment. In certain embodiments, the positions of characteristic peaks in two figures may be within + / - 5%, + / - 4%, + / - 3%, + / - 2%, or + / - Two patterns are considered to be substantially the same if they do not vary by more than 1%. For example, a person skilled in the art can easily distinguish whether two X-ray diffraction patterns or two DSC thermograms are substantially the same. In some embodiments, the characteristic peaks of two X-ray diffraction patterns are within ±0.3° 2-theta, ±0.2° 2-theta, or ±0.1° 2-theta. X-ray diffraction patterns are considered to be substantially the same if they do not vary by more than 2-theta.

[0062]

[0094] This description also uses numerical ranges to quantify certain parameters related to various aspects of the present disclosure. When numerical ranges are provided, it should be understood that such ranges should be interpreted as providing literal support for claim limitations reciting only the lower values ​​in the range as well as for claim limitations reciting only the higher values ​​in the range. For example, a disclosed numerical range of about 10 to about 100 provides literal support for claims reciting "greater than about 10" (without an upper limit) and claims reciting "less than about 100" (without a lower limit). The present specification includes the following aspects of the invention. [1] A crystalline salt or co-crystal of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with phosphoric acid, wherein the crystalline salt or co-crystal has the following properties: (a) An X-ray powder diffraction (XRPD) pattern substantially identical to the XRPD pattern shown in Figure 19 when measured using the parameters listed in Table 1; (b) an XRPD pattern substantially identical to the XRPD pattern shown in Figure 1 when measured using the parameters set forth in Table 1; (c) an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.4, 7.5, 10.2, 12.7, 13.3, 14.5, 16.0, 17.1, 17.4, 17.9, 18.5, 19.1, 19.7, 20.3, 20.9, 21.5, 22.6, 23.7, 26.2, 26.7, 26.9, 27.5, 28.4, 30.2, and 32.1±0.2 degrees two-theta, when measured using the parameters set forth in Table 1; (d) an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.4, 7.5, 12.7, 13.3, 17.1, 17.4, 18.5, 19.1, 19.7, 26.7, 30.2, and 32.1±0.2 degrees two-theta, when measured using the parameters set forth in Table 1; (e) Differential scanning calorimetry (DSC) thermogram substantially identical to the DSC thermogram shown in Figure 2A; (f) DSC thermogram with an endothermic peak at about 205°C; (g) stable at about 40°C for at least 1 week; and (h) stable at approximately 25°C for at least 1 week; A crystalline salt or co-crystal having at least one of: [2] A crystalline salt or co-crystal according to [1], wherein the crystalline salt or co-crystal provides an XRPD pattern substantially the same as the XRPD pattern shown in Figure 19 when measured using the parameters set out in Table 1. [3] A crystalline salt or co-crystal according to [1], wherein the crystalline salt or co-crystal provides an XRPD pattern substantially identical to the XRPD pattern shown in Figure 1 when measured using the parameters set out in Table 1. [4] The crystalline salt or co-crystal according to [1], wherein the crystalline salt or co-crystal has a viscosity of about 6.4, 7.5, 10.2, 12.7, 13.3, 14.5, 16.0, 17.1, 17.4, 17.9, 18.5, 19.1, 19.7, 20.3, 20.9, 21.5, 22.6, 23.7, 26.2, 26.7, 26.9, 27.5, 28.4, 30.2 and 32.1 ± 0.2 degrees, 2 seams, when measured using the parameters set forth in Table 1. A crystalline salt or co-crystal that provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of: [5] The crystalline salt or co-crystal of [1], wherein the crystalline salt or co-crystal provides an XRPD pattern having characteristic peak positions of at least six values ​​selected from the group consisting of about 6.4, 7.5, 10.2, 12.7, 13.3, 14.5, 16.0, 17.1, 17.4, 17.9, 18.5, 19.1, 19.7, 20.3, 20.9, 21.5, 22.6, 23.7, 26.2, 26.7, 26.9, 27.5, 28.4, 30.2, and 32.1 ± 0.2 degrees two-theta, when measured using the parameters set forth in Table 1. [6] The crystalline salt or co-crystal according to [1], wherein the crystalline salt or co-crystal provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.4, 7.5, 12.7, 13.3, 17.1, 17.4, 18.5, 19.1, 19.7, 26.7, 30.2, and 32.1±0.2 degrees two-theta, when measured using the parameters set forth in Table 1. [7] The crystalline salt or co-crystal according to [1], wherein the crystalline salt or co-crystal provides a DSC thermogram substantially the same as the DSC thermogram shown in Figure 2A. [8] The crystalline salt or co-crystal according to [1], wherein the crystalline salt or co-crystal provides a DSC thermogram having an endothermic peak at about 205°C. [9] The crystalline salt or co-crystal according to [1], wherein the crystalline salt or co-crystal is stable at about 40°C for at least one month.

[10] The crystalline salt or co-crystal according to [1], wherein the crystalline salt or co-crystal is stable at about 25°C for at least one month.

[11] The crystalline salt or co-crystal according to [1], wherein the crystalline salt or co-crystal provides substantially the same XRPD pattern after storage at 40°C and 75% RH for at least one week.

[12] The crystalline salt or co-crystal according to [1], wherein the crystalline salt or co-crystal provides substantially the same XRPD pattern after storage at 40°C and 75% RH for at least two weeks.

[13] The crystalline salt or co-crystal according to [1], wherein the crystalline salt or co-crystal is a salt.

[14] The crystalline salt or co-crystal according to [1], wherein the crystalline salt or co-crystal is a co-crystal.

[15] A crystalline polymorph of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile, Form C, having a molecular weight of about 5.4, 10.8, 12.3, 12.6, 13.5, 14.8, 15.9, 16.3, 16.4, 17.3, when measured using the parameters listed in Table 1; A crystalline polymorph that provides an X-ray powder diffraction (XRPD) pattern having characteristic peak positions of at least three values ​​selected from the group consisting of 17.8, 19.3, 20.4, 21.5, 21.7, 22.7, 23.4, 24.4, 24.7, 25.0, 26.1, 26.6, 27.0, 27.2, 27.5, 28.4, 28.7, 29.0, 29.6, 30.2 and 32.3±0.2 degrees two-theta.

[16] The crystalline polymorph according to

[15] , wherein the crystalline polymorph exhibits an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 5.4, 10.8, 12.3, 12.6, 13.5, 14.8, 16.2, 17.3, 19.3, 20.4, 21.7, 22.7, 23.4, 24.4, 25.0, 27.2, 29.6 and 32.2±0.2 degrees two-theta when measured using the parameters set forth in Table 1.

[17] The crystalline polymorph according to

[15] or

[16] , wherein the crystalline polymorph provides an XRPD pattern substantially identical to the XRPD pattern designated as Form C in Figure 12. Crystal polymorphism.

[18] The crystalline polymorph according to any one of

[15] to

[17] , wherein the crystalline polymorph has a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 210°C.

[19] The crystalline polymorph according to any one of

[15] to

[18] , wherein the crystalline polymorph has a DSC thermogram substantially the same as the DSC thermogram shown in FIG.

[20] A crystalline polymorph of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile, Form B, which provides an X-ray powder diffraction (XRPD) pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 7.4, 7.7, 10.0, 13.2, 17.2, 20.4, and 29.9±0.2 degrees two-theta, when measured using the parameters set forth in Table 1.

[21]

[20] , which provides an XRPD pattern substantially the same as the XRPD pattern shown in Figure 11.

[22] The crystalline polymorph according to

[20] or

[21] , wherein the crystalline polymorph is an ethanol solvate.

[23] A crystalline salt or co-crystal of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with toluenesulfonic acid, which provides an X-ray powder diffraction (XRPD) pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 7.0, 12.4, 12.6, 13.0, 14.1, 15.4, 15.7, 16.3, 17.5, 18.3, 19.0, 21.0, 22.3, 23.0, and 24.9 ± 0.2 degrees two-theta when measured using the parameters listed in Table 1.

[24] A crystalline salt or co-crystal according to

[23] , which provides an XRPD pattern substantially the same as the XRPD pattern shown in FIG. 17.

[25] The crystalline salt or co-crystal according to

[23] or

[24] , wherein the crystalline salt or co-crystal is a hydrate or a solvate.

[26] The crystalline salt or co-crystal according to any one of

[23] to

[25] , wherein the crystalline salt or co-crystal provides a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 170°C.

[27] The crystalline salt or co-crystal according to any one of

[23] to

[26] , wherein the crystalline salt or co-crystal provides a DSC thermogram substantially the same as the DSC thermogram shown in Figure 18.

[28] A therapeutic or prophylactic composition comprising a compound according to any one of [1] to

[27] .

[29] A method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of [1] to

[27] or a composition according to

[28] .

[30] The method according to

[29] , wherein the disease or disorder is associated with α2 / α3 GABAA receptors.

[31] The method according to

[29] , wherein the disease or disorder is selected from pain, anxiety, epilepsy, muscle spasms, pruritus, itching, cognitive impairment, alcoholism, drug addition, schizophrenia, depression, autism, panic disorder, and generalized anxiety disorder.

[32] The method according to

[31] , wherein the disease or disorder is pain.

[33] The method according to

[32] , wherein the pain is fibromyalgia, inflammatory pain, neuropathic pain, peripheral diabetic neuropathy, chemotherapy-induced pain, HIV-associated neuropathy, postherpetic neuralgia, musculoskeletal pain, rheumatoid arthritis, osteoarthritis, post-operative pain, How it is burn pain, sunburn pain or phantom limb pain.

[34] The method according to

[31] , wherein the disease or disorder is pruritus.

[35] The method according to

[34] , wherein the itch is chronic itch, neurogenic itch, uremic itch, neurodermatitis, paresthesia back pain, atopic dermatitis, prurigo nodularis, psoriasis, psychogenic itch, or water-related itch.

[36] The method according to

[31] , wherein the disease or disorder is epilepsy.

[37] The method according to

[36] , wherein the epilepsy is selected from the group consisting of focal epilepsy, generalized epilepsy, Dravet syndrome, childhood absence epilepsy (CEA), juvenile absence epilepsy, juvenile myoclonic epilepsy (JME), West syndrome, Lennox-Gastaut syndrome (LGS), sunflower syndrome, status epilepticus, nerve agent-induced seizures, alcohol withdrawal-related tremors, traumatic brain injury, tuberous sclerosis complex, Doze syndrome, Rasmussen syndrome, early myoclonic encephalopathy, and breast cancer. malignant migratory partial seizures of infancy, epilepsy with continuous spikes and waves during slow wave sleep, Landau-Kleffner syndrome, benign epilepsy with centrotemporal spikes, benign familial neonatal infantile seizures, cortical dysplasia, focal epilepsy syndrome, generalized epilepsy with febrile seizures plus (GEFS+), myoclonic atonic epilepsy, malignant migratory partial seizures of infancy, Ohtahara syndrome (also known as early infantile epileptic encephalopathy) or partial epilepsy and febrile seizures plus.

[38] The method according to

[31] , wherein the disease or disorder is autism.

[39] The method according to

[38] , wherein the autism is autism resulting from an SCN2a mutation, fragile X syndrome, or autism associated with ion channel dysfunction.

[40] A method for preparing a crystalline salt or co-crystal of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with phosphoric acid, the method comprising the following steps: 2',6-Difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile phosphate is crystallized from a solution containing one or more of ethyl acetate, methyl ethyl ketone, 2-methylbutanone, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, acetone, water, tetrahydrofuran (THF), 2-methyl-THF, isopropyl acetate (IPAC), acetonitrile, and dichloromethane; wherein the crystalline salt or co-crystal provides an X-ray powder diffraction (XRPD) pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.4, 7.5, 10.2, 12.7, 13.3, 14.5, 16.0, 17.1, 17.4, 17.9, 18.5, 19.1, 19.7, 20.3, 20.9, 21.5, 22.6, 23.7, 26.2, 26.7, 26.9, 27.5, 28.4, 30.2 and 32.1 ± 0.2 degrees two-theta when measured using the parameters set out in Table 1.

[41] The method according to

[40] , wherein the crystalline salt or co-crystal provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.4, 7.5, 12.7, 13.3, 17.1, 17.4, 18.5, 19.1, 19.7, 26.7, 30.2 and 32.1±0.2 degrees two-theta when measured using the parameters set out in Table 1.

[42] The method of

[40] or

[41] , wherein the crystalline salt or co-crystal provides an XRPD pattern substantially the same as the XRPD pattern shown in Figure 19 when measured using the parameters set out in Table 1. [Example]

[0063]

[0095] The following examples describe methods according to the present disclosure, however, it should be understood that these examples are provided by way of illustration and that nothing therein should be taken as a limitation on the overall scope of the present disclosure.

[0064] Example 1 Salt screening

[0096] Preliminary salt screening by reactive crystallization was performed using five acids in four solvents or solvent mixtures. For hydrochloric, sulfuric, phosphoric, and methanesulfonic acids, approximately 20 mg of TPA023B was stirred in approximately 0.5 mL of the solvent, and approximately 1.1 molar equivalents of the corresponding acid solution was added. For p-toluenesulfonic acid, approximately 20 mg of TPA023B and approximately 1.1 molar equivalents of the corresponding acid were stirred in approximately 0.5 mL of each solvent. For the control, approximately 20 mg of TPA023B was stirred in approximately 0.5 mL of the corresponding solvent. The resulting mixture was heated to approximately 50°C with continuous stirring for approximately 4 hours and then slowly cooled to approximately 20-25°C overnight.

[0065]

[0097] Because TPA023B has a tertiary alcohol that is also alpha to the aromatic ring, it may be susceptible to decomposition by elimination under acidic conditions. HPLC analysis was performed on the acetone samples to determine the extent of decomposition, if any, that occurred. The results showed that TPA023B with H3PO4 in acetone had lower decomposition than the other acids.

[0066] [Table 2]

[0067]

[0098] For all experiments that produced observable solids, solids were isolated by centrifugation (approximately 14,000 rpm for approximately 5 minutes) and analyzed by XRPD. For clear solutions, solids were produced by evaporation to dryness in vacuo at 35°C and checked by XRPD. TGA and DSC characterization data were collected for all solids that demonstrated novel crystallinity by XRPD. The results are shown in Table 3, and the XRPD patterns are shown in Figures 20-24. The DSC / TGA of the solid obtained from the "hydrochloric acid in acetone" experiment is provided in Figure 25. The DSC / TGA of the solid obtained from the "phosphoric acid in acetonitrile" experiment is provided in Figure 26.

[0068] [Table 3]

[0069]

[0099] The phosphate salt was found to readily form a stable novel crystalline form. In addition, a trace of a novel crystalline form was observed, which may represent a novel polymorph of the hydrochloride salt or free base. It was designated Chloride Polymorph Pattern A. Considering the pKa of TPA023B (approximately 2.19) and its highly planar, aromatic structure, it was unexpected that, among the strong acids tested, only phosphoric acid readily formed a highly crystalline solid with properties suitable for manufacture and use in pharmaceutical formulations, especially considering the very similar pKas of TPA023B and phosphoric acid. The relative stability of TPA023B with phosphoric acid, compared with other stronger acids, provides a significant advantage in the manufacturability of the phosphate salt or co-crystal that could not have been predicted beforehand. Having salt or co-crystal formation as the final particle formation step is highly beneficial, as any additional purification steps after this stage significantly increase the cost of goods. Therefore, the reduced impurity formation afforded by the phosphate salt or co-crystal reduces the risk of requiring additional purification and offers an advantage over other counterions.

[0070] Example 2 Crystallization screening of amorphous salt of TPA023B

[0100] Additional attempts were made to find a crystalline salt form of TPA023B. The amorphous TPA023B salt formed in Example 1 and about 0.5 ml of the corresponding solvent shown (Table 4) were heated to about 50° C. with continuous stirring for about 2 days. Only in the case of the p-toluenesulfonate in toluene did a crystalline solid result. In all other cases, an amorphous solid result was obtained. This salt was designated tosylate polymorph Form A.

[0071] [Table 4]

[0072] Example 3 Accelerated Stability Testing of Phosphate Polymorph Form A and Free Base Polymorph Form A

[0101] The stability of phosphate polymorph Form A and free base polymorph Form A was evaluated under accelerated conditions.

[0073] [Table 5]

[0074] [Table 6]

[0075] Example 4

[0102] The hygroscopicity of phosphate polymorph Form A was measured by dynamic vapor sorption (DVS). A reversible mass gain of approximately 1.08% was observed. After DVS, XRPD confirmed that the crystalline form was retained (see Figure 19).

[0076] Example 5 Preparation of polymorphic form A of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile as a salt or co-crystal with phosphoric acid.

[0077] (Phosphate Polymorph Form A)

[0103] A 0.5 M solution of phosphoric acid in acetonitrile (44 mL, 22 mmol, 1.1 equiv.) was added to 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile (8.0 g, 20 mmol, 1.0 equiv.) in acetonitrile (200 mL) and stirred at about 50°C for about 4 hours. The resulting mixture was slowly cooled to room temperature overnight. The resulting solid was collected and dried to give phosphate polymorphic Form A (9.2 g, 92% yield). The XRPD pattern of TPA023B phosphate polymorphic Form A is illustrated in Figure 1. The DSC / TGA thermogram and NMR spectrum of TPA023B phosphate polymorphic Form A are illustrated in Figures 2A and 2B, respectively. Additional DSC / TGA thermograms of TPA023B phosphate polymorph A are illustrated in Figure 2C. The phosphate polymorph A samples for Figures 1, 2A, and 2B were taken from the same batch; the sample for Figure 2C was taken from a different batch.

[0078] Example 6 Preparation of polymorphic pattern B of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile salt or co-crystal with phosphoric acid.

[0079] (Phosphate polymorphic pattern B)

[0104] The salt or co-crystal of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with phosphoric acid (20.9 mg, 0.041 mmol) was stirred in methanol (0.2 mL) at about 20°C to 25°C for about 3 days. The resulting solid was isolated by centrifugation (14,000 rpm for 5 minutes) and dried overnight in a vacuum oven heated to about 30°C, yielding phosphate polymorph pattern B. TPA023B phosphate pattern B likely contains a mixture of phosphate form A and phosphate form G.

[0080]

[0105] The XRPD pattern of TPA023B phosphate polymorph pattern B is illustrated in Figure 3. The DSC / TGA thermogram of TPA023B phosphate polymorph pattern B is illustrated in Figure 4. As shown in Figure 4, the DSC trace exhibited two endothermic peaks with onset temperatures of 189°C (10.49 J / g) and 201°C (76.46 J / g). The TGA results showed that the original form exhibited a three-step weight loss of 3.428% from 30°C to 120°C, which can be attributed to the removal of residual solvent.

[0081] Example 7 Preparation of polymorphic free base form C.

[0106] 2',6-Difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile salt or co-crystal with phosphoric acid (100 mg, 0.204 mmol) was transferred to a vial containing methanol (approximately 1.0 mL). The mixture was heated to approximately 60 °C, stirred for approximately 4 hours, and then cooled to 20 °C to 25 °C. This heating and cooling cycle was repeated two more times. The resulting solid was collected by centrifugation and dried in a vacuum oven at approximately 30 °C to yield free base Form C.

[0082]

[0107] The XRPD pattern of TPA023B free base polymorph Form C is illustrated in Figure 5. The DSC / TGA thermogram of TPA023B free base polymorph Form C is illustrated in Figure 6. As shown in Figure 6, the DSC trace exhibited one endothermic peak with an onset temperature of 195°C (96.04 J / g). The TGA trace exhibited a three-step weight loss of 0.7862% from 30°C to 120°C, which can be attributed to the removal of residual solvent.

[0083] Example 8 Preparation of polymorphic pattern E of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile salts or co-crystals with phosphoric acid.

[0084] (Phosphate polymorphism pattern E)

[0108] Water (approximately 1.0 mL) was added dropwise to a vial containing 0.2 mL of a 100 mg / mL stock solution of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with phosphoric acid (150 mg, 0.307 mmol) in dimethyl sulfoxide until a precipitate formed. The precipitate was collected by centrifugation and dried overnight in a vacuum oven at approximately 30°C, yielding phosphate polymorph pattern E. The XRPD pattern of TPA023B phosphate polymorph pattern E is illustrated in Figure 7. The DSC / TGA thermogram of TPA023B phosphate polymorph pattern E is illustrated in Figure 8. As shown in Figure 8, the DSC pattern showed two endothermic peaks with onset temperatures of 185°C (63.40 J / g) and 196°C (19.60 J / g). TPA023B phosphate pattern E is believed to contain a mixture possibly including phosphate form A and another form.

[0085] Example 9 Preparation of polymorphic form A of the salt of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with 4-methylbenzenesulfonic acid.

[0086] (Tosylate Polymorph Form A)

[0109] 2',6-Difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile (100 mg, 0.256 mmol) and toluene (1.5 mL) were heated to 110 °C and stirred vigorously for 15 minutes. The mixture was cooled to 95 °C, and 1,4-dioxane (0.8 mL) was slowly added. A 0.5 M solution of 4-methylbenzenesulfonic acid in 1,4-dioxane (0.05 mL, 0.1 equiv.) was added, followed by approximately 1 mg of seed material. An additional 0.5 M solution of 4-methylbenzenesulfonic acid in 1,4-dioxane (0.49 mL, 0.95 equiv.) was added over 30 minutes, and the resulting mixture was stirred at 95 °C for 30 minutes. The mixture was then allowed to cool to room temperature, and the solid was collected by centrifugation (1000 rpm, 5 minutes). The isolated solid was washed with n-heptane and dried in a vacuum oven at about 30° C. for 4 hours to yield tosylate polymorph Form A. The XRPD pattern of TPA023B tosylate Form A is provided in FIG. 17A, and the NMR spectrum of TPA023B tosylate is provided in FIG. 17B. TPA023B tosylate exhibits birefringence under polarized light.

[0087] Example 10 Preparation of polymorphic form A of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile.

[0088] (Free Base Polymorph Form A)

[0110] 2',6-Difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile (25 mg, 0.064 mmol) was added to a vial containing acetonitrile (0.5 ml). The mixture was mixed at about 20°C to 25°C for about 4 hours and then heated to about 50°C overnight. The slurry was allowed to cool to ambient temperature. The resulting solid was isolated by centrifugation at about 14,000 rpm for 5 minutes and dried in a vacuum oven at about 35°C to obtain free base polymorphic Form A. The XRPD pattern of TPA023B free base polymorphic Form A is provided in Figure 9. The DSC / TGA thermogram and NMR spectrum of TPA023B free base polymorphic Form A are provided in Figures 10A and 10B, respectively.

[0089] Example 11 Preparation of polymorphic form B of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile.

[0090] (Free Base Polymorph Form B)

[0111] 2',6-Difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile (25 mg, 0.064 mmol) was added to a vial containing ethanol (0.5 ml). The mixture was mixed at about 20°C to 25°C for about 4 hours and then heated to about 50°C overnight. When the final mixture was a clear solution, the solution was evaporated in a vacuum drying oven at about 35°C, and the resulting solid was checked by XRPD. The resulting solid was isolated by centrifugation at about 14,000 rpm for about 5 minutes and dried in a vacuum oven at about 35°C to give the free base polymorph Form B. Preliminary analysis suggested that this was an ethanol solvate polymorph, which expunges Pd and is a key intermediate.

[0091] Example 12 2',6-Difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazoline Preparation of polymorphic form C of zo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile.

[0092] (Free base polymorphic form C)

[0112] 2',6-Difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile (25 mg, 0.064 mmol) was added to a vial containing dichloromethane (0.5 mL) and the vial was sealed. The mixture was stirred at about 20°C to about 25°C for about 4 hours and then heated to about 50°C overnight. The resulting slurry was allowed to cool to ambient temperature, and the resulting solid was isolated by centrifugation at about 14,000 rpm for about 5 minutes and dried in a vacuum oven at about 35°C to obtain free base polymorph Form C.

[0093] Example 13 Preparation of polymorphic pattern D of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile.

[0094] (Free base polymorphism pattern D)

[0113] 2',6-Difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile (25 mg, 0.064 mmol) was added to a vial containing 1,4-dioxane (0.5 mL) and the vial was sealed. The mixture was stirred at about 20-25°C for about 4 hours and then heated to about 50°C overnight. The resulting solution was cooled to about 20-25°C and evaporated to dryness in a vacuum oven at about 35°C to yield free base polymorph pattern D. Free base pattern D likely contains a mixture of free base form A and a novel form, which may be a dioxane solvate.

[0095] Example 14 Competitive slurry experiments.

[0114] The determination of which polymorph is more thermodynamically stable can be experimentally determined by conventional methods known in the art. For example, a competitive slurry experiment can be performed, in which a 1:1 mixture of polymorphic forms is stirred for a period of time in a solvent in which both polymorphic forms are partially soluble. It is accepted by those skilled in the art that if a 1:1 mixture is completely converted into one polymorphic form, the resulting form is the more thermodynamically stable of the two, while the other form is metastable.

[0096] Example 15 Solubility of Free Base Polymorph Form A and Phosphate Polymorph Form A

[0115] Approximately 2 mg of test article was added to a 1.5 mL vial containing approximately 1.0 mL of one of the media listed in Tables 7 and 8, which was then sealed. The mixture was stirred at approximately 20-25°C for approximately 24 hours. The mixture was then filtered through a 0.45 μm membrane filter, and the supernatant was analyzed by HPLC. The results are shown in Tables 7 and 8. The results indicated that phosphate polymorph Form A had higher solubility than free base polymorph Form A in simulated gastric fluid (SGF), fasted-state simulated intestinal fluid (FaSSIF), and fed-state simulated intestinal fluid (FeSSIF).

[0097] [Table 7]

[0098] [Table 8]

[0099] Example 16 Intrinsic dissolution rates of free base polymorph Form A and phosphate polymorph Form A

[0116] Approximately 100 mg of free base polymorph Form A or phosphate polymorph Form A was weighed into the intrinsic dissolution apparatus, and the sample was compressed at a compression force of approximately 4 MPa for 1 minute to form a compressed pellet within a stainless steel die. All loose powder was removed from the surface of the die. The intrinsic dissolution shaft was connected to the stainless steel die and clamped so that only one surface of the pellet was exposed (surface area = 0.496 cm). 2 ). The axis in the spindle was adjusted to ensure that the exposed surface of the compressed tablet was approximately 3.8 cm from the bottom of the container when lowered. The chamber water temperature was set at 37°C ± 0.5°C, axis rotation at 100 rpm, and sampling time points at 2, 5, 10, 15, 30, 45, 60, and 120 minutes. SGF was used as the dissolution medium (900 ml). At each time point, solution samples were filtered and the supernatant was analyzed by HPLC-UV.

[0100]

[0117] The intrinsic dissolution rate of the free base polymorphic Form A in SGF is 5×10 -5 mg cm 2 ·minute -1 The intrinsic dissolution rate of phosphate polymorph Form A in SGF was 0.184 mg cm (linear range: 2–120 min). 2 ·minute -1 (The linear range was 2 to 120 minutes).

[0101] Example 17 Pharmacokinetic studies with phosphate polymorphic form A in rats

[0118] To evaluate the pharmacokinetics (PK) of phosphate polymorph Form A, normal healthy male Sprague-Dawley rats were administered suspensions or solutions either by oral gavage (0.5% methylcellulose) or IV (60% PEG400 / 40% saline), with serial blood sampling conducted over the first 48 hours of exposure. Rats were dosed with vehicle or test compound at 1 mg / kg (IV) or 2 mg / kg (PO). Approximately 0.2 mL of blood was collected at each time point. Whole blood samples were collected by jugular vein puncture. Whole blood samples were transferred to plastic microcentrifuge tubes containing 5 μL of EDTA-K2 as an anticoagulant or pre-chilled commercial EDTA-K2 tubes and placed on wet ice until centrifugation. Collected blood samples were centrifuged at 7,000 rpm for 10 minutes within 30 minutes of collection. Extracts were analyzed for compound concentration by LC / MS / MS. Data were analyzed using IV Noncompartmental Model 201 (IV bolus injection) and PO Noncompartmental Model 200 (extravascular injection) methods in Phoenix WinNonlin 6.3.

[0102] [Table 9]

[0103] [Table 10]

[0104] Example 18 Dog pharmacokinetic studies using phosphate polymorphic form A

[0119] To evaluate the pharmacokinetics (PK) of phosphate polymorph Form A, suspensions or solutions were administered either by oral gavage (0.5% methylcellulose) or IV (60% PEG400 / 40% saline) to normal, healthy male beagle dogs, with serial blood sampling focused on the first 48 hours of exposure. Dogs were dosed with vehicle or test compound at 1 mg / kg (IV) or 2 mg / kg (PO). Approximately 0.5 mL of blood was collected at each time point. Whole blood samples were collected from a peripheral vein. Blood was diluted with potassium (K2) EDTA * Commercially available tubes containing 2H2O (Jiangsu Kangjian Blood samples were collected in a 1000-mL syringe (Panasonic Medical Supplies Co., Ltd.) and placed on wet ice until processed for plasma. Samples were centrifuged (3,000 × g for 10 minutes at 2-8°C) within 1 hour of collection. Extracts were analyzed for compound concentration by LC / MS / MS. Data were analyzed using Phoenix WinNonlin 6.3 with the IV Noncompartmental Model 201 (IV bolus administration) and PO Noncompartmental Model 200 (extravascular administration) methods.

[0105] [Table 11]

[0106] [Table 12]

[0107]

[0120] The bioavailability of phosphate polymorph Form A is more than three times higher than the previously reported bioavailability of TPA023B in dogs, which is highly adventitious for a therapeutic drug intended to treat dogs and significantly reduces the amount of active pharmaceutical ingredient that needs to be available for completion of GLP toxicology studies.

[0108] Example 19 Preparation of polymorphic forms of TPA023B salts or cocrystals

[0121] Combining TPA023B and a pharmaceutically acceptable acid and / or a previously prepared TPA023B salt or co-crystal and stirring for a period of time in one or more solvents, with or without a heating and / or cooling step; and / or dissolving in one or more solvents, with or without heating, followed by removal of some or all of the solvent(s); and / or dissolving in one or more solvents and adding an anti-solvent or a combination of anti-solvents or a mixture of a solvent and an anti-solvent; any other method known to those skilled in the art; and combinations of any or all of the above processes.

[0109] Example 20 Preparation of polymorphic forms of TPA023B free base

[0122] and / or by slurrying TPA023B in one or more solvents, with or without heating; and / or by dissolving TPA023B in one or more solvents, with or without heating, and then removing some or all of the solvent(s) by methods such as evaporation or distillation; and / or by dissolving TPA023B in one or more solvents and adding an anti-solvent, a combination of anti-solvents, or a mixture of a solvent and an anti-solvent; and / or by dissolving TPA023B in one or more solvents, with or without heating, and then allowing the solution to cool or actively cooling; and / or by heating in the absence of solvent; and / or by heating at atmospheric or reduced pressure until it sublimes and collecting on a cooled surface; and / or by melting TPA023B and allowing it to cool; and / or by exposing it to water vapor or solvent vapor, with or without heating; and / or by any other method known to those of skill in the art; and by using a combination of any or all of the above processes.

[0110] Example 21 HPLC protocol Table 13 provides an exemplary set of parameters and conditions used in HPLC.

[0111] [Table 13]

[0112] Example 22 Purity Test

[0123] 2 mg of compound was accurately weighed into a glass vial, then diluted to a target concentration of 0.2 mg / mL with diluent (ACN / water, 50 / 50) and sonicated for 2 minutes. The solution was allowed to equilibrate to room temperature, and the purity of the compound was then determined by HPLC.

[0113] Example 23 pKa measurement 10 mg of TPA023B was used for pKa determination.

[0114] Solution preparation:

[0124] ISA water (ionic strength adjusted water, 0.15 M KCl): Accurately weigh 5.591 g of KCl into a 500 mL volumetric flask, dissolve the sample with water to make up to volume and mix thoroughly.

[0115] 60% (v / v) DMSO co-solvent: Dissolve 2.795 g of potassium chloride in 100 mL of distilled or deionized water and supplement with analytical grade DMSO to 250 mL (ionic strength adjusted DMSO solution).

[0116]

[0125] 80% (v / v) MeOH co-solvent: Dissolve 2.795 g of potassium chloride in 50 mL of distilled or deionized water and make up to 250 mL with analytical grade MeOH (ionic strength adjusted MeOH solution).

[0117] pHmetric pKa determination (with or without cosolvent):

[0126] Approximately 1 mg of sample was weighed into a sample vial, and approximately 1.5 mL of ISA water or 1.5 mL of cosolvent (80% MeOH or 60% DMSO) was automatically added to the vial. The sample solution was automatically pre-acidified to pH 2.0 with 0.5 M HCl by the instrument, then titrated three times with base from pH 2 to pH 12 to obtain the pKa value, which was then extrapolated to obtain the aqueous pKa value. Using this method, the pKa of TPA023B was determined to be 2.19.

[0118] Example 24 Approximate solubility study of TPA023B in organic solvents

[0127] Approximately 25 mg of compound (TPA023B) was added to a 2.0 mL vial containing 0.5 mL of each organic solvent in Table 14 and then sealed. The mixture was stirred at 800 rpm at room temperature (25°C) for 4 hours. If the compound was not completely dissolved in the solvent, the mixture was stirred at 800 rpm at 50°C overnight. If the final mixture was a clear solution, the solution was evaporated in a vacuum oven at 35°C, and the resulting solid was checked by XRPD. If the final mixture was a slurry, the slurry was centrifuged at 14,000 rpm for 5 minutes, and the residue was then dried in a vacuum oven at 35°C and checked by XRPD.

[0119]

[0128] The raw material form of TPA023B was designated "Free Base Form A" and its corresponding XRPD pattern was designated "Pattern A." Characterization of the solubility test sample of TPA023B is provided in Table 15. Overlays of the corresponding XRPD profiles of TPA023B slurries in solvents are provided in Figures 27 and 28.

[0120] [Table 14]

[0121] [Table 15]

[0122] Example 25 Approximate solubility study of TPA023B phosphate

[0129] Approximately 2 mg of TPA023B phosphate Form A was weighed into each 1.5 mL vial, and then solvent was added stepwise under stirring until no particles could be visually observed. The total amount of solvent was recorded to calculate the approximate solubility in these solvents. The solubility results are shown in Table 16. TPA023B phosphate showed relatively high solubility in DMF and DMSO.

[0123] [Table 16]

[0124] Example 26 Polymorph screening of TPA023B phosphate by a slurry method

[0130] TPA023B phosphate (approximately 20 mg) was added to various appropriate solvents. The suspension was stirred at 500 rpm for 3 days at room temperature. The residue of the compound (TPA023B phosphate) was separated by centrifugation (14,000 rpm for 5 minutes) and further dried overnight in a vacuum oven at 30°C. The dried solid was analyzed by XRPD. If the XRPD changed, the dried solid was analyzed by PLM, DSC, and TGA. Table 17 illustrates the results of the slurry screening method using selected solvents. For example, if a form of TPA023B phosphate is designated "Form A," its corresponding XRPD pattern is designated "Pattern A."

[0125] [Table 17]

[0126] Example 27 Polymorph screening of TPA023B phosphate by heating-cooling method

[0131] TPA023B phosphate (approximately 20 mg) was weighed and transferred into a vial containing 200 μL of each selected solvent. The suspension was stirred at 700 rpm at 60° C. for 4 hours, and the suspension was allowed to cool to room temperature. This cycle was repeated twice. Any resulting solids were collected by centrifugation and dried in a vacuum oven at 30° C. Samples were analyzed by XRPD. If the XRPD patterns differed, the samples were analyzed by PLM, DSC, and TGA. As shown in Table 18 and Figure 30, in addition to TPA023B phosphate pattern A, free base pattern C and phosphate pattern D were observed.

[0127]

[0132] The DSC / TGA thermogram of TPA023B phosphate polymorph pattern D is illustrated in Figure 31. As shown in Figure 31, the DSC trace exhibits a single endothermic peak with an onset temperature of 199°C (95.92 J / g), and the TGA results indicate that the original form exhibits a three-step weight loss of 1.489% from 30°C to 150°C, which can be attributed to the removal of residual solvent.

[0128] [Table 18]

[0129] Example 28 Polymorph screening of TPA023B phosphate by antisolvent method

[0133] TPA023B phosphate (approximately 150 mg) was dissolved in 1.5 mL of either DMSO or DMF to prepare a stock solution (100 mg / mL). Antisolvent was added until precipitation occurred or the amount of antisolvent added reached 5 times the volume of the solvent. The precipitate was collected by centrifugation and dried overnight in a vacuum oven at 30°C. The resulting sample was analyzed by XRPD. If the XRPD pattern changed, the dried solid was analyzed by PLM, DSC, and TGA. As shown in Table 19 and Figure 32, TPA023B free base Form C and TPA023B phosphate Pattern E (a mixture containing phosphate Form A) were observed.

[0130] [Table 19]

[0131] Example 29 Scale-up of polymorph screening of TPA023B phosphate by heating-cooling method

[0134] TPA023B phosphate (approximately 100 mg) was used in scaled-up repeats of the experiment in Example 27 using the solvents methanol and isopropanol, respectively. The solid obtained using methanol exhibited the same XRPD pattern of free base Form C as that shown in Example 27. The solid obtained using isopropanol (IPA) also exhibited the XRPD pattern of free base Form C in the scaled-up run. The XRPD patterns of the resulting solids are illustrated in Figure 33. The yields of the scaled-up run are shown in Table 20.

[0132]

[0135] As shown in Figure 34, the DSC / TGA thermogram of the product produced in IPA by the heating-cooling method showed one endothermic peak by DSC with an onset temperature of 188°C (112.9 J / g). The TGA trace showed a three-step weight loss of 0.32% from 30°C to 120°C, which can be attributed to the removal of residual solvent.

[0133] Table 20

Claims

1. 1. A crystalline salt or co-crystal of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with phosphoric acid, wherein the crystalline salt or co-crystal has the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as the XRPD pattern shown in Figure 19, when measured using the parameters set forth in Table 1; (b) an XRPD pattern substantially the same as the XRPD pattern shown in Figure 1 when measured using the parameters set forth in Table 1; (c) an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.4, 7.5, 10.2, 12.7, 13.3, 14.5, 16.0, 17.1, 17.4, 17.9, 18.5, 19.1, 19.7, 20.3, 20.9, 21.5, 22.6, 23.7, 26.2, 26.7, 26.9, 27.5, 28.4, 30.2 and 32.1±0.2 degrees two-theta, when measured using the parameters set forth in Table 1; (d) an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.4, 7.5, 12.7, 13.3, 17.1, 17.4, 18.5, 19.1, 19.7, 26.7, 30.2, and 32.1±0.2 degrees two-theta, when measured using the parameters set forth in Table 1; (e) a differential scanning calorimetry (DSC) thermogram substantially the same as the DSC thermogram shown in Figure 2A; (f) a DSC thermogram with an endothermic peak at about 205°C; (g) stable at about 40°C for at least 1 week; and (h) stable at about 25°C for at least 1 week; A crystalline salt or co-crystal having at least one of:

2. 19. The crystalline salt or co-crystal of claim 1, wherein the crystalline salt or co-crystal provides an XRPD pattern substantially the same as the XRPD pattern shown in Figure 19, when measured using the parameters set out in Table 1.

3. 2. The crystalline salt or co-crystal of claim 1, wherein the crystalline salt or co-crystal provides an XRPD pattern substantially the same as the XRPD pattern shown in FIG. 1 when measured using the parameters set forth in Table 1.

4. 2. The crystalline salt or co-crystal of claim 1, wherein the crystalline salt or co-crystal provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.4, 7.5, 10.2, 12.7, 13.3, 14.5, 16.0, 17.1, 17.4, 17.9, 18.5, 19.1, 19.7, 20.3, 20.9, 21.5, 22.6, 23.7, 26.2, 26.7, 26.9, 27.5, 28.4, 30.2, and 32.1±0.2 degrees two-theta, when measured using the parameters set out in Table 1.

5. 2. The crystalline salt or co-crystal of claim 1, wherein the crystalline salt or co-crystal provides an XRPD pattern having characteristic peak positions of at least six values ​​selected from the group consisting of about 6.4, 7.5, 10.2, 12.7, 13.3, 14.5, 16.0, 17.1, 17.4, 17.9, 18.5, 19.1, 19.7, 20.3, 20.9, 21.5, 22.6, 23.7, 26.2, 26.7, 26.9, 27.5, 28.4, 30.2, and 32.1 ± 0.2 degrees two-theta, when measured using the parameters set out in Table 1.

6. 2. The crystalline salt or co-crystal of claim 1, wherein the crystalline salt or co-crystal provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.4, 7.5, 12.7, 13.3, 17.1, 17.4, 18.5, 19.1, 19.7, 26.7, 30.2, and 32.1±0.2 degrees two-theta, when measured using the parameters set forth in Table 1.

7. 2. The crystalline salt or co-crystal of claim 1, wherein the crystalline salt or co-crystal provides a DSC thermogram substantially the same as the DSC thermogram shown in FIG. 2A.

8. 10. The crystalline salt or co-crystal of claim 1, wherein the crystalline salt or co-crystal provides a DSC thermogram with an endothermic peak at about 205°C.

9. 10. The crystalline salt or co-crystal of claim 1, wherein the crystalline salt or co-crystal is stable at about 40°C for at least one month.

10. 10. The crystalline salt or co-crystal of claim 1, wherein the crystalline salt or co-crystal is stable at about 25°C for at least one month.

11. 10. The crystalline salt or co-crystal of claim 1, wherein the crystalline salt or co-crystal provides substantially the same XRPD pattern after storage at 40° C. and 75% RH for at least one week.

12. 10. The crystalline salt or co-crystal of claim 1, wherein the crystalline salt or co-crystal provides substantially the same XRPD pattern after storage at 40° C. and 75% RH for at least two weeks.

13. 2. The crystalline salt or co-crystal of claim 1, wherein the crystalline salt or co-crystal is a salt.

14. 2. The crystalline salt or co-crystal of claim 1, wherein the crystalline salt or co-crystal is a co-crystal.

15. A crystalline polymorph of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile of Form C, having a molecular weight of about 5.4, 10.8, 12.3, 12.6, 13.5, 14.8, 15.9, 16.3, 16.4, 17.3, 17.0, 18.0, 19.0, 20.0, 21.0, 22.0, 23.0, 24.0, 25.0, 26.0, 27.0, 28.0, 29.0, 30.0, 31.0, 32.0, 33.0, 34.0, 35.0, 36.0, 37.0, 38.0, 39.0, 40.0, 41.0, 42.0, 43.0, 44.0, 45.0, 46.0, 47.0, 48.0, 49.0, 50.0, 51.0, 52.0, 53.0, 54.0, 55.0, 56.0, 57.0, 58.0, 59.0, 60.0, 61.0, 62.0, 63.0, 64.0, 65.0, 66.0, 67.0, 68.0, 69.0, 70.0, 71.0, 72.0, 73.0, 74.0, 75.0, 76.0, 77.0, 78.0, 79.0 27.0, 27.2, 27.5, 28.4, 28.7, 29.0, 29.6, 30.2 and 32.3±0.2 degrees two-theta.

16. 16. The crystalline polymorph of claim 15, wherein the crystalline polymorph exhibits an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 5.4, 10.8, 12.3, 12.6, 13.5, 14.8, 16.2, 17.3, 19.3, 20.4, 21.7, 22.7, 23.4, 24.4, 25.0, 27.2, 29.6, and 32.2±0.2 degrees two-theta when measured using the parameters set forth in Table 1.

17. 17. The crystalline polymorph of claim 15 or 16, wherein the crystalline polymorph provides an XRPD pattern substantially the same as the XRPD pattern labeled Form C in Figure 12.

18. The crystalline polymorph according to any one of claims 15 to 17, wherein the crystalline polymorph has a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 210°C.

19. 19. The crystalline polymorph of any one of claims 15 to 18, wherein the crystalline polymorph has a DSC thermogram substantially the same as the DSC thermogram shown in Figure 13.

20. A crystalline polymorph of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile of Form B, which provides an X-ray powder diffraction (XRPD) pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 7.4, 7.7, 10.0, 13.2, 17.2, 20.4, and 29.9±0.2 degrees two-theta, when measured using the parameters set forth in Table 1.

21. 21. The crystalline polymorph of claim 20, which provides an XRPD pattern substantially the same as the XRPD pattern shown in Figure 11.

22. 22. The crystalline polymorph of claim 20 or 21, wherein the crystalline polymorph is an ethanol solvate.

23. 1. A crystalline salt or co-crystal of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with toluenesulfonic acid, which provides an X-ray powder diffraction (XRPD) pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 7.0, 12.4, 12.6, 13.0, 14.1, 15.4, 15.7, 16.3, 17.5, 18.3, 19.0, 21.0, 22.3, 23.0, and 24.9±0.2 degrees two-theta, when measured using the parameters set forth in Table 1.

24. 24. The crystalline salt or co-crystal of claim 23, which provides an XRPD pattern substantially the same as the XRPD pattern shown in Figure 17.

25. 25. The crystalline salt or co-crystal of claim 23 or 24, wherein the crystalline salt or co-crystal is a hydrate or a solvate.

26. 26. The crystalline salt or co-crystal of any one of claims 23 to 25, wherein the crystalline salt or co-crystal provides a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 170°C.

27. 27. The crystalline salt or co-crystal of any one of claims 23 to 26, wherein the crystalline salt or co-crystal provides a DSC thermogram substantially the same as the DSC thermogram shown in Figure 18.

28. A therapeutic or prophylactic composition comprising a compound according to any one of claims 1 to 27.

29. 28. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 27 or a composition according to claim 28. administering to said subject.

30. 30. The method of claim 29, wherein the disease or disorder is associated with α2 / α3 GABAA receptors.

31. 30. The method of claim 29, wherein the disease or disorder is selected from pain, anxiety, epilepsy, muscle spasms, pruritus, itching, cognitive impairment, alcoholism, drug addiction, schizophrenia, depression, autism, panic disorder, and generalized anxiety disorder.

32. 32. The method of claim 31, wherein the disease or disorder is pain.

33. 33. The method of claim 32, wherein the pain is fibromyalgia, inflammatory pain, neuropathic pain, peripheral diabetic neuropathy, chemotherapy-induced pain, HIV-associated neuropathy, post-herpetic neuralgia, musculoskeletal pain, rheumatoid arthritis, osteoarthritis, post-surgical pain, burn pain, sunburn pain, or phantom limb pain.

34. 32. The method of claim 31, wherein the disease or disorder is itch.

35. 35. The method of claim 34, wherein the itch is chronic itch, neurogenic itch, uremic itch, neurodermatitis, paresthesia back pain, atopic dermatitis, prurigo nodularis, psoriasis, psychogenic itch, or water-related itch.

36. 32. The method of claim 31, wherein the disease or disorder is epilepsy.

37. 37. The method of claim 36, wherein the epilepsy is selected from the group consisting of focal epilepsy, generalized epilepsy, Dravet syndrome, childhood absence epilepsy (CEA), juvenile absence epilepsy, juvenile myoclonic epilepsy (JME), West syndrome, Lennox-Gastaut syndrome (LGS), sunflower syndrome, status epilepticus, nerve agent-induced seizures, alcohol withdrawal-related tremors, traumatic brain injury, tuberous sclerosis complex, Doze syndrome, Rasmussen syndrome, early myoclonic encephalopathy, and infantile epilepsy. malignant migrating partial seizures of infancy, epilepsy with continuous spikes and waves during slow wave sleep, Landau-Kleffner syndrome, benign epilepsy with centrotemporal spikes, benign familial neonatal infantile seizures, cortical dysplasia, focal epilepsy syndrome, generalized epilepsy with febrile seizures plus (GEFS+), myoclonic atonic epilepsy, malignant migrating partial seizures of infancy, Ohtahara syndrome (also known as early infantile epileptic encephalopathy) or partial epilepsy and febrile seizures plus.

38. 32. The method of claim 31, wherein the disease or disorder is autism.

39. 39. The method of claim 38, wherein the autism is autism resulting from an SCN2a mutation, fragile X syndrome, or autism associated with ion channel dysfunction.

40. 1. A method for preparing a crystalline salt or co-crystal of 2′,6-difluoro-5′-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with phosphoric acid, the method comprising the steps of: 2',6-Difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile phosphate was dissolved in ethyl acetate, methyl ethyl ketone, 2-methylbutanone, dimethyl sulfoxide, crystallization from a solution containing one or more of sulfoxide, dimethylformamide, dimethylacetamide, acetone, water, tetrahydrofuran (THF), 2-methyl-THF, isopropyl acetate (IPAC), acetonitrile, and dichloromethane; wherein the crystalline salt or co-crystal provides an X-ray powder diffraction (XRPD) pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.4, 7.5, 10.2, 12.7, 13.3, 14.5, 16.0, 17.1, 17.4, 17.9, 18.5, 19.1, 19.7, 20.3, 20.9, 21.5, 22.6, 23.7, 26.2, 26.7, 26.9, 27.5, 28.4, 30.2 and 32.1±0.2 degrees two-theta, when measured using the parameters set out in Table 1.

41. 41. The method of claim 40, wherein the crystalline salt or co-crystal provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.4, 7.5, 12.7, 13.3, 17.1, 17.4, 18.5, 19.1, 19.7, 26.7, 30.2, and 32.1±0.2 degrees two-theta when measured using the parameters set forth in Table 1.

42. 42. The method of claim 40 or 41, wherein the crystalline salt or co-crystal provides an XRPD pattern substantially the same as the XRPD pattern shown in Figure 19 when measured using the parameters set forth in Table 1.

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