Gabaa positive allosteric modulator compounds, methods of making, and uses thereof

Abstract

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 are provided.SOLUTION: Provided is a crystalline form of 2 ', 6-difluoro-5 ' - [3 - (1-hydroxy-1-methylethyl) - imidazo [1, 2-b] [1,2,4] triazin-7-yl] biphenyl-2-carbonitrile containing sulfuric acid, e.g., having an X-ray powder diffraction (XRPD) pattern substantially the same as shown in the Figures, when measured using the specified parameters.SELECTED DRAWING: Figure 61

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 924,276, filed October 22, 2019, which is incorporated herein by reference in its entirety. Summary of the Invention [Means for solving the problem]

[0002]

[0002] In one aspect, the present disclosure 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, but not limited to, stable polymorphs of salts of TPA023B and sulfuric acid.

[0003] [ka]

[0004] Also described are polymorphs of the free base compound that are suitable for use as active pharmaceutical ingredients in products intended for therapeutic use in mammals, humans, or animals, and as chemical intermediates in the synthesis of active pharmaceutical ingredients.

[0005] In one aspect, described herein is a crystalline form of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing sulfate, wherein the crystalline form has at least one of the following characteristics: (a) an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 61, when measured using the parameters set forth in Table 26-4; (b) a molecular weight of about 6.1, 10.9, 11.3, 11.8, 12.2, 13.8, 14.8, 16.1, 16.8, 17.3, 17.9, 18.3, 19.2, 19.6, 21.4, 21.8, 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 (c) an XRPD pattern having characteristic peak positions at at least three values ​​selected from the group consisting of 2.8, 23.6, 24.4, 25.4, 27.2, 29.9, 30.5, 31.5, 32.6, 33.9, and 39.1±0.2 degrees two-theta; (d) a DSC thermogram substantially identical to that shown in Figure 53C; (e) stable at about 40°C for at least three days; and (f) stable at about 60°C for at least three days. In some embodiments, the crystalline form provides an XRPD pattern substantially identical to that shown in Figure 61 when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.1, 10.9, 11.3, 11.8, 12.2, 13.8, 14.8, 16.1, 16.8, 17.3, 17.9, 18.3, 19.2, 19.6, 21.4, 21.8, 22.8, 23.6, 24.4, 25.4, 27.2, 29.9, 30.5, 31.5, 32.6, 33.9, and 39.1±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least six values ​​selected from the group consisting of about 6.1, 10.9, 11.3, 11.8, 12.2, 13.8, 14.8, 16.1, 16.8, 17.3, 17.9, 18.3, 19.2, 19.6, 21.4, 21.8, 22.8, 23.6, 24.4, 25.4, 27.2, 29.9, 30.5, 31.5, 32.6, 33.9, and 39.1±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.1, 10.9, 12.2, 16.1, 16.8, 21.4, 21.8, 25.4, and 27.2±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4.In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.1, 12.2, 16.1, 21.8, 24.4, and 25.4±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of all values ​​selected from the group consisting of about 6.1, 12.2, and 21.8±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline form provides a DSC thermogram substantially identical to that shown in Figure 53C. In some embodiments, the crystalline form provides a DSC thermogram with an endothermic peak at about 192°C. In some embodiments, the crystalline form is stable at about 40°C for at least one month. In some embodiments, the crystalline form is stable at about 60°C for at least one month. In some embodiments, the crystalline form provides a substantially identical XRPD pattern after storage at 40°C and 75% RH for at least 3 days. In some embodiments, the crystalline form provides a substantially identical XRPD pattern after storage at 40°C and 75% RH for at least 7 days. In some embodiments, the crystalline form provides a substantially identical XRPD pattern after storage at 60°C and 75% RH for at least 3 days. In some embodiments, the crystalline form provides a substantially identical XRPD pattern after storage at 60°C and 75% RH for at least 7 days. In some embodiments, the crystalline form is a salt. In some embodiments, the crystalline form is a co-crystal.

[0006] In one aspect, described herein is a crystalline form of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with hydrochloric acid, wherein the crystalline form has at least one of the following characteristics: (a) an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 63, when measured using the parameters set forth in Table 26-4; (b) a molecular weight of about 6.3, 11.7, 12.8, 14.1, 15.1, 16.5, 17.6, 18.8, 19.9, 20.9, 21.4, 22.2, 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, (c) an XRPD pattern having characteristic peak positions of at least three, at least nine, at least six, or all values ​​selected from the group consisting of 9.3, 20.6, 21.8, 23.2, 24.3, 25.7, 26.5, 26.9, 28.5, 30.3, 32.2, 32.7, and 33.5±0.2 degrees two-theta; (d) a DSC thermogram substantially identical to that labeled Chloride Form C in Figure 52F; (e) an XRPD pattern substantially identical to that shown in Figure 63 after storage at 40°C and 75% RH for at least three days; and (f) an XRPD pattern substantially identical to that shown in Figure 63 after storage at 60°C and 75% RH for at least three days. In some embodiments, the crystalline form provides an XRPD pattern substantially identical to that shown in Figure 63 when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least three, at least nine, at least six, or all values ​​selected from the group consisting of about 6.3, 11.7, 12.8, 14.1, 15.1, 16.5, 17.6, 18.8, 19.3, 20.6, 21.8, 23.2, 24.3, 25.7, 26.5, 26.9, 28.5, 30.3, 32.2, 32.7, and 33.5±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.3, 11.7, 12.8, 16.5, 17.6, and 21.8±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of about 11.7, 12.8, and 21.8±0.2 degrees two-theta, all values ​​selected from the group consisting of: about 11.7, 12.8, and 21.8±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline form provides a differential scanning calorimetry (DSC) thermogram substantially identical to that labeled Chloride Form C in Figure 52F. In some embodiments, the crystalline form provides a DSC thermogram with an endothermic peak at about 179°C.In some embodiments, the crystalline form provides a substantially identical XRPD pattern after storage at 40° C. and 75% RH for at least 3 days. In some embodiments, the crystalline form provides a substantially identical XRPD pattern after storage at 60° C. and 75% RH for at least 3 days.

[0007]

[0006] In one aspect, described 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 Form E, 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 6.6, 7.5, 9.6, 10.3, 13.3, 13.8, 14.5, 15.4, 15.9, 16.5, 17.3, 17.8, 19.5, 20.3, 22.3, 23.2, 23.7, 26.1, 26.9, 27.9, 29.0, 31.1, and 35.8±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline polymorph provides an XRPD pattern substantially identical to the XRPD pattern labeled Form E in Figure 36A. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, or all values ​​selected from the group consisting of about 6.6, 7.5, 9.6, 10.3, 13.3, 13.8, 14.5, 15.4, 15.9, 16.5, 17.3, 17.8, 19.5, 20.3, 22.3, 23.2, 23.7, 26.1, 26.9, 27.9, 29.0, 31.1, and 35.8±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 7.5, 9.6, 10.3, 13.3, 19.5, and 20.3±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. ... provides an XRPD pattern having characteristic peak positions at at least three values ​​selected from the group consisting of about 7.5, 9.6, and 10.3±0.2 degrees two-theta, as measured using the parameters.

[0008]

[0007] In one aspect, 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 F is described, 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, 7.7, 8.1, 9.2, 10.9, 12.3, 13.1, 14.0, 14.2, 15.2, 15.4, 15.7, 16.3, 17.2, 17.8, 19.4, 19.9, 21.0, 22.9, 26.7, and 27.6±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline polymorph provides an XRPD pattern substantially identical to the XRPD pattern labeled Form F in Figure 36A. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, or all values ​​selected from the group consisting of about 7.0, 7.7, 8.1, 9.2, 10.9, 12.3, 13.1, 14.0, 14.2, 15.2, 15.4, 15.7, 16.3, 17.2, 17.8, 19.4, 19.9, 21.0, 22.9, 26.7, and 27.6±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions at least three values ​​selected from the group consisting of about 7.0, 7.7, 8.1, 12.3, 13.1, and 15.2±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions at least three values ​​selected from the group consisting of about 7.7, 8.1, and 13.1±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4.

[0009]

[0008] In one aspect, described 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 Form G, 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 6.3, 7.5, 8.0, 11.7, 12.0, 12.8, 13.3, 14.1, 14.8, 15.3, 17.2, 18.0, 19.2, 19.6, 21.5, 23.2, 23.8, 25.9, 26.6, 27.7, and 32.4±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline polymorph provides an XRPD pattern substantially identical to the XRPD pattern labeled Form G in Figure 36A. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, or all values ​​selected from the group consisting of about 6.3, 7.5, 8.0, 11.7, 12.0, 12.8, 13.3, 14.1, 14.8, 15.3, 17.2, 18.0, 19.2, 19.6, 21.5, 23.2, 23.8, 25.9, 26.6, 27.7, and 32.4±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions at least three values ​​selected from the group consisting of about 6.3, 8.0, 12.0, 12.8, and 13.3±0.2 degrees two-theta when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions at least three values ​​selected from the group consisting of about 6.3, 8.0, and 13.3±0.2 degrees two-theta when measured using the parameters set forth in Table 26-4.

[0010]

[0009] In one aspect, described 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 Form H, 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, 7.9, 9.4, 10.9, 12.7, 13.4, 14.0, 14.3, 14.6, 16.0, 16.3, 18.0, 19.2, 19.7, 20.1, 21.2, 24.1, 25.7, 26.9, and 28.0±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline polymorph provides an XRPD pattern substantially identical to the XRPD pattern labeled Form H in Figure 36A. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, or all values ​​selected from the group consisting of about 7.0, 7.9, 9.4, 10.9, 12.7, 13.4, 14.0, 14.3, 14.6, 16.0, 16.3, 18.0, 19.2, 19.7, 20.1, 21.2, 24.1, 25.7, 26.9, and 28.0±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 7.0, 7.9, 9.4, 10.9, 12.7, and 14.0±0.2 degrees two-theta when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, or all values ​​selected from the group consisting of about 7.9, 12.7, and 14.0±0.2 degrees two-theta when measured using the parameters set forth in Table 26-4.

[0011]

[0010] In one aspect, described herein is a crystalline form of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile selected from the group consisting of: (a) a chloride salt that provides an XRPD pattern substantially identical to that shown in Figure 62; and (b) a besylate salt that provides an XRPD pattern substantially identical to the XRPD pattern labeled Besylate Form A shown in Figure 57A.

[0012] In one aspect, described herein is a crystalline form of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid, wherein the crystalline form has at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 67, when measured using the parameters set forth in Table 35; (b) an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 67, when measured using the parameters set forth in Table 35. (c) an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.3, 7.4, 10.1, 12.6, 13.2, 14.0, 15.7, 17.0, 17.3, 18.0, 19.0, 20.2, 20.7, 26.4, 27.2, and 27.5±0.2 degrees two-theta; (d) a differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 69; (e) a DSC thermogram with an endothermic peak at about 200°C; and (f) a DSC thermogram with an endothermic peak having an onset temperature at about 197°C. In some embodiments, the crystalline form provides an XRPD pattern substantially identical to that shown in Figure 67 when measured using the parameters set forth in Table 35. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least three, at least six, or at least nine values ​​selected from the group consisting of about 6.3, 7.4, 10.1, 12.6, 13.2, 14.0, 15.7, 17.0, 17.3, 18.0, 19.0, 20.2, 20.7, 26.4, 27.2, and 27.5±0.2 degrees two-theta, when measured using the parameters set forth in Table 35. In embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least three, at least six, or at least nine values ​​selected from the group consisting of about 6.3, 13.2, 14.0, 15.7, 17.0, 17.3, 18.0, 19.0, 20.2, 20.7, and 26.4±0.2 degrees two-theta, when measured using the parameters set forth in Table 35. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least three, at least six, or at least nine values ​​selected from the group consisting of about 6.3, 13.2, 14.0, 15.7, 17.0, 17.3, 18.0, 20.2, 20.7, and 26.4±0.2 degrees two-theta, when measured using the parameters set forth in Table 35. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least three, at least six, or at least nine values ​​selected from the group consisting of about 6.3, 13.2, 14.0, 15.7, 17.0, 17.3, 18.0, 19.0, 20.2, 20.7, and 26.4±0.2 degrees two-theta, when measured using the parameters set forth in Table 35. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least three, at least six, or at least nine values ​​selected from the group consisting of about 6.3, 13.2, 14.0, 15.7, 17.0, 17.3, 18.0, and 26.4±0.2 degrees two-theta, when measured using the parameters set forth in Table 35. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least three, at least six, or at least nine values ​​selected from the group consisting of about 6.3, 13.2, 14.0, 15.7, 17.0, 17.3, 18.0, 19.0, and 26.4±0.2 degrees two-theta, when measured using the parameters set forth in Table 35. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of all values ​​selected from the group consisting of about 6.3, 17.0, and 19.0±0.2 degrees two-theta, when measured using the parameters set forth in Table 35.In some embodiments, the crystalline form provides a DSC thermogram substantially identical to that shown in Figure 69. In some embodiments, the crystalline form provides a DSC thermogram with an endothermic peak at about 200°C. In some embodiments, the crystalline form provides a DSC thermogram with an endothermic peak having an onset temperature at about 197°C. In some embodiments, the crystalline form is a salt. In some embodiments, the crystalline form is a co-crystal. In some embodiments, described herein are methods for preparing a crystalline form of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid.

[0013]

[0012] In one aspect, disclosed herein are therapeutic or prophylactic compositions comprising the compounds described. In another aspect, disclosed herein are methods for treating a disease or disorder in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a compound or composition described herein. In one aspect, disclosed herein are compounds for use in treating a disease or disorder in a subject in need of treatment. In one aspect, disclosed herein are compositions for use in treating a disease or disorder in a subject in need of treatment. In some embodiments, the disease or disorder is associated with α2 / α3 GABAA receptors. In some embodiments, the disease or disorder is selected from pain, neuropathic pain, inflammatory pain, anxiety, epilepsy, convulsions, muscle spasms, pruritus, itch, cognitive dysfunction, alcoholism, drug addiction, schizophrenia, depression, autism, panic disorder, noise phobia, and generalized fear and anxiety disorder. In some embodiments, the disease or disorder is pain. In some embodiments, the pain is fibromyalgia, inflammatory pain, neuropathic pain, diabetic peripheral neuropathy, chemotherapy-induced pain, HIV-associated neuropathy, postherpetic neuralgia, musculoskeletal pain, rheumatoid arthritis, osteoarthritis, postoperative pain, burning 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, or rheumatoid arthritis. The disease or disorder is selected from the group consisting of: inflammatory bowel disease, pruritus, pruritus caused by contact dermatitis, uremic pruritus, neurodermatitis, atopic dermatitis, atopic eczema, prurigo nodularis, dorsal paresthesia, psoriasis, psychogenic itch, and aquagenic itch. In some embodiments, the disease or disorder is epilepsy. In some embodiments, the epilepsy is 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 tremors, traumatic brain injury, tuberous sclerosis, Doze syndrome, Rasmussen syndrome, early myoclonic encephalopathy, and migratory foci. The disease or disorder may be infantile epilepsy with seizures, epilepsy with persistent spikes and waves during slow-wave sleep, Landau-Kleffner syndrome, benign epilepsy with centrotemporal spikes, benign familial neonatal infantile epilepsy, cortical dysplastic focal epilepsy syndrome, generalized epilepsy with febrile seizures plus (GEFS+), myoclonic-atonic epilepsy, infantile epilepsy with migratory focal seizures, 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 SCN2a mutation-related autism, fragile X syndrome, or autism associated with ion channel dysfunction.

[0014] In one aspect, disclosed herein is a method for preparing a crystalline form of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid, the method comprising the steps of: (a) preparing a crystalline form of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid; (b) preparing a crystalline form of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid; and (c) preparing a crystalline form of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid; the method comprises the steps of: (a) preparing a crystalline form of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid; and (d) preparing a crystalline form of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid; 64. The method of claim 64, further 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 isopropyl alcohol (IPAC), acetonitrile, and dichloromethane, wherein the crystalline form provides an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 64, when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.5, 7.6, 10.2, 13.4, 14.0, 14.4, 15.4, 16.0, 16.2, 17.2, 17.5, 17.8, 18.6, 19.2, 19.8, 20.4, 20.9, 21.6, 23.5, 26.2, 26.6, 27.4, 28.3, 29.0, 30.2, and 32.7±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.5, 13.4, 14.0, 15.4, 17.2, 17.5, and 26.6±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of all values ​​selected from the group consisting of about 6.5, 14.4, 16.0, 18.6, 19.2, 21.6, and 26.6±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, at least 500 grams of the crystalline form are prepared.In some embodiments, at least 1000 grams of the crystalline form is prepared. In some embodiments, the solution comprises THF. In some embodiments, the solution comprises 2-Me THF. In some embodiments, the solution comprises IPAC. In some embodiments, the solution comprises heptane. In some embodiments, the solution comprises acetonitrile. In some embodiments, the solution comprises methyl tert-butyl ether. In some embodiments, the solution comprises ethyl acetate. In some embodiments, the solution comprises acetone. In some embodiments, the solution comprises a mixture of acetone and water. In some embodiments, the method comprises azeotropic drying, activated sieves, magnesium sulfate, sulfuric acid. In some embodiments, the method includes removing water by some means, such as sodium, or other drying agent. In some embodiments, the method includes an azeotropic drying step to remove water. In some embodiments, the solution does not contain water or alcohol. In some embodiments, the method includes removing acetone by distillation one or more times. In some embodiments, the method includes removing acetone by distillation one to three times. In some embodiments, the method includes removing ethyl acetate by distillation one or more times. In some embodiments, the method includes removing ethyl acetate by distillation one to three times. In some embodiments, the method includes removing water by distillation of a solvent having a boiling point lower than that of water. In some embodiments, the solvent is ethyl acetate, methyl ethyl ketone, 2-methylbutanone, acetone, tetrahydrofuran, 2-methyl-THF, isopropyl acetate, acetonitrile, or dichloromethane. [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 shows the XRPD pattern for TPA023B phosphate Form A. [Figure 2A]2A-2C show the DSC / TGA thermogram for TPA023B phosphate form A (FIG. 2A); the NMR spectrum for TPA023B phosphate form A (FIG. 2B); and an additional DSC / TGA thermogram for TPA023B phosphate form A (FIG. 2C). [Figure 2B] 2A-2C show the DSC / TGA thermogram for TPA023B phosphate form A (FIG. 2A); the NMR spectrum for TPA023B phosphate form A (FIG. 2B); and an additional DSC / TGA thermogram for TPA023B phosphate form A (FIG. 2C). [Figure 2C] 2A-2C show the DSC / TGA thermogram for TPA023B phosphate form A (FIG. 2A); the NMR spectrum for TPA023B phosphate form A (FIG. 2B); and an additional DSC / TGA thermogram for TPA023B phosphate form A (FIG. 2C). [Figure 3]

[0016] FIG. 3 shows the XRPD pattern for TPA023B phosphate pattern B. [Figure 4]

[0017] FIG. 4 shows the DSC / TGA thermogram for TPA023B phosphate pattern B. [Figure 5]

[0018] FIG. 5 shows the XRPD pattern for TPA023B free base form C. [Figure 6]

[0019] FIG. 6 shows the DSC / TGA thermogram for TPA023B free base form C. [Figure 7]

[0020] FIG. 7 shows the XRPD pattern for a TPA023B phosphate mixture containing TPA023B phosphate Form A. [Figure 8]

[0021] FIG. 8 shows the DSC / TGA thermogram for TPA023B phosphate mixtures containing TPA023B phosphate Form A. [Figure 9]

[0022] FIG. 9 shows the XRPD pattern for TPA023B free base form A. [Figure 10]

[0023] FIG. 10A shows the DSC / TGA thermogram for TPA023B free base form A; FIG. 10B shows the NMR spectrum for TPA023B free base form A. [Figure 11]

[0024] FIG. 11 shows the XRPD pattern for TPA023B free base form B. [Figure 12]

[0025] FIG. 12 shows the XRPD pattern for TPA023B free base form C. [Figure 13]

[0026] FIG. 13 shows the DSC thermogram for TPA023B free base form C. [Figure 14]

[0027] FIG. 14 shows the XRPD pattern for the TPA023B free base mixture containing free base Form A. [Figure 15]

[0028] FIG. 15 shows the XRPD pattern for TPA023B chloride Pattern A. [Figure 16]

[0029] FIG. 16 shows the DSC / TGA thermogram for TPA023B chloride Pattern A. [Figure 17]

[0030] FIG. 17A shows the XRPD pattern for TPA023B tosylate Form A; FIG. 17B shows the NMR spectrum of TPA023B tosylate Form A. [Figure 18]

[0031] FIG. 18 shows the DSC / TGA thermogram for TPA023B tosylate Form A. [Figure 19]

[0032] FIG. 19 shows the XRPD pattern for TPA023B phosphate Form A after DVS. [Figure 20]

[0033] FIG. 20 shows the XRPD pattern of the TPA023B HCl salt screen. [Figure 21]

[0034] FIG. 21 shows the XRPD pattern of the TPA023B sulfate screen. [Figure 22]

[0035] FIG. 22 shows the XRPD pattern of the TPA023B phosphate screen. [Figure 23]

[0036] FIG. 23 shows the XRPD pattern of the TPA023B tosylate screen. [Figure 24]

[0037] FIG. 24 shows the XRPD pattern of the TPA023B methanesulfonate salt screen. [Figure 25]

[0038] FIG. 25 shows 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]

[0039] FIG. 26 shows the TGA and DSC results of TPA023B phosphate salt (TPA023B Phosphate Form A) in the ACN system. [Figure 27]

[0040] FIG. 27 shows an XRPD profile overlay of TPA023B slurry in solvent (I). [Figure 28]

[0041] FIG. 28 shows an XRPD profile overlay of TPA023B slurry in solvent (II). [Figure 29]

[0042] FIG. 29 shows the XRPD pattern of TPA023B phosphate solid obtained by polymorph screening using the slurry method. [Figure 30]

[0043] FIG. 30 shows the XRPD pattern of TPA023B phosphate solid obtained by polymorph screening using the heating-cooling method. [Figure 31]

[0044] FIG. 31 shows the DSC / TGA thermogram for TPA023B phosphate pattern D. [Figure 32]

[0045] FIG. 32 shows the XRPD pattern of TPA023B phosphate solid obtained by polymorph screening using the antisolvent method. [Figure 33]

[0046] FIG. 33 shows additional XRPD patterns of TPA023B polymorph screening by the heat-cool method. [Figure 34]

[0047] FIG. 34 shows additional DSC / TGA thermograms of TPA023B polymorph screening in IPA by the heat-cool method. [Figure 35]

[0048] Figure 35A shows the XRPD patterns of two batches of TPA023B free base, and Figure 35B shows the DSC diagrams of two batches of TPA023B free base. [Figure 36A]

[0049] Figures 36A-36H show the XRPD patterns of seven TPA023B free base forms (Figure 36A); the DSC and TGA profile of TPA023B free base form A (Figure 36B); the DSC and TGA profile of TPA023B free base form C (Figure 36D); the DSC and TGA profile of TPA023B free base form E (Figure 36C); the DSC and TGA profile of TPA023B free base form F (Figure 36E); the DSC and TGA profile of TPA023B free base form G (Figure 36F); the DSC and TGA profile of TPA023B free base form H (Figure 36G); and the DSC and TGA profile of TPA023B free base form I (Figure 36H). [Figure 36B]

[0049] Figures 36A-36H show the XRPD patterns of seven TPA023B free base forms (Figure 36A); the DSC and TGA profile of TPA023B free base form A (Figure 36B); the DSC and TGA profile of TPA023B free base form C (Figure 36D); the DSC and TGA profile of TPA023B free base form E (Figure 36C); the DSC and TGA profile of TPA023B free base form F (Figure 36E); the DSC and TGA profile of TPA023B free base form G (Figure 36F); the DSC and TGA profile of TPA023B free base form H (Figure 36G); and the DSC and TGA profile of TPA023B free base form I (Figure 36H). [Figure 36C]

[0049] Figures 36A-36H show the XRPD patterns of seven TPA023B free base forms (Figure 36A); the DSC and TGA profile of TPA023B free base form A (Figure 36B); the DSC and TGA profile of TPA023B free base form C (Figure 36D); the DSC and TGA profile of TPA023B free base form E (Figure 36C); the DSC and TGA profile of TPA023B free base form F (Figure 36E); the DSC and TGA profile of TPA023B free base form G (Figure 36F); the DSC and TGA profile of TPA023B free base form H (Figure 36G); and the DSC and TGA profile of TPA023B free base form I (Figure 36H). [Figure 36D]

[0049] Figures 36A-36H show the XRPD patterns of seven TPA023B free base forms (Figure 36A); the DSC and TGA profile of TPA023B free base form A (Figure 36B); the DSC and TGA profile of TPA023B free base form C (Figure 36D); the DSC and TGA profile of TPA023B free base form E (Figure 36C); the DSC and TGA profile of TPA023B free base form F (Figure 36E); the DSC and TGA profile of TPA023B free base form G (Figure 36F); the DSC and TGA profile of TPA023B free base form H (Figure 36G); and the DSC and TGA profile of TPA023B free base form I (Figure 36H). [Figure 36E]

[0049] Figures 36A-36H show the XRPD patterns of seven TPA023B free base forms (Figure 36A); the DSC and TGA profile of TPA023B free base form A (Figure 36B); the DSC and TGA profile of TPA023B free base form C (Figure 36D); the DSC and TGA profile of TPA023B free base form E (Figure 36C); the DSC and TGA profile of TPA023B free base form F (Figure 36E); the DSC and TGA profile of TPA023B free base form G (Figure 36F); the DSC and TGA profile of TPA023B free base form H (Figure 36G); and the DSC and TGA profile of TPA023B free base form I (Figure 36H). [Figure 36F]

[0049] Figures 36A-36H show the XRPD patterns of seven TPA023B free base forms (Figure 36A); the DSC and TGA profile of TPA023B free base form A (Figure 36B); the DSC and TGA profile of TPA023B free base form C (Figure 36D); the DSC and TGA profile of TPA023B free base form E (Figure 36C); the DSC and TGA profile of TPA023B free base form F (Figure 36E); the DSC and TGA profile of TPA023B free base form G (Figure 36F); the DSC and TGA profile of TPA023B free base form H (Figure 36G); and the DSC and TGA profile of TPA023B free base form I (Figure 36H). [Figure 36G]

[0049] Figures 36A-36H show the XRPD patterns of seven TPA023B free base forms (Figure 36A); the DSC and TGA profile of TPA023B free base form A (Figure 36B); the DSC and TGA profile of TPA023B free base form C (Figure 36D); the DSC and TGA profile of TPA023B free base form E (Figure 36C); the DSC and TGA profile of TPA023B free base form F (Figure 36E); the DSC and TGA profile of TPA023B free base form G (Figure 36F); the DSC and TGA profile of TPA023B free base form H (Figure 36G); and the DSC and TGA profile of TPA023B free base form I (Figure 36H). [Figure 36H]

[0049] Figures 36A-36H show the XRPD patterns of seven TPA023B free base forms (Figure 36A); the DSC and TGA profile of TPA023B free base form A (Figure 36B); the DSC and TGA profile of TPA023B free base form C (Figure 36D); the DSC and TGA profile of TPA023B free base form E (Figure 36C); the DSC and TGA profile of TPA023B free base form F (Figure 36E); the DSC and TGA profile of TPA023B free base form G (Figure 36F); the DSC and TGA profile of TPA023B free base form H (Figure 36G); and the DSC and TGA profile of TPA023B free base form I (Figure 36H). [Figure 37]

[0050] Figure 37A shows the XRPD pattern of TPA023B phosphate Form A and several phosphate patterns. Figure 37B shows the P-NMR spectrum of TPA023B phosphate Form A and several phosphate patterns. [Figure 38A]

[0051] Figures 38A-38D show the XRPD pattern (Figure 38A), DSC / TGA thermogram (Figure 38B), DVS results (Figure 38C), and XRPD patterns before and after DVS (Figure 38D) for TPA023B phosphate Form A. [Figure 38B] 38A-38D show the XRPD pattern (FIG. 38A), DSC / TGA thermogram (FIG. 38B), DVS results (FIG. 38C), and XRPD patterns before and after DVS (FIG. 38D) for TPA023B phosphate Form A. [Figure 38C] 38A-38D show the XRPD pattern (FIG. 38A), DSC / TGA thermogram (FIG. 38B), DVS results (FIG. 38C), and XRPD patterns before and after DVS (FIG. 38D) for TPA023B phosphate Form A. [Figure 38D]38A-38D show the XRPD pattern (FIG. 38A), DSC / TGA thermogram (FIG. 38B), DVS results (FIG. 38C), and XRPD patterns before and after DVS (FIG. 38D) for TPA023B phosphate Form A. [Figure 39]

[0052] FIG. 39 shows the DSC / TGA thermogram of TPA023B phosphate pattern F. [Figure 40]

[0053] FIG. 40 shows the DSC / TGA thermogram of TPA023B phosphate pattern G. [Figure 41]

[0054] FIG. 41 shows the DSC / TGA thermogram of TPA023B phosphate pattern H. [Figure 42]

[0055] FIG. 42 shows the estimated solubility of TPA023B phosphate Form A in various solvents. [Figure 43]

[0056] Figure 43 shows the XRPD pattern of TPA023B phosphate Form A slurried in a single solvent. [Figure 44]

[0057] FIG. 44 shows the XRPD pattern of TPA023B phosphate Form A converted to free base Form C. [Figure 45]

[0058] FIG. 45 shows the XRPD patterns of TPA023B phosphate Form A converted to free base Forms F and G. [Figure 46A]

[0059] Figures 46A and 46B show the XRPD pattern of TPA023B free base obtained by dissociation of TPA023B phosphate (Figure 46A); and the XRPD patterns of TPA023B free base Form E, Form H, and Form I (Figure 46B). [Figure 46B]

[0059] Figures 46A and 46B show the XRPD pattern of TPA023B free base obtained by dissociation of TPA023B phosphate (Figure 46A); and the XRPD patterns of TPA023B free base Form E, Form H, and Form I (Figure 46B). [Figure 47]

[0060] FIG. 47 shows the XRPD patterns of TPA023B phosphate Form A before and after mechanical treatment. [Figure 48]

[0061] Figure 48 shows the XRPD patterns of phosphate Form A before and after heat and moisture treatment. [Figure 49]

[0062] Figure 49 shows the XRPD pattern of the TPA023B free base starting material. [Figure 50]

[0063] Figure 50 shows the DSC / TGA diagram of TPA023B free base starting material. [Figure 51]

[0064] Figure 51 shows the XRPD patterns of the solid samples produced from reaction with acid in a 96-well plate. [Figure 52A]

[0065] Figures 52A-52I show the XRPD pattern of TPA023B chloride (Figure 52A), the XRPD pattern of TPA023B chloride after DVS testing (Figure 52B), the NMR spectrum of TPA023B chloride prepared in THF / EtOH-acetone (Figure 52C), the NMR spectrum of a TPA023B chloride sample prepared in THF / EtOH-1,4-dioxane (Figure 52D), and the NMR spectrum of TPA023B chloride. Shown are a DSC / TGA thermogram of Form B (Figure 52E), a DSC / TGA thermogram of chloride Form C of TPA023B (Figure 52F), a DSC / TGA thermogram of TPA023B chloride Form C after slurried in EA (Figure 52G), a DSC / TGA thermogram of TPA023B chloride Form C after slurried in heptane (Figure 52H), and a DVS profile of TPA023B chloride. [Figure 52B]52A-52I show the XRPD pattern of TPA023B chloride (FIG. 52A), the XRPD pattern of TPA023B chloride after DVS testing (FIG. 52B), the NMR spectrum of TPA023B chloride prepared in THF / EtOH-acetone (FIG. 52C), the NMR spectrum of a TPA023B chloride sample prepared in THF / EtOH-1,4-dioxane (FIG. 52D), and the NMR spectrum of TPA023B chloride sample prepared in THF / EtOH-1,4-dioxane (FIG. 52E). Shown are a DSC / TGA thermogram of chloride Form B (Figure 52E), a DSC / TGA thermogram of chloride Form C of TPA023B (Figure 52F), a DSC / TGA thermogram of TPA023B chloride Form C after being slurried in EA (Figure 52G), a DSC / TGA thermogram of TPA023B chloride Form C after being slurried in heptane (Figure 52H), and a DVS profile of TPA023B chloride. [Figure 52C] 52A-52I show the XRPD pattern of TPA023B chloride (FIG. 52A), the XRPD pattern of TPA023B chloride after DVS testing (FIG. 52B), the NMR spectrum of TPA023B chloride prepared in THF / EtOH-acetone (FIG. 52C), the NMR spectrum of a TPA023B chloride sample prepared in THF / EtOH-1,4-dioxane (FIG. 52D), and the NMR spectrum of TPA023B chloride sample prepared in THF / EtOH-1,4-dioxane (FIG. 52E). Shown are a DSC / TGA thermogram of chloride Form B (Figure 52E), a DSC / TGA thermogram of chloride Form C of TPA023B (Figure 52F), a DSC / TGA thermogram of TPA023B chloride Form C after being slurried in EA (Figure 52G), a DSC / TGA thermogram of TPA023B chloride Form C after being slurried in heptane (Figure 52H), and a DVS profile of TPA023B chloride. [Figure 52D]52A-52I show the XRPD pattern of TPA023B chloride (FIG. 52A), the XRPD pattern of TPA023B chloride after DVS testing (FIG. 52B), the NMR spectrum of TPA023B chloride prepared in THF / EtOH-acetone (FIG. 52C), the NMR spectrum of a TPA023B chloride sample prepared in THF / EtOH-1,4-dioxane (FIG. 52D), and the NMR spectrum of TPA023B chloride sample prepared in THF / EtOH-1,4-dioxane (FIG. 52E). Shown are a DSC / TGA thermogram of chloride Form B (Figure 52E), a DSC / TGA thermogram of chloride Form C of TPA023B (Figure 52F), a DSC / TGA thermogram of TPA023B chloride Form C after being slurried in EA (Figure 52G), a DSC / TGA thermogram of TPA023B chloride Form C after being slurried in heptane (Figure 52H), and a DVS profile of TPA023B chloride. [Figure 52E] 52A-52I show the XRPD pattern of TPA023B chloride (FIG. 52A), the XRPD pattern of TPA023B chloride after DVS testing (FIG. 52B), the NMR spectrum of TPA023B chloride prepared in THF / EtOH-acetone (FIG. 52C), the NMR spectrum of a TPA023B chloride sample prepared in THF / EtOH-1,4-dioxane (FIG. 52D), and the NMR spectrum of TPA023B chloride sample prepared in THF / EtOH-1,4-dioxane (FIG. 52E). Shown are a DSC / TGA thermogram of chloride Form B (Figure 52E), a DSC / TGA thermogram of chloride Form C of TPA023B (Figure 52F), a DSC / TGA thermogram of TPA023B chloride Form C after being slurried in EA (Figure 52G), a DSC / TGA thermogram of TPA023B chloride Form C after being slurried in heptane (Figure 52H), and a DVS profile of TPA023B chloride. [Figure 52F]52A-52I show the XRPD pattern of TPA023B chloride (FIG. 52A), the XRPD pattern of TPA023B chloride after DVS testing (FIG. 52B), the NMR spectrum of TPA023B chloride prepared in THF / EtOH-acetone (FIG. 52C), the NMR spectrum of a TPA023B chloride sample prepared in THF / EtOH-1,4-dioxane (FIG. 52D), and the NMR spectrum of TPA023B chloride sample prepared in THF / EtOH-1,4-dioxane (FIG. 52E). Shown are a DSC / TGA thermogram of chloride Form B (Figure 52E), a DSC / TGA thermogram of chloride Form C of TPA023B (Figure 52F), a DSC / TGA thermogram of TPA023B chloride Form C after being slurried in EA (Figure 52G), a DSC / TGA thermogram of TPA023B chloride Form C after being slurried in heptane (Figure 52H), and a DVS profile of TPA023B chloride. [Figure 52G] 52A-52I show the XRPD pattern of TPA023B chloride (FIG. 52A), the XRPD pattern of TPA023B chloride after DVS testing (FIG. 52B), the NMR spectrum of TPA023B chloride prepared in THF / EtOH-acetone (FIG. 52C), the NMR spectrum of a TPA023B chloride sample prepared in THF / EtOH-1,4-dioxane (FIG. 52D), and the NMR spectrum of TPA023B chloride sample prepared in THF / EtOH-1,4-dioxane (FIG. 52E). Shown are a DSC / TGA thermogram of chloride Form B (Figure 52E), a DSC / TGA thermogram of chloride Form C of TPA023B (Figure 52F), a DSC / TGA thermogram of TPA023B chloride Form C after being slurried in EA (Figure 52G), a DSC / TGA thermogram of TPA023B chloride Form C after being slurried in heptane (Figure 52H), and a DVS profile of TPA023B chloride. [Figure 52H]52A-52I show the XRPD pattern of TPA023B chloride (FIG. 52A), the XRPD pattern of TPA023B chloride after DVS testing (FIG. 52B), the NMR spectrum of TPA023B chloride prepared in THF / EtOH-acetone (FIG. 52C), the NMR spectrum of a TPA023B chloride sample prepared in THF / EtOH-1,4-dioxane (FIG. 52D), and the NMR spectrum of TPA023B chloride sample prepared in THF / EtOH-1,4-dioxane (FIG. 52E). Shown are a DSC / TGA thermogram of chloride Form B (Figure 52E), a DSC / TGA thermogram of chloride Form C of TPA023B (Figure 52F), a DSC / TGA thermogram of TPA023B chloride Form C after being slurried in EA (Figure 52G), a DSC / TGA thermogram of TPA023B chloride Form C after being slurried in heptane (Figure 52H), and a DVS profile of TPA023B chloride. [Figure 52I] 52A-52I show the XRPD pattern of TPA023B chloride (FIG. 52A), the XRPD pattern of TPA023B chloride after DVS testing (FIG. 52B), the NMR spectrum of TPA023B chloride prepared in THF / EtOH-acetone (FIG. 52C), the NMR spectrum of a TPA023B chloride sample prepared in THF / EtOH-1,4-dioxane (FIG. 52D), and the NMR spectrum of TPA023B chloride sample prepared in THF / EtOH-1,4-dioxane (FIG. 52E). Shown are a DSC / TGA thermogram of chloride Form B (Figure 52E), a DSC / TGA thermogram of chloride Form C of TPA023B (Figure 52F), a DSC / TGA thermogram of TPA023B chloride Form C after being slurried in EA (Figure 52G), a DSC / TGA thermogram of TPA023B chloride Form C after being slurried in heptane (Figure 52H), and a DVS profile of TPA023B chloride. [Figure 53A]

[0066] Figures 53A-53D show the XRPD pattern (Figure 53A), the XRPD pattern of TPA023B sulfate after performing a DVS experiment (Figure 53B), the DSC / TGA thermogram (Figure 53C), and the DVS profile of TPA023B sulfate (Figure 53D). [Figure 53B]53A-53D show the XRPD pattern (FIG. 53A), the XRPD pattern of TPA023B sulfate after performing a DVS experiment (FIG. 53B), the DSC / TGA thermogram (FIG. 53C), and the DVS profile of TPA023B sulfate (FIG. 53D). [Figure 53C] 53A-53D show the XRPD pattern (FIG. 53A), the XRPD pattern of TPA023B sulfate after performing a DVS experiment (FIG. 53B), the DSC / TGA thermogram (FIG. 53C), and the DVS profile of TPA023B sulfate (FIG. 53D). [Figure 53D] 53A-53D show the XRPD pattern (FIG. 53A), the XRPD pattern of TPA023B sulfate after performing a DVS experiment (FIG. 53B), the DSC / TGA thermogram (FIG. 53C), and the DVS profile of TPA023B sulfate (FIG. 53D). [Figure 54]

[0067] Figure 54 shows the XRPD pattern of TPA023B bromide along with the free base reference. [Figure 55]

[0068] Figure 55 shows the XRPD pattern of TPA023B tosylate along with the free base reference. [Figure 56]

[0069] Figure 56 shows the XRPD pattern of TPA023B mesylate along with the free base reference. [Figure 57A]

[0070] Figures 57A-57G show the XRPD pattern (Figure 57A), the XRPD pattern (Figure 57B) of TPA023B besylate after performing a DVS study, the NMR spectrum (Figure 57C), the DSC / TGA thermograms (Figures 57D-F), and the DVS profile (Figure 57G) of TPA023B besylate. [Figure 57B]

[0070] Figures 57A-57G show the XRPD pattern (Figure 57A), the XRPD pattern (Figure 57B) of TPA023B besylate after performing a DVS study, the NMR spectrum (Figure 57C), the DSC / TGA thermograms (Figures 57D-F), and the DVS profile (Figure 57G) of TPA023B besylate. [Figure 57C]

[0070] Figures 57A-57G show the XRPD pattern (Figure 57A), the XRPD pattern (Figure 57B) of TPA023B besylate after performing a DVS study, the NMR spectrum (Figure 57C), the DSC / TGA thermograms (Figures 57D-F), and the DVS profile (Figure 57G) of TPA023B besylate. [Figure 57D]

[0070] Figures 57A-57G show the XRPD pattern (Figure 57A), the XRPD pattern (Figure 57B) of TPA023B besylate after performing a DVS study, the NMR spectrum (Figure 57C), the DSC / TGA thermograms (Figures 57D-F), and the DVS profile (Figure 57G) of TPA023B besylate. [Figure 57E]

[0070] Figures 57A-57G show the XRPD pattern (Figure 57A), the XRPD pattern (Figure 57B) of TPA023B besylate after performing a DVS study, the NMR spectrum (Figure 57C), the DSC / TGA thermograms (Figures 57D-F), and the DVS profile (Figure 57G) of TPA023B besylate. [Figure 57F]

[0070] Figures 57A-57G show the XRPD pattern (Figure 57A), the XRPD pattern (Figure 57B) of TPA023B besylate after performing a DVS study, the NMR spectrum (Figure 57C), the DSC / TGA thermograms (Figures 57D-F), and the DVS profile (Figure 57G) of TPA023B besylate. [Figure 57G]

[0070] Figures 57A-57G show the XRPD pattern (Figure 57A), the XRPD pattern (Figure 57B) of TPA023B besylate after performing a DVS study, the NMR spectrum (Figure 57C), the DSC / TGA thermograms (Figures 57D-F), and the DVS profile (Figure 57G) of TPA023B besylate. [Figure 58]

[0071] Figure 58 shows the XRPD pattern of TPA023B phosphate. [Figure 59A]

[0072] Figures 59A-59D show the XRPD patterns of stability samples of TPA023B free base (Figure 59A), TPA023B chloride (Figure 59B), TPA023B sulfate (Figure 59C), and TPA023B besylate (Figure 59D). [Figure 59B]

[0072] Figures 59A-59D show XRPD patterns of stability samples of TPA023B free base (Figure 59A), TPA023B chloride (Figure 59B), TPA023B sulfate (Figure 59C), and TPA023B besylate (Figure 59D). [Figure 59C]

[0072] Figures 59A-59D show XRPD patterns of stability samples of TPA023B free base (Figure 59A), TPA023B chloride (Figure 59B), TPA023B sulfate (Figure 59C), and TPA023B besylate (Figure 59D). [Figure 59D]

[0072] Figures 59A-59D show XRPD patterns of stability samples of TPA023B free base (Figure 59A), TPA023B chloride (Figure 59B), TPA023B sulfate (Figure 59C), and TPA023B besylate (Figure 59D). [Figure 60]

[0073] FIG. 60 shows the annotated XRPD pattern of TPA023B besylate Form A. [Figure 61]

[0074] FIG. 61 shows the annotated XRPD pattern of TPA023B sulfate Form A. [Figure 62]

[0075] FIG. 62 shows the annotated XRPD pattern of TPA023B chloride Form B. [Figure 63]

[0076] FIG. 63 shows the annotated XRPD pattern of TPA023B chloride Form C. [Figure 64]

[0077] Figure 64 shows the XRPD pattern of TPA023B phosphate Form A produced by the kilogram-scale preparative procedure. [Figure 65]

[0078] Figure 65A shows the DSC thermogram of TPA023B phosphate Form A produced by the kilogram-scale preparative procedure. Figure 65B shows the TGA thermogram of TPA023B phosphate Form A produced by the kilogram-scale preparative procedure. [Figure 66]

[0079] Figure 66 shows the solid state form transformation map between the amorphous form and phosphate Form A and phosphate Form J anhydrate. [Figure 67]

[0080] Figure 67 shows the XRPD pattern of phosphate Form J. [Figure 68]

[0081] FIG. 68 shows the overlaid XRPD patterns of phosphate Form A and phosphate Form J. [Figure 69]

[0082] Figure 69 shows the TGA and DSC thermograms of phosphate Form J. [Figure 70]

[0083] FIG. 70 shows the overlaid XRPD of phosphate Form J converting to phosphate Form A from the slurry. [Figure 71]

[0084] Figure 71 shows overlaid XRPDs of the conversion of the amorphous 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 phosphoric acid to phosphate form J and phosphate form A by solid-vapor diffusion. [Figure 72]

[0085] Figure 72 shows the XRPD of the conversion of the amorphous 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 phosphoric acid to phosphate Form J by mechanical grinding and rapid evaporation of the solvent. [Figure 73]

[0086] Figure 73 shows the XRPD pattern of TPA023B free base pattern K. DETAILED DESCRIPTION OF THE INVENTION

[0016]

[0087] Described herein are novel free base polymorphs, pharmaceutical salts and salt polymorphs, and pharmaceutical co-crystals and co-crystal polymorphs that have beneficial properties, such as improved solubility, improved oral bioavailability, more consistent oral bioavailability, improved stability, and improved manufacturability, and corresponding improved formulations. Salts, co-crystals, polymorphs, salt polymorphs, and co-crystal polymorphs of TPA023B are described herein and are useful for treating several disorders in addition to itch. As will be appreciated by those skilled in the art, the use of TPA023B in treating itch may be beneficial. Such compounds may be used to treat 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, including, but not limited to, pain, anxiety, epilepsy, muscle spasms, pruritus, itching, cognitive impairment, alcoholism, schizophrenia, depression, autism, etc. Phosphate form Phosphate Form A

[0088] In one or more embodiments, the present disclosure discloses a stable 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. 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. The similar pKa values ​​unexpectedly demonstrate 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. 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," exhibits an X-ray powder diffraction (XRPD) pattern with 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, 7.5, 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, as measured using the parameters set forth in Table 1. In one or more embodiments, phosphate polymorph Form A exhibits an XRPD pattern substantially identical to the XRPD pattern shown in FIG.In some embodiments, "phosphate polymorph Form A" (i.e., phosphate Form A) exhibits an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, at least twelve, at least fifteen, or all values ​​selected from the group consisting of about 6.5, 7.6, 10.2, 13.4, 14.0, 14.4, 15.4, 16.0, 16.2, 17.2, 17.5, 17.8, 18.6, 19.2, 19.8, 20.4, 20.9, 21.6, 23.5, 26.2, 26.6, 27.4, 28.3, 29.0, 30.2, and 32.7±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In one or more embodiments, phosphate polymorph Form A exhibits an XRPD pattern substantially identical to the XRPD pattern shown in Figure 38A. In some embodiments, phosphate polymorph Form A exhibits an XRPD pattern with a characteristic peak located at about 6.5±0.2 degrees two-theta. In some embodiments, phosphate polymorph Form A exhibits an XRPD pattern with a characteristic peak located at about 7.6±0.2 degrees two-theta. In some embodiments, phosphate polymorph Form A exhibits an XRPD pattern with a characteristic peak located at about 13.4±0.2 degrees two-theta. In some embodiments, phosphate polymorph Form A exhibits an XRPD pattern with a characteristic peak located at about 17.2±0.2 degrees two-theta. In some embodiments, phosphate polymorph Form A exhibits an XRPD pattern with a characteristic peak located at about 17.8±0.2 degrees two-theta. In some embodiments, phosphate polymorph Form A exhibits an XRPD pattern with a characteristic peak located at about 26.2±0.2 degrees two-theta. In some embodiments, phosphate polymorph Form A exhibits an XRPD pattern with a characteristic peak located at about 30.2±0.2 degrees two-theta. In one or more embodiments, phosphate polymorph Form A exhibits an XRPD pattern substantially identical to the XRPD patterns shown in Figures 48A and 48B. In one or more embodiments, phosphate polymorph Form A exhibits an XRPD pattern substantially identical to any of the XRPD patterns described herein for phosphate Form A. show.

[0017] Table 1

[0018]

[0089] 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, and about 60°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, or 90% RH. In some embodiments, phosphate polymorph Form A 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, or at least 24 months. 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 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% w / w or more of the initial phosphate amount at the end of a given storage period. In some embodiments, stable phosphate polymorph Form A 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 some embodiments, phosphate polymorph Form A provides a substantially identical XRPD pattern after at least 1 week of storage at about 40°C and 75% RH.In some embodiments, phosphate polymorph Form A provides a substantially identical XRPD pattern after storage at about 40° C. and 75% RH for at least two weeks. In some embodiments, phosphate polymorph Form A provides a substantially identical XRPD pattern after storage at about 40° C. and 75% RH for at least one month. In some embodiments, phosphate polymorph Form A provides a substantially identical XRPD pattern after storage at about 40° C. and 75% RH for at least three months. In some embodiments, phosphate polymorph Form A provides a substantially identical XRPD pattern after storage at about 40° C. and 75% RH for at least six months. In some embodiments, phosphate polymorph Form A provides a substantially identical XRPD pattern after storage at about 25° C. and 92.5% RH for at least one week. In some embodiments, phosphate polymorph Form A provides a substantially identical XRPD pattern after storage at about 25° C. and 92.5% RH for at least two weeks. In some embodiments, phosphate polymorph Form A provides a substantially identical XRPD pattern after storage at about 25° C. and 92.5% RH for at least one month. In some embodiments, phosphate polymorph Form A provides a substantially identical XRPD pattern after storage at about 25° C. and 92.5% RH for at least 3 months. In some embodiments, phosphate polymorph Form A provides a substantially identical XRPD pattern after storage at about 25° C. and 92.5% RH for at least 6 months.

[0019]

[0090] 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 including an endothermic peak at about 205°C. In one or more embodiments, phosphate polymorph Form A provides a DSC thermogram including an endothermic peak at about 206°C. In some embodiments, phosphate polymorph Form A provides a DSC thermogram including a single endothermic peak with an onset temperature of 203°C. In some embodiments, phosphate polymorph Form A provides a DSC thermogram including a single endothermic peak with an onset temperature of 204°C. In one or more embodiments, phosphate polymorph Form A exhibits a DSC thermogram substantially identical to the DSC thermogram shown in Figure 2A. In one or more embodiments, phosphate polymorph Form A exhibits a DSC thermogram substantially identical to the DSC thermogram shown in Figure 38B. In some embodiments, phosphate polymorph Form A provides a DSC thermogram substantially identical to that shown in Figure 2C. This melting point is obtained using DSC at a heating rate of 10°C / min. In some embodiments, phosphate polymorph Form A exhibits birefringence under polarized light. Phosphate polymorph Form A can be synthesized using the methods of Example 5, Example 33, or Example 50. 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.

[0020]

[0091] In one or more embodiments, the phosphate polymorph Form A described herein 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 phosphate polymorph Form A described herein contains impurities. In some embodiments, 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% as measured by HPLC as described herein.

[0021]

[0092] In some embodiments, phosphate polymorph Form A has a plasma half-life in rat plasma that is 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 that is 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 that is about 8 hours to about 15 hours. In some embodiments, phosphate polymorph Form A has a plasma half-life in rat plasma that is about 10 hours to about 13 hours.

[0022]

[0093] 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 gastric 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 gastric fluid (FeSSIF).

[0023]

[0094] In one aspect, disclosed herein is a method of preparing a crystalline form (e.g., a salt or co-crystal) of phosphate polymorph Form A from solution. In some embodiments, the crystalline salt or co-crystal of phosphate polymorph Form A provides an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 64, when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline salt or co-crystal provides an XRPD pattern having characteristic peak positions of at least three, at least six, or at least nine values ​​selected from the group consisting of about 6.5, 7.6, 10.2, 13.4, 14.0, 14.4, 15.4, 16.0, 16.2, 17.2, 17.5, 17.8, 18.6, 19.2, 19.8, 20.4, 20.9, 21.6, 23.5, 26.2, 26.6, 27.4, 28.3, 29.0, 30.2, and 32.7±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, or at least twelve values ​​selected from the group consisting of about 6.5, 7.6, 10.2, 13.4, 14.0, 14.4, 15.4, 16.0, 16.2, 17.2, 17.5, 17.8, 18.6, 19.2, 19.8, 20.4, 20.9, 21.6, 23.5, 26.2, 26.6, 27.4, 28.3, 29.0, 30.2, and 32.7±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, or at least twelve values ​​selected from the group consisting of about 6.5, 7.6, 10.2, 13.4, 14.0, 14.4, 15.4, 16.0, 16.2, 17.2, 17.5, 17.8, 18.6, 19.2, 19.8, 20.4, 20.9, 21.6, 23.5, 26.2, 26.6, 27.4, 28.3, 29.0, 30.2, and 32.7±0.2 degrees two-theta, when measured using the parameters set forth in Table 35.In some embodiments, the method comprises crystallizing phosphate polymorph Form A from a solution. In some embodiments, the solution comprises 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. In some embodiments, at least 500 grams of crystalline salt or co-crystal is prepared. In some embodiments, the solution comprises THF. In some embodiments, the solution comprises 2-MeTHF. In some embodiments, the solution comprises IPAC. In some embodiments, the solution comprises heptane. In some embodiments, the solution comprises acetonitrile. In some embodiments, the solution comprises methyl tert-butyl ether. In some embodiments, the solution comprises low levels of water and / or alcohol. For example, in some embodiments, the water content in the solution is at most 10 wt%, at most 5 wt%, at most 4 wt%, at most 3 wt%, at most 2 wt%, at most 1 wt%, at most 0.5 wt%, at most 0.2 wt%, at most 0.1 wt%, or at most 0.01 wt%. The water and alcohol content is at most 10 wt%, at most 5 wt%, at most 4 wt%, at most 3 wt%, at most 2 wt%, at most 1 wt%, at most 0.5 wt%, at most 0.2 wt%, at most 0.1 wt%, or at most 0.01 wt%. In some embodiments, at least 1000 grams, at least 2000 grams, at least 2500 grams, or at least 5000 grams of crystalline salt or co-crystal are prepared. In some embodiments, the solution comprises ethyl acetate. In some embodiments, the solution comprises acetone. In some embodiments, the solution comprises acetone, water, and ethyl acetate. In some embodiments, the solution comprises a mixture of acetone and water. In some embodiments, the method comprises removing water by some means, such as azeotropic drying, activated sieves, magnesium sulfate, sodium sulfate, or other drying agents. In some embodiments, the method comprises an azeotropic drying step to remove water. In some embodiments, the solution does not contain water or alcohol. In some embodiments, the method comprises removing acetone one or more times by distillation. In some embodiments, the method comprises removing acetone by distillation one, two, three, or more times. In some embodiments, the method comprises removing ethyl acetate by distillation one or more times. In some embodiments, the method comprises removing ethyl acetate by distillation one, two, three, or more times. In some embodiments, the method comprises removing water by distillation of a solvent having a lower boiling point than water. In some embodiments, the solvent comprises ethyl acetate, methyl ethyl ketone, 2-methylbutanone, acetone, tetrahydrofuran, 2-methyl-THF, isopropyl acetate, acetonitrile, or dichloromethane. Phosphate Form J

[0095] In one aspect, disclosed herein is a new crystalline form 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 ("phosphate polymorphic form J"). Phosphate polymorphic form J can be isolated under vapor diffusion. In some embodiments, phosphate polymorphic form J is an anhydrate. In some embodiments, phosphate polymorphic form J contains water and / or other solvents. In one or more embodiments, the crystalline form is a salt. In one or more embodiments, the crystalline form is a co-crystal. In some embodiments, the coformer is phosphoric acid. In some embodiments, phosphate polymorphic form J exhibits birefringence under polarized light. In some embodiments, phosphate polymorphic form J is isolated under vapor diffusion in ethyl acetate and / or isopropyl acetate, as seen in Figure 66. In some embodiments, phosphate polymorph Form J (i.e., phosphate Form J) exhibits an X-ray powder diffraction (XRPD) pattern having characteristic peak positions of at least three, at least six, at least nine, or all values ​​selected from the group consisting of about 6.3, 13.2, 14.0, 15.7, 17.0, 17.3, 18.0, 20.2, 20.7, and 26.4±0.2 degrees two-theta, when measured using the parameters set forth in Table 35. In some embodiments, phosphate Form J exhibits an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, or all values ​​selected from the group consisting of about 6.3, 7.4, 10.1, 12.6, 13.2, 14.0, 15.7, 17.0, 17.3, 18.0, 19.0, 20.2, 20.7, 26.4, 27.2, and 27.5±0.2 degrees two-theta, when measured using the parameters set forth in Table 35. In one or more embodiments, phosphate polymorph Form J exhibits an XRPD pattern substantially identical to the XRPD pattern shown in Figure 67.

[0024]

[0096] In Figure 68, the overlaid XRPD shows both phosphate forms A and J when measured using the parameters set forth in Table 35. As shown in Figure 68, phosphate form A exhibits an XRPD of 6.5, 13. 68, Phosphate Form J exhibits an XRPD pattern with characteristic peak positions at 6.3, 13.2, 14.0, 15.7, 17.0, 17.3, 18.0, 20.2, 20.7, and 26.4±0.2 degrees two-theta when measured using the parameters set forth in Table 35.

[0025]

[0097] In some embodiments, phosphate polymorphic Form J exhibits an XRPD pattern with a characteristic peak located at about 6.3±0.2 degrees two-theta. In some embodiments, phosphate polymorphic Form J exhibits an XRPD pattern with a characteristic peak located at about 7.4±0.2 degrees two-theta. In some embodiments, phosphate polymorphic Form J exhibits an XRPD pattern with a characteristic peak located at about 13.2±0.2 degrees two-theta. In some embodiments, phosphate polymorphic Form J exhibits an XRPD pattern with a characteristic peak located at about 14.0±0.2 degrees two-theta. In some embodiments, phosphate polymorphic Form J exhibits an XRPD pattern with a characteristic peak located at about 15.7±0.2 degrees two-theta. In some embodiments, phosphate polymorphic Form J exhibits an XRPD pattern with a characteristic peak located at about 17.0±0.2 degrees two-theta. In some embodiments, phosphate polymorphic Form J exhibits an XRPD pattern with a characteristic peak located at about 17.3±0.2 degrees two-theta. In some embodiments, phosphate polymorph Form J exhibits an XRPD pattern with a characteristic peak located at about 18.0±0.2 degrees two-theta. In some embodiments, phosphate polymorph Form J exhibits an XRPD pattern with a characteristic peak located at about 19.0±0.2 degrees two-theta. In some embodiments, phosphate polymorph Form J exhibits an XRPD pattern with a characteristic peak located at about 20.2±0.2 degrees two-theta. In some embodiments, phosphate polymorph Form J exhibits an XRPD pattern with a characteristic peak located at about 20.7±0.2 degrees two-theta. In some embodiments, phosphate polymorph Form J exhibits an XRPD pattern with a characteristic peak located at about 26.4±0.2 degrees two-theta. In some embodiments, the XRPD pattern of phosphate polymorph Form J is measured using the parameters set forth in Table 35.

[0026]

[0098] In some embodiments, phosphate polymorph Form J exhibits an XRPD pattern lacking a characteristic peak located at about 21.6±0.2 degrees two-theta. In some embodiments, phosphate polymorph Form J exhibits an XRPD pattern lacking a characteristic peak located at about 17.8±0.2 degrees two-theta. In some embodiments, phosphate polymorph Form J exhibits an XRPD pattern lacking a characteristic peak located at about 18.6±0.2 degrees two-theta. In some embodiments, phosphate polymorph Form J exhibits an XRPD pattern lacking a characteristic peak located at about 14.4±0.2 degrees two-theta. In some embodiments, the XRPD pattern of phosphate polymorph Form J is measured using the parameters set forth in Table 35.

[0027]

[0099] In some embodiments, phosphate polymorphic Form J is a metastable form. In some embodiments, phosphate polymorphic Form J readily converts to phosphate polymorphic Form A. In some embodiments, phosphate polymorphic Form J can be stored at a variety of temperatures and relative humidity. For example, phosphate polymorphic Form J 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, phosphate polymorphic Form J can be stored at 10% RH, 20% RH, 30% RH, 40% RH, 50% RH, 60% RH, 75% RH, or 90% RH. In some embodiments, phosphate polymorphic Form J can be stored at or below 10% RH, 20% RH, 30% RH, or 40% RH. In some embodiments, phosphate polymorphic Form J can be stored at about 25°C for at least 7 days. In some embodiments, phosphate polymorphic Form J is stable for 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 12 months. In some embodiments, phosphate polymorphic Form J is stable at about 25° C. for at least 1 month. In some embodiments, phosphate polymorphic Form J is stable at about 40° C. 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, or at least 12 months. In some embodiments, phosphate polymorphic Form J is stable at about 60° C. 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 6 months, or at least 12 months. In some embodiments, stable phosphate polymorph Form J has about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% w / w or more of the initial phosphate amount at the end of a given storage period. In some embodiments, a sample of phosphate polymorph Form J has about 95% w / w or more of the initial phosphate amount at the end of a given storage period. In some embodiments, a sample of phosphate polymorph Form J 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 some embodiments, phosphate polymorph Form J provides a substantially identical XRPD pattern after at least one week of storage at about 25°C and 40% RH. In some embodiments, phosphate polymorph Form J provides a substantially identical XRPD pattern after at least two weeks of storage at about 25°C and 40% RH. In some embodiments, the phosphate polymorph Form J provides a substantially identical XRPD pattern after storage at about 25° C. and 40% RH for at least 1 month.

[0028]

[0100] In one or more embodiments, phosphate polymorph J has a melting range of about 197-200°C, as seen in Figure 69. In some embodiments, phosphate polymorph J has a melting range of about 195-202°C. In some embodiments, phosphate polymorph J has a melting range of about 192-205°C. In one or more embodiments, phosphate polymorph J exhibits a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 197°C. In one or more embodiments, phosphate polymorph J provides a DSC thermogram including an endothermic peak at about 198°C. In one or more embodiments, phosphate polymorph J provides a DSC thermogram including an endothermic peak at about 199°C. In one or more embodiments, phosphate polymorph J provides a DSC thermogram including an endothermic peak at about 200°C. In one or more embodiments, phosphate polymorph J provides a DSC thermogram including an endothermic peak at about 201°C. In one or more embodiments, phosphate polymorph Form J provides a DSC thermogram including an endothermic peak at about 202°C. In one or more embodiments, phosphate polymorph Form J provides a DSC thermogram including an endothermic peak between about 198°C and 202°C. In one or more embodiments, phosphate polymorph Form J provides a DSC thermogram including an endothermic peak between about 195°C and 205°C. In some embodiments, phosphate polymorph Form J provides a DSC thermogram including a single endothermic peak with an onset temperature of 195°C. In some embodiments, phosphate polymorph Form J provides a DSC thermogram including a single endothermic peak with an onset temperature of 196°C. In some embodiments, phosphate polymorph Form J provides a DSC thermogram including a single endothermic peak with an onset temperature of 197°C. In some embodiments, phosphate polymorph Form J provides a DSC thermogram including a single endothermic peak with an onset temperature of 198°C. In some embodiments, phosphate polymorph Form J provides a DSC thermogram containing a single endothermic peak with an onset temperature of 199° C. In some embodiments, phosphate polymorph Form J provides a DSC thermogram containing a single endothermic peak with an onset temperature of 195° C. to 199° C.In some embodiments, the phosphate polymorph Form J provides a DSC thermogram comprising a single endothermic peak with an onset temperature of 192° C. to 202° C. In some embodiments,. Phosphate polymorph Form J provides a DSC thermogram containing a single endothermic peak with an onset temperature of 197° C. and a peak temperature of 200° C. In one or more embodiments, phosphate polymorph Form J exhibits a DSC thermogram substantially identical to the DSC thermogram shown in Figure 69. This melting point is obtained using DSC at a heating rate of 10° C. / min.

[0029]

[0101] Phosphate polymorph Form J can be synthesized using the methods described in Example 62 and Example 69. In one or more embodiments, described are pharmaceutical compositions comprising phosphate polymorph Form J. In one or more embodiments, the disclosure includes purified forms of crystalline phosphate polymorph Form J.

[0030]

[0102] In one or more embodiments, the phosphate polymorph Form J described herein 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 one or more embodiments, the phosphate polymorph Form J described herein is at least 95% pure as measured by HPLC as described herein. In some embodiments, the phosphate polymorph Form J described herein contains impurities. In some embodiments, the impurities in phosphate polymorph Form J 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. In some embodiments, the impurities in phosphate polymorph Form J are at most 5% impurities.

[0031]

[0103] Phosphate polymorph Form J 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 J 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 J 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 gastric fluid (FaSSIF) than the solubility of free base Form A. In some embodiments, the solubility of phosphate polymorph Form J 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 gastric fluid (FeSSIF).

[0032]

[0104] In one aspect, methods for preparing crystalline salts or co-crystals of phosphate polymorph Form J are disclosed herein. In some embodiments, the method for preparing crystalline salts or co-crystals of phosphate polymorph Form J comprises converting an amorphous 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 phosphoric acid to Form J. In some embodiments, the conversion occurs by drying at room temperature. In some embodiments, the conversion occurs by solid-vapor diffusion. In some embodiments, a method for forming an amorphous 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 phosphoric acid is by rotary evaporation of polymorphic phosphate Form A in a solvent such as THF. In some embodiments, the method for crystallizing polymorphic form J comprises a phosphoric acid solution containing 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazol-1-one. and drying the amorphous salt 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 amorphous salt of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid solution comprises an amorphous salt of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid and a solvent. In some embodiments, the solvent used to dissolve the amorphous salt of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid is THF.

[0033]

[0105] In some embodiments, a method for preparing a crystalline salt or co-crystal of phosphate polymorph Form J comprises crystallizing phosphate polymorph Form J from a solution. In some embodiments, the solution comprises one or more of ethyl acetate, methyl ethyl ketone, water, tetrahydrofuran (THF), isopropyl acetate (IPAC), and acetonitrile. In some embodiments, the solution comprises ethyl acetate. In some embodiments, the solution comprises methyl ethyl ketone. In some embodiments, the solution comprises THF. In some embodiments, the solution comprises IPAC. In some embodiments, the solution comprises acetonitrile. In some embodiments, the solution contains low levels of water and / or alcohol. For example, in some embodiments, the water content in the solution is at most 10 wt%, at most 5 wt%, at most 4 wt%, at most 3 wt%, at most 2 wt%, at most 1 wt%, at most 0.5 wt%, at most 0.2 wt%, at most 0.1 wt%, or at most 0.01 wt%. In some embodiments, the combined water and alcohol content in the solution is at most 10 wt%, at most 5 wt%, at most 4 wt%, at most 3 wt%, at most 2 wt%, at most 1 wt%, at most 0.5 wt%, at most 0.2 wt%, at most 0.1 wt%, or at most 0.01 wt%. In some embodiments, at least 1000 grams, at least 2000 grams, at least 2500 grams, or at least 5000 grams of crystalline salt or co-crystal are prepared. In some embodiments, the solvent comprises ethyl acetate, methyl ethyl ketone, acetone, tetrahydrofuran, isopropyl acetate, acetonitrile, or a combination thereof.

[0034]

[0106] In some embodiments, a method for crystallizing phosphate polymorph Form J comprises subjecting an amorphous 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 phosphoric acid to solid-vapor diffusion. In some embodiments, solid-vapor diffusion is carried out at RT. In some embodiments, solid-vapor diffusion is carried out at 20°C to 25°C. In some embodiments, solid-vapor diffusion is carried out at about 10°C, 15°C, 20°C, 25°C, or 30°C. In some embodiments, solid-vapor diffusion is carried out for a period of 2 hours to 2 weeks, or any range therebetween. In some embodiments, solid-vapor diffusion is carried out for a period of 12 hours to 3 days or 12 hours to 2 days. In some embodiments, solid-vapor diffusion is carried out for a period of 1 day, 2 days, 3 days, 4 days, or 5 days. In some embodiments, solid-vapor diffusion is carried out for a period of 1 day. In some embodiments, solid-vapor diffusion is carried out for a period of 1 to 3 days. In some embodiments, solid-vapor diffusion is carried out according to the procedure of Example 62. In some embodiments, the solvent used in solid-vapor diffusion is IPAC or ethyl acetate. In some embodiments, the solvent used in solid-vapor diffusion is methyl acetate. In some embodiments, the solvent used in solid-vapor diffusion is MEK. In some embodiments, the method for crystallizing phosphate polymorph Form J comprises phosphoric acid, 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)- The method comprises storing an amorphous salt of imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile in a desiccator at room temperature. In some embodiments, the method for crystallizing phosphate polymorph Form J comprises mechanically grinding an amorphous 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 phosphoric acid in a solvent. In some embodiments, the solvent used for grinding is acetonitrile or ethyl acetate. In some embodiments, the solvent used for grinding is acetonitrile. In some embodiments, the solvent used for grinding is ethyl acetate. Phosphate Pattern

[0107] In some embodiments, described herein are mixtures comprising crystalline polymorphs 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. This crystalline polymorph mixture is designated "phosphate polymorph pattern B" (i.e., phosphate pattern B) and exhibits an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, at least twelve, at least fifteen, 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 identical to 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 and 203°C. In one or more embodiments, phosphate polymorph pattern B exhibits a DSC thermogram substantially identical to the DSC thermogram shown in Figure 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.

[0035]

[0108] In some embodiments, described herein are other mixtures comprising crystalline polymorphs 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. This crystalline polymorph mixture is designated "phosphate polymorph pattern D" (i.e., phosphate pattern D) and exhibits an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, at least twelve, at least fifteen, 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 identical to the XRPD pattern labeled Phosphate Pattern D shown in Figure 30. In one or more embodiments, phosphate polymorph pattern D has a melting / dehydration / desolvation range of about 30°C to about 150°C. In one or more embodiments, phosphate polymorph pattern D exhibits a DSC pattern comprising an endothermic peak at about 202°C. 31 shows a DSC thermogram. In one or more embodiments, phosphate polymorph pattern D exhibits a DSC thermogram substantially identical to the DSC thermogram shown in Figure 31. In one or more embodiments, phosphate polymorph pattern D can be synthesized using the method described in Example 27. In one or more embodiments, pharmaceutical compositions comprising phosphate polymorph pattern D are described.

[0036]

[0109] 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 polymorph mixture is designated "Phosphate Polymorph Pattern E" and exhibits an XRPD pattern 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 identical to 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 identical to the DSC thermogram shown in Figure 8. This melting point is obtained using DSC at a heating rate of 10°C / min. In one or more embodiments, phosphate polymorph pattern E can be synthesized using the method of Example 8. In one or more embodiments, pharmaceutical compositions comprising phosphate polymorph Pattern E are described.

[0037]

[0110] In one or more embodiments, a mixture containing a crystalline polymorph of the free base, 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 identified and designated as "phosphate polymorph pattern F" (i.e., phosphate pattern F). Phosphate polymorph pattern F appears to contain primarily TPA023B free base. Phosphate polymorph pattern F exhibits an XRPD pattern substantially identical to the XRPD pattern labeled Pattern F in Figure 37A. In one or more embodiments, phosphate polymorph pattern F exhibits a DSC thermogram substantially identical to Figure 39. In one or more embodiments, phosphate polymorph pattern F has a melting / desolvation / dehydration range of about 75°C to about 115°C. In one or more embodiments, phosphate polymorph pattern F exhibits a DSC thermogram comprising an endothermic peak at about 104°C. In one or more embodiments, phosphate polymorph pattern F exhibits a DSC thermogram comprising an endothermic peak at about 194°C. In one or more embodiments, phosphate polymorph pattern F is provided with a DSC thermogram comprising an endothermic peak at about 205°C. In one or more embodiments, phosphate polymorph pattern F exhibits a DSC thermogram comprising three endothermic peaks at about 104°C, 194°C, and 205°C. Phosphate polymorph pattern F can be synthesized using the method described in Example 33. In one or more embodiments, pharmaceutical compositions comprising phosphate polymorph pattern F are described. In one or more embodiments, the present disclosure includes purified forms of crystalline phosphate polymorph pattern F.

[0038]

[0111] In one or more embodiments, the phosphate-containing 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]trifluoromethanesulfonate is 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]trifluoromethanesulfonate] A mixture containing a crystalline polymorph of the free base, salt, or co-crystal of [azin-7-yl]biphenyl-2-carbonitrile is identified and designated as "phosphate polymorph pattern G" (i.e., phosphate pattern G). Phosphate polymorph pattern G appears to contain primarily PA023B free base. Phosphate polymorph pattern G exhibits an XRPD pattern substantially identical to the XRPD pattern labeled Pattern G in Figure 37A. In one or more embodiments, phosphate polymorph pattern G exhibits a DSC thermogram substantially identical to Figure 40. In one or more embodiments, phosphate polymorph pattern G has a melting / desolvation / dehydration range of about 95°C to about 115°C. In one or more embodiments, phosphate polymorph pattern G exhibits a DSC thermogram including an endothermic peak at about 108°C. In one or more embodiments, phosphate polymorph pattern G exhibits a DSC thermogram including an endothermic peak at about 194°C. In one or more embodiments, phosphate polymorph pattern G exhibits a DSC thermogram comprising an endothermic peak at about 205° C. In one or more embodiments, phosphate polymorph pattern G exhibits a DSC thermogram comprising three endothermic peaks at about 108° C., 194° C., and 205° C. Phosphate polymorph pattern G can be synthesized using the method described in Example 33. In one or more embodiments, pharmaceutical compositions comprising phosphate polymorph pattern G are described. In one or more embodiments, the present disclosure includes purified forms of crystalline phosphate polymorph pattern G.

[0039]

[0112] In one or more embodiments, a mixture containing a crystalline polymorph of the free base, 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 identified and designated as "phosphate polymorph pattern H" (i.e., phosphate pattern H). Phosphate polymorph pattern H appears to contain primarily TPA023B free base. Phosphate polymorph pattern H exhibits an XRPD pattern substantially identical to the XRPD pattern labeled Pattern H in Figure 37A. In one or more embodiments, phosphate polymorph pattern H exhibits a DSC thermogram substantially identical to Figure 41. In one or more embodiments, phosphate polymorph pattern H has a melting range of about 185°C to about 210°C. In one or more embodiments, phosphate polymorph pattern H has a melting range of about 185°C to about 195°C. In one or more embodiments, phosphate polymorph pattern H exhibits a DSC thermogram containing an endothermic peak at about 194°C. In one or more embodiments, phosphate polymorph pattern H exhibits a DSC thermogram containing an endothermic peak at about 205°C. In one or more embodiments, phosphate polymorph pattern H exhibits a DSC thermogram containing two endothermic peaks at about 194°C and 205°C. In some embodiments, phosphate polymorph pattern H can be synthesized using the method described in Example 33. In one or more embodiments, pharmaceutical compositions comprising phosphate polymorph pattern H are described. In one or more embodiments, the present disclosure provides purified forms of crystalline phosphate polymorph pattern H. Tosylate

[0113] In one or more embodiments, a crystalline polymorph 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 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 three, at least six, at least nine, at least twelve, at least fifteen, 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 exhibits an XRPD pattern substantially identical to the XRPD pattern shown in Figure 55. 18 shows a PD pattern. 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 containing 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 FIG. 18. This melting point was obtained using DSC at a heating rate of 10°C / min. In some 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 a purified form of crystalline tosylate polymorph Form A. Free base

[0114] 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 three, at least six, at least nine, at least twelve, at least fifteen, 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 identical to the XRPD pattern shown in Figure 9. In one or more embodiments, free base polymorph Form A exhibits an XRPD pattern substantially identical to the XRPD pattern shown in Figure 36A labeled "Form A." 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 including an endothermic peak at about 206°C. In one or more embodiments, free base polymorph Form A exhibits a DSC thermogram substantially identical to the DSC thermogram shown in Figure 10A. In one or more embodiments, free base polymorph Form A exhibits a DSC thermogram substantially identical to the DSC thermogram shown in Figure 36B. This melting point is obtained using DSC at a heating rate of 10°C / min. In some embodiments, free base polymorph Form A exhibits birefringence under polarized light. In some embodiments, free base polymorph Form A is anhydrous. In some embodiments, free base polymorph Form A can be synthesized using the method of Example 10. In one or more embodiments, pharmaceutical compositions are described comprising free base polymorph Form A. In one or more embodiments, the disclosure includes purified forms of crystalline free base polymorph Form A.

[0040]

[0115] 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 exhibits an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, at least twelve, at least fifteen, 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, when measured using the parameters set forth in Table 1. In one or more embodiments, the free base polymorph Form B exhibits an XRPD pattern substantially identical to the XRPD pattern shown in Figure 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 disclosure provides an ethanol solvate. In one or more embodiments, the disclosure provides crystalline free base polymorph Form B. A purified form of

[0041]

[0116] 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 three, at least six, at least nine, at least twelve, at least fifteen, 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 some embodiments, the free base polymorph Form C provides an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, at least twelve, at least fifteen, 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 some embodiments, the free base polymorph Form C has a molecular weight of about 5.3, 7.9, 10.7, 12.3, 12.6, 13.4, 14.1, 14.7, 15.8, 16.2, 16.4, 17.2, 17.8, 18.6, 19.2, 20.4, 21.4, 21.6, 22.6, 23.3, 23.8, 24.3, 24.7, 24.9, 25. 26.0, 26.6, 26.9, 27.2, 27.5, 28.4, 28.7, 28.9, 29.6, 30.1, 31.7, 32.2, 33.5, 35.1, and 39.6±0.2 degrees two-theta. In some embodiments, the free base polymorph Form C provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 5.3, 10.7, 12.3, 12.5, 13.4, and 14.7±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In one or more embodiments, TPA023B free base polymorph Form C exhibits an XRPD pattern substantially identical to the XRPD pattern shown in FIG. 5. In one or more embodiments, the free base polymorph Form C exhibits an XRPD pattern substantially identical to the XRPD pattern shown in Figure 12. In one or more embodiments, the free base polymorph Form C exhibits an XRPD pattern substantially identical to the XRPD pattern shown in Figure 36A and labeled Form C. In one or more embodiments, the free base polymorph Form C exhibits an XRPD pattern substantially identical to the XRPD pattern shown in Figure 46A and labeled Form C.

[0042]

[0117] 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, 210, or 211°C. In one or more embodiments, free base polymorph Form C exhibits a DSC thermogram substantially identical to that shown in Figure 13. In one or more embodiments, free base polymorph Form C exhibits a DSC thermogram substantially identical to that shown in Figure 36D. In one or more embodiments, free base polymorph Form C exhibits a DSC thermogram substantially identical to that shown in Figure 6. This melting point is obtained using DSC at a heating rate of 10°C / min. In some embodiments, free base polymorph Form C exhibits birefringence under polarized light. In one or more embodiments, free base polymorph Form C can be synthesized using the methods of Example 12 or Example 35. In embodiments, the free base polymorph Form C is anhydrous. In one or more embodiments, pharmaceutical compositions are described comprising the free base polymorph Form C. In one or more embodiments, the present disclosure provides purified forms of crystalline free base polymorph Form C.

[0043]

[0118] 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, or 90% 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 free base amount at the end of a given storage period. In some 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 some embodiments, free base polymorph Form C provides a substantially identical XRPD pattern after at least 1 week of storage at about 40° C. and 75% RH.In some embodiments, the free base polymorph Form C provides a substantially identical 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. In some embodiments, the free base polymorph Form C provides a substantially identical XRPD pattern after storage at about 25° C. and 92.5% RH for at least 1 week, 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.

[0044]

[0119] 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.

[0045]

[0120] 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 polymorph mixture is designated "free base polymorph pattern D" and exhibits an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, at least twelve, at least fifteen, or all values ​​selected from the group consisting of about 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, 20.6, 21.6, 22.6, 23.3, 24.5, 26.8, 27.1, 28.4, 29.5, and 30.2±0.2 degrees two-theta, when measured using the parameters set forth in Table 1. In one or more embodiments, TPA023B free base polymorph pattern D can comprise free base form A. In one or more embodiments, TPA023B free base polymorph pattern D can comprise free base form C. In one or more embodiments, free base polymorph pattern D comprises a dioxane solvate. In one or more embodiments, free base polymorph pattern D exhibits an XRPD pattern substantially identical to the XRPD pattern shown in Figure 14. In one or more embodiments, free base polymorph pattern D has a melting / desolvation range of about 50°C to about 225°C. Free base polymorph pattern D can be synthesized using the method of Example 13. In one or more embodiments, pharmaceutical compositions comprising free base polymorph pattern D are described. In one or more embodiments, the present disclosure provides purified forms of crystalline free base polymorph pattern D.

[0046]

[0121] 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 is described. This crystalline polymorph is designated "free base polymorph Form E" (i.e., free base Form E) and exhibits an XRPD pattern substantially identical to the XRPD pattern labeled Form E in Figure 36A. In some embodiments, the free base polymorph Form E exhibits an XRPD pattern having characteristic peak positions for at least three, at least six, at least nine, at least twelve, at least fifteen, or all values ​​selected from the group consisting of about 6.6, 7.5, 9.6, 10.3, 13.3, 13.8, 14.5, 15.4, 15.9, 16.5, 17.3, 17.8, 19.5, 20.3, 22.3, 23.2, 23.7, 26.1, 26.9, 27.9, 29.0, 31.1, and 35.8±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, free base polymorph Form E exhibits an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.6, 7.5, 9.6, 10.3, 13.3, and 19.5±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In one or more embodiments, free base polymorph Form E exhibits a DSC thermogram substantially identical to Figure 36C. In one or more embodiments, free base polymorph Form E has a melting / desolvation / dehydration range of about 90°C to about 110°C. In one or more embodiments, free base polymorph Form E exhibits a DSC thermogram comprising an endothermic peak at about 104°C. In one or more embodiments, free base polymorph Form E can be synthesized using the method described in Example 35. In some embodiments, free base polymorph Form E is a solvate. In one or more embodiments, pharmaceutical compositions comprising free base polymorph Form E are described. In one or more embodiments, the present disclosure provides a purified form of crystalline free base polymorph Form E.

[0047]

[0122] 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 polymorphic Form F" (i.e., free base Form F) and has an average molecular weight of about 7.0, 7.7, 8.1, 9.0, 10.2, 11.4, 12.6, 13.8, 14.9, 15.0, 16.1, 17.2, 18.3, 19.4, 20.5, 21.6, 22.7, 23.8, 24.9, 25.0, 26.0, 27.1, 28.1, 29.2, 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, 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, 2, 10.9, 12.3, 13.1, 14.0, 14.2, 15.2, 15.4, 15.7, 16.3, 17.2, 17.8, 19.4, 19.9, 21.0, 22.9, 26.7, and 27.6±0.2 degrees two-theta. In some embodiments, the free base polymorph Form F provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 7.0, 7.7, 8.1, 9.2, 10.9, and 13.1±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, the free base polymorph Form F provides an XRPD pattern substantially identical to the XRPD pattern labeled Form F in Figure 36A. In one or more embodiments, free base polymorph Form F exhibits a DSC thermogram substantially identical to Figure 36E. In one or more embodiments, free base polymorph Form F has a melting / desolvation / dehydration range of about 90°C to about 110°C. In one or more embodiments, free base polymorph Form F exhibits a DSC thermogram including an endothermic peak at about 104°C. In one or more embodiments, free base polymorph Form F exhibits a DSC thermogram including an endothermic peak at about 195°C. In one or more embodiments, free base polymorph Form F exhibits a DSC thermogram including an endothermic peak at about 205°C. In one or more embodiments, free base polymorph Form F exhibits a DSC thermogram including one or more endothermic peaks selected from peaks at 104°C, 195°C, and 205°C. In some embodiments, free base polymorph Form F is an anhydrate. In some embodiments, free base polymorph Form F is a solvate. Free base polymorph Form F can be synthesized using the methods described in Example 35. In one or more embodiments, described are pharmaceutical compositions comprising the free base polymorph Form F. In one or more embodiments, the present disclosure provides a purified form of the crystalline free base polymorph Form F.

[0048]

[0123] In one or more embodiments, 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. This crystalline polymorph is designated "free base polymorph Form G" (i.e., free base Form G) and exhibits an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, at least twelve, at least fifteen, or all values ​​selected from the group consisting of about 6.3, 7.5, 8.0, 11.7, 12.0, 12.8, 13.3, 14.1, 14.8, 15.3, 17.2, 18.0, 19.2, 19.6, 21.5, 23.2, 23.8, 25.9, 26.6, 27.7, and 32.4±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, free base polymorph Form G provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.3, 7.5, 11.7, 12.8, and 13.3±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, free base polymorph Form G provides an XRPD pattern substantially identical to the XRPD pattern labeled Form G in Figure 36A. In one or more embodiments, free base polymorph Form G exhibits a DSC thermogram substantially identical to Figure 36F. In one or more embodiments, free base polymorph Form G has a melting range of about 205°C to about 215°C. In one or more embodiments, free base polymorph Form G exhibits a DSC thermogram including an endothermic peak at about 210°C. In some embodiments, free base polymorph Form G is an anhydrate. In some embodiments, free base polymorph Form G is a solvate. In one or more embodiments, free base polymorph Form G can be synthesized using the method described in Example 35. In one or more embodiments, described are pharmaceutical compositions comprising the free base polymorph Form G. In one or more embodiments, the present disclosure provides a purified form of the crystalline free base polymorph Form G.

[0049]

[0124] In one or more embodiments, 2',6-difluoro-5'-[3-(1-hydroxypropyl)amino]-A crystalline polymorph of [(1,2-b)-(1,2,4)triazin-7-yl)biphenyl-2-carbonitrile is described. This crystalline polymorph is designated "Free Base Polymorph Form H" and exhibits an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, at least twelve, at least fifteen, or all values ​​selected from the group consisting of about 7.0, 7.9, 9.4, 10.9, 12.7, 13.4, 14.0, 14.3, 14.6, 16.0, 16.3, 18.0, 19.2, 19.7, 20.1, 21.2, 24.1, 25.7, 26.9, and 28.0±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, free base polymorph Form H provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 7.0, 7.9, 9.4, 10.9, 12.7, and 14.0±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, free base polymorph Form H provides an XRPD pattern substantially identical to the XRPD pattern labeled Form H in Figure 36A. In one or more embodiments, free base polymorph Form H exhibits a DSC thermogram substantially identical to Figure 36G. In one or more embodiments, free base polymorph Form H has a melting range of about 100°C to about 120°C. In one or more embodiments, free base polymorph Form H exhibits a DSC thermogram including an endothermic peak at about 108°C. In one or more embodiments, free base polymorph Form H exhibits a DSC thermogram including an endothermic peak at about 194°C. In one or more embodiments, free base polymorph Form H exhibits a DSC thermogram comprising an endothermic peak at about 205° C. In one or more embodiments, free base polymorph Form H exhibits a DSC thermogram comprising one or more endothermic peaks selected from peaks at 108° C., 194° C., and 205° C. In some embodiments, free base polymorph Form H is a hydrate. Free base polymorph Form H can be synthesized using the method described in Example 32. In one or more embodiments, pharmaceutical compositions comprising free base polymorph Form H are described.In one or more embodiments, the present disclosure provides a purified form of crystalline free base polymorph Form H.

[0050]

[0125] In one or more embodiments, a mixture containing 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 is described. This crystalline polymorph mixture is designated "free base polymorph pattern I" and provides an XRPD pattern substantially identical to the XRPD pattern labeled Pattern I in Figure 36A. In some embodiments, free base polymorph pattern I provides an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, at least twelve, at least fifteen, or all values ​​selected from the group consisting of about 5.7, 6.3, 11.0, 11.9, 12.4, 16.0, 16.5, 17.1, 18.1, 18.9, 19.3, 19.9, 20.3, 20.5, 23.5, 24.5, 24.9, and 29.3±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. Free base polymorph pattern I can comprise free base form A. Free base polymorph pattern I can also comprise a new free base form, free base form J. In one or more embodiments, free base polymorph pattern I exhibits a DSC thermogram substantially identical to that shown in Figure 36H. In one or more embodiments, free base polymorph pattern I has a melting range of about 189°C to about 210°C. In one or more embodiments, free base polymorph pattern I has a melting range of about 189°C to about 199°C. In one or more embodiments, free base polymorph pattern I has a melting range of about 200°C to about 210°C. In one or more embodiments, free base polymorph pattern I exhibits a DSC thermogram containing an endothermic peak at about 194°C. In one or more embodiments, free base polymorph pattern I exhibits a DSC thermogram containing an endothermic peak at about 205°C. In one or more embodiments, free base polymorph pattern I exhibits a DSC thermogram containing two endothermic peaks at about 194°C and about 205°C. Free base polymorph pattern I can be synthesized using the method described in Example 35. In one or more embodiments, pharmaceutical compositions are described comprising free base polymorphic Form J. In one or more embodiments, the present disclosure provides a purified form of crystalline free base polymorphic Form J. In some embodiments, free base polymorphic Form J provides a DSC thermogram comprising an endothermic peak at about 194° C. In some embodiments, free base polymorphic Form J provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 11.9, 16.0, 18.9, 20.0, 20.3, and 23.5±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In one or more embodiments, pharmaceutical compositions are described comprising free base polymorphic Form J.

[0051]

[0126] 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 is described. This crystalline polymorph mixture is designated "free base polymorph pattern K" and provides an XRPD pattern substantially identical to the XRPD pattern labeled Pattern K in Figure 73, when measured using the parameters set forth in Table 26-4. Free base polymorph pattern K can be prepared according to Example 63.

[0052] sulfate

[0127] In one aspect, a crystalline form (e.g., 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 sulfuric acid is described. This crystalline polymorph is designated "sulfate polymorph Form A" (i.e., sulfate Form A) and exhibits an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, at least twelve, at least fifteen, or all values ​​selected from the group consisting of about 6.1, 10.9, 11.3, 11.8, 12.2, 13.8, 14.8, 16.1, 16.8, 17.3, 17.9, 18.3, 19.2, 19.6, 21.4, 21.8, 22.8, 23.6, 24.4, 25.4, 27.2, 29.9, 30.5, 31.5, 32.6, 33.9, and 39.1±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In one or more embodiments, sulfate polymorph Form A exhibits an XRPD pattern having characteristic peak positions of at least three, at least six, or all values ​​selected from the group consisting of about 6.1, 10.9, 11.3, 11.8, 12.2, 16.1, 16.8, 21.4, 21.8, 25.4, and 27.2±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In one or more embodiments, sulfate polymorph Form A exhibits an XRPD pattern substantially identical to the XRPD pattern labeled Sulfate Form A in Figure 53A, when measured using the parameters set forth in Table 26-4. In one or more embodiments, sulfate polymorph Form A exhibits an XRPD pattern substantially identical to the XRPD pattern labeled Sulfate Form A in Figure 61, when measured using the parameters set forth in Table 26-4. In one or more embodiments, sulfate polymorph Form A exhibits an XRPD pattern substantially identical to the XRPD pattern labeled Sulfate Form A in Figure 59C, when measured using the parameters set forth in Table 26-4. In some embodiments, sulfate polymorph Form A exhibits an XRPD pattern with a characteristic peak located at about 6.1±0.2 degrees two-theta.In some embodiments, sulfate polymorph Form A exhibits an XRPD pattern with a characteristic peak located at about 12.2±0.2 degrees two-theta. In some embodiments, sulfate polymorph Form A exhibits an XRPD pattern with a characteristic peak located at about 16.1±0.2 degrees two-theta. In some embodiments, sulfate polymorph Form A exhibits an XRPD pattern with a characteristic peak located at about 21.4±0.2 degrees two-theta. In some embodiments, sulfate polymorph Form A exhibits an XRPD pattern with a characteristic peak located at about 21.8±0.2 degrees two-theta. In some embodiments, sulfate polymorph Form A exhibits an XRPD pattern with a characteristic peak located at about 25. The sulfate polymorphic form A exhibits an XRPD pattern with a characteristic peak located at 0.4±0.2 degrees 2-theta. In some embodiments, sulfate polymorphic form A exhibits birefringence under polarized light. In one or more embodiments, sulfate polymorphic form A has a melting / desolvation range of about 175°C to about 205°C. In one or more embodiments, sulfate polymorphic form A has a melting range of about 160°C to about 210°C. In one or more embodiments, sulfate polymorphic form A has a DSC thermograph substantially identical to the DSC curve in Figure 53C. In one or more embodiments, sulfate polymorphic form A has one endothermic peak with an onset temperature of about 184°C. In one or more embodiments, sulfate polymorphic form A has one endothermic peak with an onset temperature of about 182°C to 186°C. In one or more embodiments, sulfate polymorphic form A has one endothermic peak with an onset temperature of about 179°C to 189°C. In one or more embodiments, sulfate polymorph Form A exhibits a DSC thermogram containing an endothermic peak at about 192° C. In one or more embodiments, sulfate polymorph Form A exhibits a DSC thermogram containing an endothermic peak between about 190° C. and 194° C. In one or more embodiments, sulfate polymorph Form A exhibits a DSC thermogram containing an endothermic peak between about 187° C. and 197° C.

[0053]

[0128] In some embodiments, sulfate polymorph Form A is a stable form. In some embodiments, sulfate polymorph Form A can be stored at various temperatures and relative humidities. For example, sulfate 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, and about 60°C. As another example, sulfate polymorph Form A can be stored at 10% RH, 20% RH, 30% RH, 40% RH, 50% RH, 60% RH, 75% RH, or 90% RH. In some embodiments, sulfate polymorph Form A 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, or at least 24 months. In some embodiments, sulfate polymorph Form A is stable at about 25°C for at least 1 month. In some embodiments, sulfate 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, stable sulfate polymorph Form A has about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% w / w or more of the initial sulfate salt amount at the end of a given storage period. In some embodiments, stable sulfate polymorph Form A has about 95% w / w or more of the initial sulfate salt amount at the end of a given storage period. In some embodiments, stable sulfate polymorph Form A 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 some embodiments, sulfate polymorph Form A is stable at about 40° C. 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.In some embodiments, sulfate polymorph Form A is stable at about 60° C. 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. In some embodiments, sulfate polymorph Form A provides a substantially identical XRPD pattern after storage at about 40° C. and 75% RH for at least 3 days. In some embodiments, sulfate polymorph Form A provides a substantially identical XRPD pattern after storage at about 40° C. and 75% RH for at least 7 days. In some embodiments, sulfate polymorph Form A provides a substantially identical XRPD pattern after storage at about 40° C. and 75% RH for at least 2 weeks. In some embodiments, sulfate polymorph Form A provides a substantially identical XRPD pattern after storage at about 40° C. and 75% RH for at least 1 month. In some embodiments, sulfate polymorph Form A provides a substantially identical XRPD pattern after storage at about 40° C. and 75% RH. provides a substantially identical XRPD pattern after storage for at least two months. In some embodiments, sulfate polymorph Form A provides a substantially identical XRPD pattern after storage for at least three days at about 60° C. and 75% RH. In some embodiments, sulfate polymorph Form A provides a substantially identical XRPD pattern after storage for at least seven days at about 60° C. and 75% RH. In some embodiments, sulfate polymorph Form A provides a substantially identical XRPD pattern after storage for at least two weeks at about 60° C. and 75% RH. In some embodiments, sulfate polymorph Form A provides a substantially identical XRPD pattern after storage for at least one month at about 60° C. and 75% RH. In some embodiments, sulfate polymorph Form A provides a substantially identical XRPD pattern after storage for at least two months at about 60° C. and 75% RH.

[0054]

[0129] Sulfate polymorph Form A can be synthesized using the method of Example 42. In one or more embodiments, pharmaceutical compositions comprising sulfate polymorph Form A are described. In one or more embodiments, the present disclosure provides purified forms of crystalline sulfate polymorph Form A. In one or more embodiments, the sulfate polymorph Form A described herein 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 one or more embodiments, the sulfate polymorph Form A described herein is at least 95% pure as measured by HPLC as described herein. In some embodiments, the sulfate polymorph Form A described herein contains impurities. In some embodiments, impurities in sulfate 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% as measured by HPLC as described herein. In one or more embodiments, sulfate polymorph Form A described herein contains at most 5% impurities as measured by HPLC.

[0055]

[0130] In some embodiments, sulfate polymorph Form A has a plasma half-life in rat plasma that is 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, sulfate polymorph Form A has a plasma half-life in rat plasma that is 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, sulfate polymorph Form A has a plasma half-life in rat plasma that is about 8 hours to about 15 hours. In some embodiments, sulfate polymorph Form A has a plasma half-life in rat plasma that is about 10 hours to about 13 hours.

[0056]

[0131] Sulfate 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 sulfate 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 sulfate polymorph Form A is at least 1.1-fold higher in simulated gastric fluid than the solubility of free base Form A. In some embodiments, the solubility of sulfate polymorph Form A is at least 2-fold higher in simulated gastric fluid than the solubility of free base Form A. In some embodiments, the solubility of sulfate 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 than the solubility of free base Form A in fasted-state simulated gastric fluid (FaSSIF). In some embodiments, the solubility of sulfate polymorph Form A is at least 1.1-fold higher in fasted-state simulated gastric fluid than the solubility of free base Form A. In some embodiments, the solubility of sulfate polymorph Form A is at least 2-fold higher in fasted-state simulated gastric fluid than the solubility of free base Form A. In some embodiments, the solubility of sulfate 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 Form A in fed-state simulated gastric fluid (FeSSIF) than the free base polymorph Form A. In some embodiments, the solubility of sulfate polymorph Form A is at least 1.1-fold greater than the solubility of free base Form A in fed-state simulated gastric fluid than the free base polymorph Form A. In some embodiments, the solubility of sulfate polymorph Form A is at least 2-fold greater than the solubility of free base Form A in fed-state simulated gastric fluid than the free base polymorph Form A. chloride

[0132] In one or more embodiments, a mixture containing 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 is described. This crystalline polymorph 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 identical to 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 identical to that of 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.

[0057]

[0133] In one or more embodiments, a crystalline polymorph 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 hydrochloric acid is described. This crystalline polymorph is designated "Chloride Polymorph Form B" (i.e., Chloride Form B), and exhibits an XRPD pattern substantially identical to the XRPD pattern displayed in Figure 62, when measured using the parameters set forth in Table 26-4. In some embodiments, chloride polymorph Form B exhibits an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, or all values ​​selected from the group consisting of about 5.5, 7.7, 9.4, 12.2, 15.4, 16.6, 17.3, 19.5, 20.7, 23.4, 23.7, and 24.8±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In one or more embodiments, chloride polymorph Form B exhibits an XRPD pattern substantially identical to the XRPD pattern labeled Form B in Figure 52A. In some embodiments, chloride polymorph Form B exhibits birefringence under polarized light. In one or more embodiments, chloride polymorph Form B has a DSC thermogram substantially identical to the curve labeled Chloride Form B in Figure 52E. In one or more embodiments, chloride polymorph Form B exhibits a DSC thermogram including an endothermic peak at about 193°C. In one or more embodiments, chloride polymorph Form B exhibits a DSC thermogram that includes an endothermic peak at about 162°C.

[0058]

[0134] In one or more embodiments, a further crystalline polymorph 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 hydrochloric acid is described. This crystalline polymorph is designated "Chloride Polymorph Form C" (i.e., Chloride Form C) and has an average molecular weight of about 6.3, 11.7, 12.8, 14.1, 15.1, 16.5, 17.6, 18.8, 19.3, 20.6, 21.8, 23.2, 24.3, 25.7, 26.5, 26.9, 28.5, 30.3, 31.6, 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 and 33.5±0.2 degrees two-theta. In one or more embodiments, chloride polymorph Form C exhibits an XRPD pattern with characteristic peak positions of at least three, at least six, at least nine, at least twelve, at least fifteen, or all values ​​selected from the group consisting of: 32.2, 32.7, and 33.5±0.2 degrees two-theta. In one or more embodiments, chloride polymorph Form C exhibits an XRPD pattern with characteristic peak positions of at least three, at least six, at least nine, or all values ​​selected from the group consisting of: about 6.3, 11.7, 12.8, 15.1, 16.5, 18.8, 19.3, 21.8, 24.3, 25.7, 26.5, 26.9, 28.5, and 30.3±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In some embodiments, chloride polymorph Form C exhibits an XRPD pattern with a characteristic peak located at 6.3±0.2 degrees two-theta. In some embodiments, chloride polymorph Form C exhibits an XRPD pattern with a characteristic peak located at about 11.7±0.2 degrees two-theta. In some embodiments, chloride polymorph Form C exhibits an XRPD pattern with a characteristic peak located at about 12.8±0.2 degrees two-theta. In some embodiments, chloride polymorph Form C exhibits an XRPD pattern with a characteristic peak located at about 17.6±0.2 degrees two-theta. In some embodiments, chloride polymorph Form C exhibits an XRPD pattern with a characteristic peak located at about 21.8±0.2 degrees two-theta. In some embodiments, chloride polymorph Form C exhibits an XRPD pattern with a characteristic peak located at about 25.7±0.2 degrees two-theta. In one or more embodiments, chloride polymorph Form C exhibits an XRPD pattern substantially identical to the XRPD pattern labeled Chloride Form C in Figure 52A when measured using the parameters set forth in Table 26-4. In one or more embodiments, chloride polymorph Form C exhibits an XRPD pattern substantially identical to the XRPD pattern in Figure 63 when measured using the parameters set forth in Table 26-4. In some embodiments, chloride polymorph Form C exhibits birefringence under polarized light. In one or more embodiments, chloride polymorph Form C has a melting / desolvation range of about 150°C to about 210°C.In one or more embodiments, chloride polymorph Form C has a DSC thermogram substantially identical to the curve in Figure 52H labeled Form C. In one or more embodiments, chloride polymorph Form C has a DSC thermogram substantially identical to one of the curves in Figure 52G and Figure 52F.

[0059]

[0135] In some embodiments, chloride polymorph Form C is a stable form. In some embodiments, chloride polymorph Form C can be stored at a variety of temperatures and relative humidities. For example, chloride 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, chloride polymorph Form C can be stored at 10% RH, 20% RH, 30% RH, 40% RH, 50% RH, 60% RH, 75% RH, or 90% RH. In some embodiments, chloride 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, chloride polymorph Form C is stable at about 40° C. 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. It is stable at 60° C. 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. In some embodiments, the stable chloride polymorph Form C has about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% w / w or more of the initial chloride salt content at the end of a given storage period. In some embodiments, the stable chloride polymorph 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 some embodiments, chloride polymorph Form C has substantially the same XRPD pattern after storage at about 40° C. and 75% RH 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, at least 24 months, at least 36 months, at least 48 months, or at least 60 months. In some embodiments, chloride polymorph Form C has substantially the same XRPD pattern after storage at about 60° C. and 75% RH for at least 3 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.

[0060]

[0136] In one or more embodiments, chloride polymorph Form C exhibits a DSC thermogram comprising an endothermic peak at about 179° C. Chloride polymorph Form C can be synthesized using the method of Example 41. In one or more embodiments, pharmaceutical compositions comprising chloride polymorph Form C are described. In one or more embodiments, the present disclosure provides purified forms of crystalline chloride polymorph Form C.

[0061]

[0137] In one or more embodiments, the chloride polymorph Form C described herein 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 chloride polymorph Form C described herein contains impurities. In some embodiments, impurities in chloride polymorph 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.

[0062]

[0138] A chloride polymorphic form, e.g., Form C, 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 a chloride polymorphic form, e.g., Form C, 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 the free base Form A. In some embodiments, the solubility of a chloride polymorphic form, e.g., Form C, 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 gastric fluid (FaSSIF) than the solubility of the free base Form A. In some embodiments, the solubility of the chloride polymorphic form, e.g., Form C, 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 the free base polymorphic Form A in fed-state simulated gastric fluid (FeSSIF). Besylate

[0139] In one or more embodiments, the 2',6-difluoromethanesulfonate-containing benzenesulfonic acidA further crystalline polymorph of a salt of besylate-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile is described. This crystalline polymorph is designated "Besylate Polymorph Form A" (i.e., Besylate Form A) and has a molecular weight of about 4.9, 9.7, 10.3, 10.6, 11.5, 13.4, 14.6, 15.0, 16.5, 16.8, 18.6, 18.9, 19.5, 20.0, 21.3, 21.9, 22.5, 23.2, 23.6, 23.9, 24.3, 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 exhibiting an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, at least twelve, at least fifteen or all values ​​selected from the group consisting of 5.1, 25.5, 26.0, 26.7, 27.0, 27.7, 28.4, 29.4, 30.2, 30.7, 31.3, 32.2, 33.0, 33.7, 34.4, and 37.2±0.2 degrees two-theta. In one or more embodiments, besylate polymorph Form A exhibits an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, or all values ​​selected from the group consisting of about 4.9, 10.3, 10.6, 11.5, 13.4, 14.6, 15.0, 16.5, 16.8, 19.5, 21.3, 21.9, 23.2, 23.6, 23.9, 27.0, and 28.4±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. In one or more embodiments, besylate polymorph Form A exhibits an XRPD pattern substantially identical to the XRPD pattern in Figure 57A, when measured using the parameters set forth in Table 26-4. In one or more embodiments, besylate polymorph Form A exhibits an XRPD pattern substantially identical to the XRPD pattern in Figure 60, when measured using the parameters set forth in Table 26-4. In some embodiments, besylate polymorph Form A exhibits birefringence under polarized light. In one or more embodiments, besylate polymorph Form A has a melting / desolvation range of about 140° C. to about 160° C. In one or more embodiments, besylate polymorph Form A has a DSC thermogram substantially identical to any one of the curves in Figures 57D-57F.In one or more embodiments, besylate polymorph Form A exhibits a DSC thermogram comprising an endothermic peak at about 157° C. In one or more embodiments, besylate polymorph Form A exhibits a DSC thermogram comprising an endothermic peak at about 148° C. Besylate polymorph Form A can be synthesized using the method of Example 46. In one or more embodiments, pharmaceutical compositions comprising besylate polymorph Form A are described. In one or more embodiments, the present disclosure provides purified forms of crystalline besylate polymorph Form A.

[0063]

[0140] In one or more embodiments, the acid may be selected from the group consisting of, but not limited to, acetic acid, benzoic acid, benzenesulfonic acid, carbonic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, glucuraonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, isethionic acid, lactic acid, laurylsulfonic acid, malic acid, maleic acid, malonic acid, methanesulfonic acid, 1-napthylenesulfonic acid, 2-napthylenesulfonic acid, oleic acid, oxalic acid, pamoic acid, phosphoric acid, succinic acid, sulfuric acid, stearic acid, and the like. Additional anhydrous, hydrated, or solvated 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 any ratio of pharmaceutically acceptable acids, including benzoyl benzoate, tartaric acid, or para-toluenesulfonic acid, are described. Additional crystalline polymorphic forms are synthesized using the method of Example 19, or any other method known to those 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.

[0064]

[0141] In one or more embodiments, 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazine-

[0010] Additional anhydrous, hydrated, or solvated crystalline polymorphs of [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 provides purified forms of the crystalline polymorphic forms.

[0065] salt

[0142] In one aspect, salts of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile are disclosed herein. In some embodiments, the disclosed salts are formed with TPA023B and an acid. The acid can be an organic or 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-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, oleic acid, oxalic acid, pamoic acid, phosphoric acid, succinic acid, sulfuric acid, stearic 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 ratio, e.g., a 5:1, 4:1, 3:1, 2:1, or 1:1 molar ratio of TPA023B free base to acid. In some embodiments, the ratio of TPA023B free base to acid may be any ratio, for example, 1:10 to 10:1 molar. 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 solvent-free. 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. In some embodiments, an amorphous form of a salt of TPA023B with sulfuric acid is described herein. In some embodiments, an amorphous form of a salt of TPA023B with phosphoric acid is described herein.

[0066]

[0143] In some embodiments, the salt is TPA023B phosphate. In some embodiments, the salt is TPA023B chloride. In some embodiments, the salt is TPA023B sulfate. In some embodiments, the salt is TPA023B besylate. In some embodiments, the salt is TPA023B mesylate. 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.

[0067]

[0144] In one aspect, mixtures comprising TPA023B or a salt thereof are disclosed herein. In some embodiments, the disclosed mixtures comprise TPA023B free base. In some embodiments, the mixtures comprise one or more TPA023B free base forms, such as free base form E, free base form F, or a combination of forms E and F. In some embodiments, the mixtures comprise a salt of TPA023B, such as TPA023B phosphate or TPA023B sulfate. In some embodiments, the mixtures comprise one or more TPA023 salt forms, such as TPA023B phosphate form G and TPA023B phosphate form F. In some embodiments, the mixtures comprise TPA023B free base and a TPA023B salt, such as free base form E and phosphate form F.

[0068]

[0145] 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 some embodiments, the TPA023B salts described herein contain impurities. In some 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 at most 50% as measured by HPLC as described herein. Cocrystals

[0146] 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 or 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-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, oleic acid, oxalic acid, pamoic acid, phosphoric acid, succinic acid, sulfuric acid, stearic acid, tartaric acid, para-toluenesulfonic acid, etc. In some embodiments, the acid is a pharmaceutically acceptable acid. In some embodiments, the cocrystal comprises TPA023B free base and an acid in a fixed 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 of TPA023B free base to acid may be any ratio, for example, 1:10 to 10:1 molar. 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, for example, an ethanol, dioxane, THF, methanol, ethyl acetate, or acetone solvate. In some embodiments, the co-crystal is solvent-free. In some embodiments, the co-crystal is in a crystalline form. In some embodiments, the co-crystal is partially crystalline.

[0069]

[0147] 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.

[0070]

[0148] In one aspect, mixtures comprising TPA023B or a co-crystal thereof are disclosed herein. In some embodiments, the disclosed mixtures comprise TPA023B free base. In some embodiments, the mixtures comprise one or more TPA023B free base forms, such as free base form E, free base form F, or a combination of forms E and F. In some embodiments, the mixtures comprise a co-crystal of TPA023B, such as TPA023B phosphate. In some embodiments, the mixtures comprise one or more TPA023 co-crystal forms. In some 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.

[0071]

[0149] In one or more embodiments, the TPA023B cocrystals described herein The TPA023B cocrystals 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 TPA023B cocrystals described herein contain impurities. In some 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.

[0072]

[0150] 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 gastric fluid (FaSSIF). 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 greater than the solubility of the free base polymorph Form A in fed-state simulated gastric fluid (FeSSIF).

[0073]

[0151] 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 regular, repeating three-dimensional pattern. Some chemical compounds can form multiple polymorphs, each with a different arrangement of atoms and / or molecules within its crystalline structure. When a compound is biologically active, such as an active pharmaceutical ingredient, differences in crystalline structure can result in polymorphs with 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 possess properties that are unexpectedly advantageous for 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 production methods and formulation development, as well as the quality and efficacy of the active pharmaceutical ingredient. Some chemical compounds and molecular complexes (e.g., solvates, cocrystals, coordination compounds) can exist as multiple polymorphs, each exhibiting different physical characteristics. Also, a less stable polymorph may convert, or partially convert, to a more stable polymorph under appropriate conditions. For these reasons, it is necessary to control the specific crystalline form of an active pharmaceutical ingredient when developing a product to be used for therapeutic benefit in humans or animals. It should be noted that it is not possible to predict whether the solid state of a compound may form one or more polymorphs, or to predict the properties of any of these crystalline forms.

[0074]

[0152] In one or more embodiments, the crystalline polymorphs described herein have a crystalline structure of 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 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, at least 119%, at least 119%, at least 120%, at least 121%, at least 122%, at least 123%, at least 124%, at least 125%, at least 126%, at least 127%, at least 128%, at least 129%, at least 129%. %, at least 99.5%, or at least 99.9% pure. In some embodiments, the crystalline polymorphs described herein contain impurities. In some embodiments, the impurities in the crystalline polymorphs 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.

[0075]

[0153] Assaying the solid phase for the presence of crystals can be performed by conventional methods known in the art. For example, it is convenient and routine to use powder X-ray diffraction techniques. Other techniques that can be used include differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and Raman or infrared spectroscopy, NMR, gas chromatography, or HPLC.

[0076]

[0154] In one or more embodiments, the present disclosure provides prophylactic and / or therapeutic compositions comprising one or more compounds described herein dispersed in a pharmaceutically acceptable carrier. The term "carrier" is used herein to refer to a diluent, excipient, vehicle, etc., into which a compound may be dispersed for administration. A suitable carrier is pharmaceutically acceptable. As used herein, the term "pharmaceutically acceptable" means that it can be administered to a subject without undue toxicity, irritation, or allergic response, and is not biologically or otherwise undesirable, in that it does not produce unacceptable biological effects or interact adversely with any of the other components of the composition containing it. A pharmaceutically acceptable carrier will, 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 is well known to those of skill in the art. Pharmaceutically acceptable components include those acceptable for veterinary and human medicine, and depend on the route of administration. For example, compositions suitable for administration by injection are typically solutions in sterile isotonic aqueous buffer. Representative carriers include aqueous solutions such as 1 normal (n.) saline (about 0.9% NaCl), phosphate buffered saline (PBS), sterile water / distilled autoclaved water (DAW), and other acceptable vehicles. Other ingredients, such as adjuvants, other active agents, preservatives, buffers, salts, and other pharmaceutically acceptable ingredients, may also be included in the composition. The composition may comprise a therapeutically effective amount of the compound dispersed in a carrier.

[0077]

[0155] In one or more embodiments, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, the method generally comprising administering a therapeutically effective amount of one or more compounds described herein. As used herein, a "therapeutically effective" amount refers to an amount that elicits the biological or medical response of a tissue, system, or subject sought by a researcher or clinician, particularly an amount that elicits some desired therapeutic or preventative effect against a targeted illness or disease. As will be appreciated by those skilled in the art, an amount is considered therapeutically "effective" if the disease or its symptoms and / or effects are partially ameliorated or alleviated in a subject, even if the disease is not completely eradicated or prevented. It is understood that, in the case of certain salts or cocrystals, formulations can be administered in an amount that provides sufficient levels of the active compound.

[0078]

[0156] In some embodiments, the disease or disorder is associated with α2 / α3 GABAA receptors. In some embodiments, the disease or disorder is pain, anxiety, epilepsy, muscle spasms, itching, itch, cognitive impairment, alcoholism, drug addiction, schizophrenia, depression, autism, panic disorder, or generalized anxiety disorder.

[0079]

[0157] In some embodiments, the disease or disorder is pain. In some embodiments, the pain is pain caused by fibromyalgia, inflammatory pain, neuropathic pain, diabetic peripheral neuropathy, or the like. 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, the pain is due to a brain or spinal cord disorder. In some embodiments, the pain is neuropathic, nociceptive, and / or inflammatory. In some embodiments, the pain can affect the somatic or visceral systems or 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 due to a defined injury, such as surgery, dental work, or a strain. n) or sprain. In some embodiments, the pain is chronic pain. In some embodiments, the chronic pain is neuropathic pain (e.g., painful diabetic neuropathy or postherpetic neuralgia), carpal tunnel syndrome, back pain, osteoarthritis, headache, cancer pain, joint pain, or chronic post-surgical pain. In some embodiments, the pain is a chronic painful disorder affecting any system. In some embodiments, the neuropathic pain is 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 can be associated with post-operative pain, post-traumatic pain, cancer pain, back pain, osteoarthritis, pain associated with gout, or pain from strains, sprains, burns, 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 responsive 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 or osteoarthritis.

[0080]

[0158] 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, such as agoraphobia, social phobia, noise 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.

[0081]

[0159] In some embodiments, the disease or disorder is itch, e.g., chronic or acute itch. In some embodiments, the disease or disorder is chronic itch, neurogenic itch, inflammatory itch, uremic itch, neurodermatitis, atopic dermatitis, dorsal paresthesia, prurigo nodularis, psoriasis, psychogenic itch, or aquagenic itch. In some embodiments, the itch is pruriceptive itch. Pruritogenic itch can be caused by an allergic reaction, inflammation, dryness, or other skin damage. Pruritogenic itch can be associated with atopic dermatitis (eczema), urticaria (hives), psoriasis, drug reactions, 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, after stroke or burns, and in dorsal paresthesia (areas of sensitive skin, usually the back). Neuropathic itch can be seen after opioid therapy. It may be associated with chronic liver and kidney disease in response to transdermal peptides. In some embodiments, the itch is psychogenic itch. Psychogenic itch may be induced in response to the chemicals serotonin or norepinephrine, which affect stress, depression, and delusional parasitosis (the false belief in parasitic infection). In some embodiments, the disease or disorder is cholestatic pruritus, uremic pruritus, neurodermatitis, atopic dermatitis, atopic eczema, contact dermatitis, prurigo nodularis, psoriasis, insect bites, parasites, fungal infections, aquagenic pruritus, urticaria, allergic pruritus, or delusional parasitosis.

[0082]

[0160] 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 tremors, traumatic brain injury, tuberous sclerosis complex, Doze syndrome, Rasmussen syndrome, early myoclonic encephalopathy, infantile epilepsy with migrating focal seizures, epilepsy with sustained spike-and-wave during slow-wave sleep, and Landau syndrome. The disease or disorder may be U-Kleffner syndrome, benign epilepsy with centrotemporal spikes, benign familial neonatal infantile epilepsy, benign centrotemporal lobe epilepsy in children, benign occipital lobe epilepsy in children (BOEC), cortical dysplastic focal epilepsy syndrome, generalized epilepsy with febrile seizures plus (GEFS+), myoclonic-atonic epilepsy, infantile epilepsy with migratory focal seizures, 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 epilepsy, 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, convulsions, essential tremor, dystonia, or premature ejaculation. In some embodiments, the disease or disorder is autism. In some embodiments, the disease or disorder is SCN2a mutation-induced autism, 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.

[0083]

[0161] 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 cognition enhancers.

[0084]

[0162] In some embodiments, the subject has or is 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 condition or disease. In other embodiments, the subject does not have a given condition before the compound is administered, and the methods described herein are useful for preventing the onset or appearance 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 ingredients 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, intravaginally, rectally, or orally. The compounds or compositions can also be administered topically via the skin via a transdermal patch, spot-on, pour-on, or microneedle. They can be administered as a suspension, solution, powder, tablet, or the like. Gelcaps and the like are also contemplated by the present invention.

[0085]

[0163] 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 single dose for human or animal use. Each unit dosage form can contain a predetermined amount of the 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 before administration to a subject. Kits containing the compound are also disclosed herein. The kit further includes instructions for administering the compound to a subject. The compound can be provided as part of a dosage unit already dispersed in a pharmaceutically acceptable carrier, or can be provided separately from the carrier. The kit can further include instructions for preparing the compound for administration to a subject, e.g., instructions for dispersing the compound in a suitable carrier.

[0086]

[0164] It is understood that the therapeutic and prophylactic methods described herein are applicable to humans and any suitable animal, including but not limited to dogs, cats, and other pets, as well as rodents, primates, horses, cattle, pigs, etc. The methods can also be applied in clinical and / or research studies.

[0087]

[0165] In yet another embodiment, the present invention provides 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 with or without heating for a period of time; dissolving the compound in one or more solvents with or without heating, and then removing some or all of the solvent by methods such as evaporation or distillation; dissolving the compound in one or more solvents, and adding an antisolvent, a combination of antisolvents, or a mixture of solvent and antisolvent; dissolving the compound in one or more solvents with or without heating, and then allowing the solution to cool or actively cooling the solution; heating the compound in the absence of solvent; heating the compound under atmospheric pressure or reduced pressure until it sublimes, and collecting 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; other methods known to those skilled in the art; and any or all of the above-mentioned processes combined.

[0088]

[0166] In yet another embodiment, the present disclosure relates to the use of a compound according to various embodiments described herein for the preparation of a therapeutic or prophylactic medicament for the treatment or prevention of a disease or condition treatable by an α2 / α3 GABAA positive allosteric modulator, and a disorder treatable by a non-selective GABAA positive allosteric modulator in mammals, animals, and humans.

[0089]

[0167] Additional advantages of various embodiments of the present disclosure will be apparent to those skilled in the art upon review of the present disclosure and the following examples. It is understood that the various embodiments described herein are not necessarily mutually exclusive unless otherwise indicated herein. For example, features described or depicted in one embodiment may, but are not necessarily, included in other embodiments. Thus, the present disclosure encompasses various combinations and / or integrations of the specific embodiments described and claimed herein.

[0090]

[0168] As used herein, the phrase "and / or," when used in a list of two or more items, means that any one of the listed items can be used by itself, or any combination of two or more of the listed items can be used. For example, if a composition is described as containing or excluding components A, B, and / or C, the composition can contain A alone; B alone; C alone; A and B in combination; A and C in combination; B and C in combination; or A, B, and C. can be included or excluded in combination.

[0091]

[0169] As used herein, the term "about" when used in conjunction with a measurement or to modify a value, unit, constant, or range of values, means a variation of + / - 3% or less.

[0092]

[0170] The term "substantially identical," when used herein to define a quantity, is intended to mean that the quantity would be considered the same as the reference quantity by a skilled artisan in light of variations accepted in the art. Such variations may be caused by factors related to equipment, operating conditions, and human factors, etc., as known in the art. For example, one skilled in the art will understand that endothermic onset and peak temperatures measured by differential scanning calorimetry (DSC) can vary significantly from experiment to experiment. In some embodiments, two values ​​are considered substantially identical when the positions of their characteristic peaks do not vary by more than + / - 5%, + / - 4%, + / - 3%, + / - 2%, or + / - 1%. For example, one skilled in the art can readily determine whether two X-ray diffraction patterns or two DSC thermograms are substantially identical. In some embodiments, two X-ray diffraction patterns are considered substantially identical when the characteristic peaks of the two X-ray diffraction patterns do not vary by more than ±0.3 degrees two-theta, ±0.2 degrees two-theta, or ±0.1 degrees two-theta.

[0093]

[0171] This specification also uses numerical ranges to quantify certain parameters related to various embodiments of the present disclosure. When a numerical range is provided, it should be understood that such range should be interpreted as providing literal basis for a claim limitation that recites only the lower limit of that range, as well as for a claim limitation that recites only the upper limit of that range. For example, a disclosed numerical range of about 10 to about 100 provides literal basis for a claim limitation that recites "greater than about 10" (without an upper limit) and a claim limitation that recites "less than about 100" (without a lower limit). [Example]

[0094]

[0172] 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 no mention thereof should be taken as a limitation on the overall scope of the present disclosure.

[0095] Example 1 Salt screening

[0173] A preliminary salt screening study was conducted by reactive crystallization 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 were 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.

[0096]

[0174] Because TPA023B has a tertiary alcohol that is also alpha to the aromatic ring, it is prone to decomposition by elimination under acidic conditions. HPLC analysis was performed on acetone samples to determine the extent of decomposition, if any, that had occurred. The results showed that TPA023B with H3PO4 in acetone decomposed less than the other acids.

[0097] [Table 2]

[0098]

[0175] For experiments that produced observable solids, the solids were isolated by centrifugation (approximately 14,000 rpm, approximately 5 minutes) and analyzed by XRPD. For clear solutions, solids were produced by evaporation at 35°C by drying in vacuo and examined by XRPD. TGA and DSC characterization data were collected for solids that showed 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 resulting solid from the "hydrochloric acid in acetone" experiment is shown in Figure 25. The DSC / TGA of the resulting solid from the "phosphoric acid in acetonitrile" experiment is provided in Figure 26.

[0099] [Table 3]

[0100]

[0176] The phosphate salt was found to readily form a stable new crystalline form. In addition, trace amounts of a new crystalline form were observed, which may be the hydrochloride salt or a new polymorph of the free base. This was designated Chloride Polymorph Pattern A. Given the pKa of TPA023B (approximately 2.19) and the highly planar aromatic structure of TPA023B, it was unexpected that, of the strong acids tested under these conditions, only phosphoric acid formed a highly crystalline solid with properties suitable for the manufacture and use of pharmaceutical formulations, especially considering the similar pKa of TPA023B and phosphoric acid. Compared to other stronger acids of TPA023B, including phosphoric acid, The relative stability of the phosphate salt or co-crystal provides significant benefits to the manufacturability of the phosphate salt or co-crystal that could not be predicted beforehand. Having the salt or co-crystal formation be the final particle formation step is extremely beneficial because additional purification steps after this stage would significantly increase the cost of goods. Therefore, the reduced impurity formation provided by the phosphate salt or co-crystal reduces the risk of requiring additional purification and provides an advantage over other counterions.

[0101] Example 2 Crystallization screening for the amorphous salt of TPA023B

[0177] 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. for about 2 days with continuous stirring. Only the p-toluenesulfonate in toluene solution resulted in a crystalline solid. In all other cases, an amorphous solid was obtained. This salt was designated tosylate polymorph Form A.

[0102] [Table 4]

[0103] Example 3 Accelerated Stability Study of Phosphate Polymorph Form A and Free Base Polymorph Form A

[0178] The stability of phosphate polymorph Form A and free base polymorph Form A was evaluated under accelerated conditions.

[0104] [Table 5]

[0105] [Table 6]

[0106] Example 4

[0179] 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 (Figure 19).

[0107] Example 5 Preparation of polymorphic form A of salts or cocrystals 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 (phosphate polymorphic form A).

[0108]

[0180] A 0.5 M solution of phosphoric acid in acetonitrile (44 mL, 22 mmol, 1.1 Eq) 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 Eq) in acetonitrile (200 mL) and stirred at approximately 50 °C for approximately 4 hours. The resulting mixture was allowed to cool slowly to room temperature overnight. The resulting solid was collected and dried to obtain phosphate polymorphic Form A (9.2 g, 92% yield). The XRPD pattern of TPA023B phosphate polymorphic Form A is shown in Figure 1. The DSC / TGA thermogram and NMR spectrum of TPA023B phosphate polymorphic Form A are shown in Figure 2A and Figure 2B, respectively. Additional DSC / TGA thermograms of TPA023B phosphate polymorph Form A are shown in Figure 2C. The phosphate polymorph Form A samples for Figures 1, 2A, and 2B are taken from the same batch; the sample for Figure 2C is taken from a different batch.

[0109] Example 6 Preparation of polymorph pattern B (phosphate polymorph pattern B) of salts or cocrystals 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.

[0110]

[0181] 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 containing phosphate (20.9 mg, 0.041 mmol) was stirred in methanol (0.2 mL) at approximately 20°C to 25°C for approximately 3 days. The resulting solid was separated by centrifugation (5 min, 14,000 rpm) and dried overnight in a vacuum oven heated to approximately 30°C to obtain phosphate polymorph pattern B. TPA023B phosphate pattern B likely contains a mixture of phosphate form A and phosphate form G.

[0111]

[0182] The XRPD pattern of TPA023B phosphate polymorphic pattern B is shown in Figure 3. The DSC / TGA thermogram of TPA023B phosphate polymorphic pattern B is shown 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). TGA results showed that the original form exhibited a three-stage weight loss of 3.428% from 30 °C to 120 °C, which is believed to be the result of the removal of residual solvent.

[0112] Example 7 Preparation of Polymorph Free Base Form C

[0183] 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 (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 obtain free base Form C.

[0113]

[0184] The XRPD pattern of TPA023B free base polymorphic form C is shown in Figure 5. The DSC / TGA thermogram of TPA023B free base polymorphic form C is shown in Figure 6. As shown in Figure 6, the DSC trace showed a single endothermic peak with an onset temperature of 195°C (96.04 J / g). The TGA trace showed a three-step weight loss of 0.7862% from 30°C to 120°C, which is believed to be the result of the removal of residual solvent.

[0114] Example 8 Preparation of polymorphic pattern E (phosphate polymorphic pattern E) salts or cocrystals 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.

[0115]

[0185] 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 salt (150 mg, 0.307 mmol) containing phosphoric acid in dimethyl sulfoxide, water (approximately 1.0 mL) was added dropwise until a precipitate formed. The precipitate was collected by centrifugation and dried overnight in a vacuum oven at approximately 30 °C to obtain phosphate polymorphic pattern E. The XRPD pattern of TPA023B phosphate polymorphic pattern E is shown in Figure 7. The DSC / TGA thermogram of TPA023B phosphate polymorphic pattern E is shown in Figure 8. As shown in Figure 8, the DSC pattern exhibited two endothermic peaks with onset temperatures of 185 °C (63.40 J / g) and 196 °C (19.60 J / g). TPA023B phosphate pattern E likely contains a mixture containing phosphate form A and another form.

[0116] 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 (tosylate polymorphic form A).

[0117]

[0186] 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 vigorously stirred for 15 min. The mixture was cooled to 95 °C, and 1,4-dioxane (0.8 mL) was slowly added. 4 in 1,4-dioxane (0.05 mL, 0.1 equiv.) was added. A 0.5 M solution of 4-methylbenzenesulfonic acid 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 Eq) was added over 30 min, and the resulting mixture was stirred at 95°C for 30 min. The mixture was then allowed to cool to room temperature, and the solid was collected by centrifugation (1000 rpm, 5 min). The isolated solid was washed with n-heptane and dried in a vacuum oven at approximately 30°C for 4 hours to obtain tosylate polymorph Form A. The XRPD pattern of TPA023B tosylate Form A is shown in Figure 17A, and the NMR spectrum of TPA023B tosylate is shown in Figure 17B. TPA023B tosylate exhibits birefringence under polarized light.

[0118] 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 (Free Base Polymorphic Form A)

[0187] To a vial containing acetonitrile (0.5 ml) was added 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). 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 shown in Figure 9. The DSC / TGA thermogram and NMR spectrum of TPA023B free base polymorphic Form A are shown in Figures 10A and 10B, respectively.

[0119] 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 (free base polymorphic form B).

[0120]

[0188] To a vial containing ethanol (0.5 ml) was added 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). 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 oven at about 35°C, and the resulting solid was examined 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 obtain free base polymorph Form B. Preliminary analysis suggests this is the ethanol solvate polymorph, which has vanished from the Pd and is a key intermediate.

[0121] Example 12 Preparation of polymorphic form C of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile (free base polymorphic form C).

[0122]

[0189] 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 the free base polymorphic Form C.

[0123] Example 13 Preparation of Polymorph Pattern D (Free Base Polymorph 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

[0190] To a vial containing 1,4-dioxane (0.5 mL) was added 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), and the vial was sealed. The mixture was stirred at about 20°C to 25°C for about 4 hours and then heated to about 50°C overnight. The resulting solution was cooled to about 20°C to 25°C and evaporated to dryness in a vacuum oven at about 35°C to obtain free base polymorph pattern D. Free base pattern D contains a mixture of free base form A and a new form, likely a dioxane solvate.

[0124] Example 14 Comparative slurry experiments

[0191] The determination of which polymorphic form is more thermodynamically stable can be experimentally determined by conventional methods known in the art.For example, a comparative slurry experiment can be carried out, 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.As will be understood by those skilled in the art, if a 1:1 mixture is completely converted into one polymorphic form, the resulting form is the more thermodynamically stable of the two, and the other form is metastable.

[0125] Example 15 Solubility of Free Base Polymorph Form A and Phosphate Polymorph Form A

[0192] 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 filter membrane, and the supernatant was analyzed by HPLC. The results are shown in Tables 7 and 8. The results indicate that phosphate polymorph Form A had higher solubility than free base polymorph Form A in simulated gastric fluid (SGF), fasted-state simulated gastric fluid (FaSSIF), and fed-state simulated gastric fluid (FeSSIF).

[0126] [Table 7]

[0127] [Table 8]

[0128] Example 16 Intrinsic dissolution rates of free base polymorph Form A and phosphate polymorph Form A

[0193] 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 in 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 shaft within 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 water temperature was set at 37°C ± 0.5°C, the shaft rotation at 100 rpm, and the sampling time points were 2, 5, 10, 15, 30, 45, 60, and 120 min. SGF was used as the dissolution medium (900 mL). At each time point, the solution samples were filtered and the supernatants were analyzed by HPLC-UV.

[0129]

[0194] The intrinsic dissolution rate of the free base polymorphic Form A in SGF is 5 × 10 -5 mg cm 2 min -1 The intrinsic dissolution rate of phosphate polymorph Form A in SGF was 0.184 mg / L (linear range: 2–120 min). · cm -2 min -1 (The linear range was within 2 to 120 min).

[0130] Example 17 Pharmacokinetic studies with phosphate polymorphic form A in rats

[0195] To evaluate the pharmacokinetics (PK) of phosphate polymorph Form A, normal, healthy male Sprague-Dawley rats were dosed with suspensions or solutions either by oral gavage (0.5% methylcellulose) or IV (60% PEG400 / 40% saline), and blood was collected continuously, centered around 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. All blood samples were collected by jugular vein puncture. All 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. Compound concentrations in extracts were analyzed by LC / MS / MS. Data were analyzed in Phoenix WinNonlin 6.3 using the IV-Noncompartmental Model 201 (IV bolus administration) and PO-Noncompartmental Model 200 (extravascular administration) methods.

[0131] [Table 9]

[0132] [Table 10]

[0133] Example 18 Pharmacokinetic studies in dogs using phosphate polymorphic form A

[0196] To evaluate the pharmacokinetics (PK) of phosphate polymorph Form A, the suspension or solution was administered to normal, healthy male Beagle dogs either by oral gavage (0.5% methylcellulose) or IV (60% PEG400 / 40% saline), and blood was collected continuously, centered around 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. All blood samples were collected from a peripheral vein. Blood was diluted with potassium (K2) EDTA * The extracts were placed in commercially available tubes (Jiangsu Kangjian Medical Supplies Co., Ltd.) containing 2H2O and placed on wet ice until processed for plasma. Samples were centrifuged (3,000 × g, 10 min, 2–8°C) within 1 h of collection. Compound concentrations in the extracts were analyzed by LC / MS / MS. Data were analyzed using Phoenix WinNonlin 6.3 using the IV-Noncompartmental Model 201 (IV bolus injection) and PO-Noncompartmental Model 200 (extravascular injection) methods.

[0134] [Table 11]

[0135] [Table 12]

[0136]

[0197] 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 fortuitous for therapeutics intended to treat dogs and significantly reduces the amount of active pharmaceutical ingredient that needs to be prepared for the completion of GLP toxicology studies.

[0137] Example 19 Preparation of polymorphic forms of TPA023B salts or cocrystals

[0198] TPA023B and a pharmaceutically acceptable acid, and / or a previously prepared TPA023B salt or co-crystal are combined and stirred in one or more solvents for a period of time, with or without a heating and / or cooling step; and / or are dissolved in one or more solvents, with or without heating, followed by removal of some or all of the solvent; and / or or one or more solvents and adding an antisolvent, or a combination of antisolvents, or a mixture of a solvent and an antisolvent; any other method known to those skilled in the art; and combinations of any or all of the above processes.

[0138] Example 20 Preparation of polymorphic forms of TPA023B free base

[0199] TPA023B can be slurried in one or more solvents for a period of time, with or without heating; and / or dissolved in one or more solvents, with or without heating, and then some or all of the solvent is removed by methods such as evaporation or distillation; and / or dissolved in one or more solvents and then an antisolvent, a combination of antisolvents, or a mixture of a solvent and an antisolvent is added; and / or dissolved in one or more solvents, with or without heating, and then the solution is allowed to cool or is actively cooled; and / or heated in the absence of a solvent; and / or heated at atmospheric or reduced pressure until sublimation and collected on a cooled surface; and / or melted and allowed to cool; and / or exposed to water vapor or solvent vapor, with or without heating; and / or any other method known to those skilled in the art; and using a combination of any or all of the above processes.

[0139] Example 21 HPLC protocol Table 13 shows a representative set of parameters and conditions used for HPLC.

[0140] [Table 13]

[0141] Example 22 Purity Test

[0200] Approximately 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.

[0142] Example 23 pKa measurement 10 mg of TPA023B was used for pKa determination.

[0143] Solution preparation:

[0201] 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 the volume, and mix well.

[0144] 60% (v / v) DMSO co-solvent: Dissolve 2.795 g of potassium chloride in 100 mL of distilled or deionized water and make up to 250 mL with analytical grade DMSO (adjusted ionic strength DMSO solution).

[0145]

[0202] 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 (adjusted ionic strength MeOH solution).

[0146] pKa determination by pH meter method (with or without co-solvent):

[0203] 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 to obtain pKa values ​​from pH 2 to pH 12, which were then extrapolated to obtain the aqueous pKa value. Using this method, the pKa of TPA023B was determined to be 2.19.

[0147] Example 24 Approximate solubility studies of TPA023B in organic solvents

[0204] Approximately 25 mg of compound (TPA023B) was added to a 2.0 mL vial containing 0.5 mL of each organic solvent listed 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 examined 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 confirmed by XRPD.

[0148]

[0205] The raw form of TPA023B was designated "Free Base Form A" and its corresponding XRPD pattern was designated "Pattern A." The properties of the solubility test samples of TPA023B are shown in Table 15. The corresponding XRPD profile overlays of TPA023B slurries in solvents are shown in Figures 27 and 28.

[0149] [Table 14]

[0150] [Table 15]

[0151] Example 25 Approximate solubility studies of TPA023B phosphate

[0206] Approximately 2 mg of TPA023B phosphate Form A was weighed into each 1.5 mL vial, and then solvent was added stepwise while stirring until no particles were visually observed. The total amount of solvent was recorded and the approximate solubility in these solvents was calculated. The solubility results are shown in Table 16. TPA023B phosphate showed relatively high solubility in DMF and DMSO.

[0152] [Table 16]

[0153] Example 26 Polymorph screening of TPA023B phosphate by a slurry method

[0207] 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 (5 min, 14,000 rpm) and further dried overnight in a vacuum oven at 30°C. The dried solid was analyzed by XRPD. If the XRPD showed a change, the dried solid was then analyzed by PLM, DSC, and TGA. Table 17 shows 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."

[0154] [Table 17]

[0155] Example 27 Polymorph screening of TPA023B phosphate by heating-cooling method

[0208] TPA023B phosphate (approximately 20 mg) was weighed and transferred to a vial containing 200 μL of each selected solvent. The suspension was stirred at 700 rpm for 4 hours at 60°C, and the suspension was allowed to cool to room temperature. This cycle was repeated twice. The resulting solid was 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.

[0156]

[0209] The DSC / TGA thermogram of TPA023B phosphate polymorph pattern D is shown 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.

[0157] [Table 18]

[0158] Example 28 Polymorph screening of TPA023B phosphate by antisolvent method

[0210] A stock solution (100 mg / mL) of TPA023B phosphate (approximately 150 mg) was dissolved in 1.5 mL of either DMSO or DMF. Antisolvent was added until precipitation occurred or the amount of antisolvent added reached 5x the amount of 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.

[0159] [Table 19]

[0160] Example 29 Scale-up of polymorph screening of TPA023B phosphate by heating-cooling method

[0211] TPA023B phosphate (approximately 100 mg) was used in a scaled-up repeat experiment of Example 27 using the solvents methanol and isopropanol, respectively. The solid obtained using methanol exhibited the XRPD pattern of free base Form C, i.e., the same pattern as shown in Example 27. The solid obtained using isopropanol (IPA) also exhibited the XRPD pattern of free base Form C in the scaled-up experiment. The XRPD pattern of the resulting solid is shown in Figure 33. The yields of the scaled-up experiment are shown in Table 20.

[0161]

[0212] As shown in Figure 34, the DSC / TGA thermogram of TPA023B phosphate produced with 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 could be attributed to the removal of residual solvent.

[0162] [Table 20]

[0163] Example 30 Additional experiments to prepare and characterize TPA023B phosphate

[0213] Additional experiments were conducted to prepare and characterize TPA023B phosphate, the results of which are shown in Examples 31-37.

[0164]

[0214] TPA023B phosphate was prepared by reacting the free base TPA023B with phosphoric acid. A total of four crystalline forms and patterns (phosphate form A, pattern F, pattern G, and pattern H) were identified during polymorph screening. TPA023B phosphate forms A and H are anhydrous, pattern F is a solvate (ethanol solvate), and pattern G is a hydrate. TPA023B phosphate form A can be prepared using the solvents THF, 2-Me-THF, IPAC, EA, acetone, MTBE, or ACN, and is stable in these solvents. Phosphate patterns F and G were obtained by slurrying phosphate form A in EtOH and EtOH-water, respectively. Desolvation of pattern F yielded pattern H.

[0165]

[0215] The properties of these forms and patterns are summarized in Table 21 below. Only phosphate Form A exhibited one single endothermic peak in DSC testing. Comparative slurries showed that phosphate Form A was the most thermodynamically stable form. Form A exhibited slight hygroscopicity and showed no change in DSC testing and after grinding.

[0166]

[0216] XRPD patterns of the four crystalline forms and patterns are shown in Figure 37A. Figure 37B shows the P-NMR of Form A, Pattern F, and Pattern G. As shown in Figure 38B, which compares the three NMR spectra, phosphate Form A provided the most intense phosphorus peak, with the intensity of the phosphorus peak significantly reduced for Patterns F and G. It is believed that phosphate Form A may dissociate in EtOH or EtOH-water, while phosphate Patterns F and G contain primarily TPA023B free base. Form A and Pattern H are needle-like crystals, while Patterns F and G are irregular crystals.

[0167] [Table 21]

[0168] Additional experiments 30.1 Free Base Polymorphism Screening

[0217] Approximately 100 mg of TPA023B free base was weighed into a certain amount of a particular solvent or mixture of solvents and stirred for 3 days at RT or 50° C. The suspension was filtered and characterized by XRPD.

[0169] 30.2 Preparation of the phosphate form

[0218] TPA023B free base (1000 mg) was dissolved in 16 mL of THF. H3PO4 (0.25 mL) was added to the solution and stirred at 35 °C for 1 h. Approximately 10 mL of solvent was removed by rotary evaporation, and a solid crystallized out during evaporation. After evaporation, the suspension was further stirred, and more solid appeared. After 1 h, MTBE (10 mL) was added, and the suspension was continued to stir for an additional 3 h, then filtered. The resulting product (1.1 g, 88% yield) was TPA023B phosphate Form A.

[0170] 30.3 Preliminary Solubility Studies

[0171] [Table 22]

[0172]

[0219] A preliminary solubility study of TPA023B phosphate Form A was performed. TPA023B phosphate Form A solid (known amount) was added to a vial and the specified solvent was added. The mixture was then agitated on a shaker block for at least 30 minutes. Additional solvent was added incrementally until all solids were dissolved. Dissolution was confirmed by visual observation, and the amount of solvent required to dissolve all solids was recorded. The solvents used are listed in Table 22, and the results are shown in Figure 42.

[0173] 30.4. Phosphate Slurry and Stability Studies

[0220] Approximately 50 mg of TPA023B phosphate Form A was weighed into a given amount of a particular solvent and stirred at RT or 50° C. for 3 days. The suspension was filtered and characterized by XRPD. If a new form was obtained, the one that did not disproportionate was further analyzed by DSC and TGA.

[0174] 30.5 Comparative Slurry Studies

[0221] The mixed form of TPA023B phosphate was added to the specified solvent and stirred for 1 day at RT or 50° C. The suspension was filtered and characterized by XRPD.

[0175] 30.6 Mechanical Treatment

[0222] An appropriate amount of TPA023B phosphate Form A was ground with a mortar and pestle for approximately 3 minutes and then analyzed by XRPD.

[0176] Analysis methods and conditions 30.7 X-ray Powder Diffraction (XRPD)

[0223] Solid samples were examined using a D8 ADVANCE X-ray diffractometer (Bruker) and a D2 Phaser X-ray powder diffractometer (Bruker). The diffractometers were equipped with a LynxEye detector. For XRPD analysis, samples were scanned from 3 to 40° 2θ with a 0.02° 2θ step. The tube voltage and current were 40 KV and 40 mA, respectively. XRPD parameters are shown in Table 26-4. Samples were scanned from 3 to 40° 2θ with a 0.02° 2θ step on a D2 Phaser X-ray powder diffractometer (Bruker). The tube voltage and current were 30 KV and 10 mA, respectively.

[0177] 30.8 Polarized Light Microscope (PLM)

[0224] PLM analysis was performed using a polarized light microscope ECLIPSE LV100POL (Nikon, JPN).

[0178] 30.9 Thermogravimetric analysis (TGA)

[0225] TGA was performed on a TGA Q500 or Discovery TGA 55 (TA Instruments, US). Samples were placed in open tarred aluminum pans, automatically weighed, and inserted into the TGA furnace. The samples were heated at 10 °C / min to the final temperature.

[0179] 30.10 Differential Scanning Calorimetry (DSC)

[0226] DSC analysis was performed on a DSC Q200 or Discovery DSC 250 (TA Instruments, US). A weighed sample was placed in a DSC pinhole pan and the weight was accurately recorded. The sample was heated at 10 °C / min to the final temperature.

[0180] Example 31 Characterization of TPA023B free base

[0227] Two batches of TPA023B free base were used, as shown below. Batch # AH-025-9-4 was the anhydrous form defined as free base pattern A, while batch AH-025-9-10 was found as a mixture: Batch 1: AH-025-9-4, free base pattern A, 98.6% purity Batch 2: AH-025-9-10, mixed pattern, 97.8% purity.

[0181]

[0228] The XRPD patterns and DSC diagrams of two batches of free base are shown in Figures 35A and 35B, respectively. PLM images show AH-025-9-4 and AH-025-9-10 as irregular crystals. The DSC diagram of AH-025-9-4 shows one split peak, while the DSC diagram of AH-025-9-10 shows a single peak. According to the XRPD and DSC results, AH-025-9-4 is a pure form of TPA023B free base (Form A), while AH-025-9-10 is a mixture of free base Form A and Form C.

[0182] Example 32 Identification of additional TPA023B free base forms

[0229] Although polymorph screening was performed on phosphate Form A, TPA023B is a weak base, and the phosphate formed readily dissociates to the free base in certain solvents. A total of six forms of TPA023B free base were identified by XRPD, which are shown in Figures 36A-36H and Table 23. The XRPD pattern of the TPA023B free base form is shown in Figure 36A, and the DSC / TGA profile of the free base form is shown in Figures 36B-36H.

[0183]

[0230] Using various free base XRPD patterns as standards, it was possible to determine whether the phosphate dissociated. Free base Form E was obtained by slurrying TPA023B free base or phosphate in EtOH. Free base Forms C, and F-H were obtained by dissociation of the phosphate, and a new pattern (Pattern I) was obtained by heating Form C or Form H to 150°C at 10°C / min by DSC. DSC and TGA data for Forms A, C, and E-I are summarized in Table 23. The profiles are shown in Figures 36B-36H. Free base Forms A and E were identified as anhydrates, Form C exhibited the highest melting point at 209°C, and Forms E, F, G, and H are hydrates or solvates.

[0184] [Table 23]

[0185] Example 33 TPA023B phosphate form

[0231] TPA023B phosphate Form A was prepared by the following procedure: 1000 mg of the free base was dissolved in 16 mL of THF, followed by 0.25 mL of H3PO4. The solution was stirred at 35°C for 1 h. Approximately 10 mL of solvent was removed by rotary evaporation, and a solid crystallized out during evaporation. After evaporation, the suspension was further stirred, and more solid appeared. After 1 h, 10 mL of MTBE was added, and the suspension was continued to stir for an additional 3 h, then filtered. TPA023B phosphate Form A (1.1 g) was obtained in 88% yield. The crystals of TPA023B phosphate Form A are needle-shaped.

[0186]

[0232] The XRPD pattern of TPA023B phosphate Form A is shown in Figure 38A. The thermal properties of TPA023B phosphate Form A are shown in Figure 38B. No significant weight loss was observed by TGA up to 175 °C, suggesting that phosphate Form A is an anhydrous form. The DSC thermogram shows one sharp endothermic peak at 206 °C, which is attributed to the melting of phosphate Form A. An exothermic peak was observed in the TGA profile immediately after melting, accompanied by weight loss, which is due to the decomposition of the phosphate. DVS showed that Form A absorbed 0.68% water from 0 to 80% RH, suggesting that phosphate Form A may be slightly hygroscopic. The crystalline form remained unchanged after the DVS test (see Figures 38C and 38D). The P-NMR spectrum of TPA023B phosphate Form A (and other forms) is shown in Figure 37B. Phosphorus signals were detected by P-NMR, indicating that the phosphate Form A is anhydrous. Separation of base pair PO4 3- The ratio was analyzed as 1:1 according to the IC results.

[0187]

[0233] TPA023B phosphate Pattern F was obtained by stirring Form A in ethanol. The thermal properties of Pattern F are shown in Figure 39. Pattern F exhibits a weight loss of about 5.57% before 115°C, which may be due to ethanol solvation. The DSC thermogram shows three endothermic peaks and one exothermic peak.

[0188]

[0234] TPA023B phosphate Pattern G was obtained by stirring Form A in EtOH-water. The thermal properties of TPA023B phosphate Pattern G are shown in Figure 40. A weight loss of approximately 3.6% was observed before 120°C for Pattern G in TGA, and three endothermic peaks were observed in DSC (Figure 40). Therefore, Pattern G is likely a hydrate.

[0189]

[0235] TPA023B phosphate pattern H was obtained by converting phosphate pattern F to pattern H by heating it to 150°C by TGA. The thermal properties of TPA023B phosphate pattern H are shown in Figure 41. As shown in Figure 41, pattern H had a weight loss of about 0.047% before 175°C, which can be attributed to solvent residues. Two endothermic peaks with peak temperatures at 194.2°C and 205.0°C were observed in the DSC thermogram.

[0190] Example 34 TPA023B phosphate preliminary solubility studies

[0236] The solubility of TPA023B phosphate Form A was measured by visual observation in 16 solvents, and the results are summarized in Table 24 and Figure 42. The solubility of Form A is high in DMF (96 mg / mL), DMSO (93 mg / mL), THF (28 mg / mL), 2-Me-THF (20 mg / mL), and 1,4-dioxane (25 mg / mL). MTBE, EA, water, and n-heptane could be used as antisolvents due to the low solubility (<2 mg / mL) of TPA023B phosphate Form A in these solvents.

[0191] [Table 24]

[0192] Example 35 Slurry and Stability Studies of TPA023B Phosphate

[0237] TPA023B phosphate Form A (100 mg) was slurried in 2 mL of various solvents (see Figures 43-45). In THF, 2-Me THF, IPAC, EA, acetone, and ACN, phosphate Form A changed at RT as shown in Figure 43. The solubility of the hydroxybenzoates in the hydroxybenzoates remains unchanged, suggesting that they are physically stable in these solvents.

[0193]

[0238] Slurrying phosphate Form A in other solvents provided new XRPD patterns that revealed the free base rather than the salt. Five forms were obtained by dissociation of the phosphate; these are TPA023B free base Form C and Forms E-H, shown in Table 25. For Forms E-H, no P signal or PO4 signal was detected by P-NMR or IC. 3- No traces of phosphate were detected. A slurry of the phosphate in EtOH provided the same XRPD pattern as the free base in EtOH (free base form C), confirming that the phosphate dissociated to the free base in EtOH. A new pattern (pattern I) was obtained by heating free base form C to 150°C, as was form H. It was analyzed as a mixture of form A and a new form (form J). The XRPD pattern of the free base is shown in Figures 46A-46B. It was found that the presence of water or alcohol can cause the phosphate to dissociate to the free base.

[0194] [Table 25]

[0195] Example 36 Stability studies of TPA023B phosphate form A

[0239] TPA023B phosphate Form A was ground and analyzed by XRPD as shown in Figure 47. After grinding, the crystalline morphology remained unchanged, but the crystallinity decreased. The solid-state stability of phosphate Form A was studied at 40°C / 75% RH and 25°C / 95% RH for up to 2 weeks. The crystalline morphology remained unchanged (see Figure 48).

[0196]

[0240] Jet mill studies were carried out on phosphate Form A. Micronization was carried out in a mini jet mill under the following conditions: Equipment: Jet mill (equipment number: PPD-OAJ-1) Feed rate: Manually adjusted according to actual results Feed pressure: 0.3~0.5MPa Mill 1 pressure: 0.4 to 0.6 MPa Mill 2 pressure: 0.4 to 0.6 MPa

[0241] The particle size of phosphate Form A decreased after micronization. The D(0.1), D(0.5), and D(0.9) of phosphate Form A before jet milling were 1.40 μm, 8.05 μm, and 27.90 μm, respectively. The D(0.1), D(0.5), and D(0.9) of phosphate Form A after jet milling were 1.18 μm, 4.77 μm, and 10.80 μm, respectively. The TGA / DSC thermograms did not show significant changes after jet milling. For example, the TGA / DSC thermogram after jet milling did not contain more peaks than the thermogram before milling. The purity of phosphate Form A did not change after jet milling, but the residual solvent and water content decreased.

[0197] Example 37 Materials used in additional salt screening of TPA023B free base

[0242] Additional salt screens were performed on TPA023B free base, the details and results of which are shown in Examples 37-48. One batch of TPA023B free base was used for the screens, as shown in Table 26-1. The acids and solvents used for the salt screens are shown in Tables 26-2 and 26-3, respectively.

[0198] [Table 26]

[0199] [Table 27]

[0200] [Table 28]

[0201] Example 38 Additional salt screening of TPA023B free base

[0243] Additional salt screens were performed on the TPA023B free base, the details and results of which are provided in Examples 37-48.

[0202]

[0244] Salt screening of TPA023B free base was performed using eight common acids in a 96-well plate. Crystalline samples were obtained with three acids: HCl, H2SO4, and benzenesulfonic acid. TPA023B sulfate exhibited good crystallinity, low solvent retention, and slight hygroscopicity. The physical and chemical stability of TPA023B free base, TPA023B chloride, TPA023B sulfate, and TPA023B besylate was evaluated. Results indicated that all samples were chemically stable for 7 days at 60°C and 40°C / 75% RH. TPA023B free base, TPA023B chloride, and TPA023B sulfate were physically stable throughout the stability study (i.e., their respective crystalline forms did not change), but TPA023B besylate exhibited three extra peaks in its XPRD pattern after 7 days at 40°C / 75% RH.

[0203] Salt screening experiment 38.1 Salt Preparation in 96-Well Plates

[0245] The appropriate amount of acid was dissolved and diluted with MeOH (10 mL) to make a 0.1 M solution. TPA023B free base (approximately 362 mg) was dissolved and diluted with THF (12 mL) to make a 30 mg / mL solution (0.08 M).

[0204]

[0246] A solution of TPA023B free base in THF was dispensed into a 96-well plate. 100 μL of TPA023B free base solution and 80 μL or 40 μL of a single acid solution for the H2SO4 solution were added to each well. The resulting solution in each well was evaporated to dryness, and 200 μL of solvent was added to each well. The wells were covered with parafilm containing one pinhole over the opening. The solvent was allowed to evaporate under ambient conditions. One sample from each row was 1Characterization by H NMR confirmed salt formation. Solid samples obtained on plates were characterized by XRPD to determine if they were crystalline. The acids and solvents used in the experiments are listed in Tables 26-2 and 26-3.

[0205] 38.2 Salt Preparation

[0247] Based on the results of the 96-well plate screening described in 38.1 above, salt formation was repeated on solid samples according to the above procedure on an approximately 30-40 mg scale.

[0206]

[0248] An appropriate amount of TPA023B free base was dissolved in each solvent, and the acid solution (1 eq.) was added to form the salt. If precipitation did not occur, the reaction solution was concentrated or an antisolvent was added to induce precipitation.

[0207] 38.3 Solid-State Stability of Free Bases and Salts

[0249] Samples of TPA023B free base, TPA023B chloride, TPA023B besylate, and TPA023B sulfate were placed on stability at 60°C and 40°C / 75% RH for up to 7 days. On days 0, 3, and 7, samples were dissolved in diluent to prepare solutions at 0.5 mg / mL for HPLC analysis. Solid samples were analyzed by XRPD to determine the crystalline form.

[0208] Analysis methods and conditions 38.4 1 H NMR

[0250] 1 H NMR was performed on a Bruker Advance 30 equipped with an autosampler. 0 (B-ACS 120).

[0209] 38.5 X-ray Powder Diffraction (XRPD)

[0251] Solid samples were examined using a D8 ADVANCE X-ray diffractometer (Bruker). The diffractometer was equipped with a LynxEye detector. For XRPD analysis, samples were scanned from 3 to 40° 2θ with a step of 0.02° 2θ. The tube voltage and current were 40 KV and 40 mA, respectively. XRPD parameters are listed in Table 26-4.

[0210] [Table 29]

[0211] 38.6 Polarized Light Microscope (PLM)

[0252] PLM analysis was performed using a polarized light microscope ECLIPSE LV100POL (Nikon, JPN).

[0212] 38.7 Thermogravimetric analysis (TGA)

[0253] TGA was performed on a Discovery TGA 55 (TA Instruments, US). Samples were placed in open tarred aluminum pans, automatically weighed, and inserted into the TGA furnace. The samples were heated at 10 °C / min to the final temperature.

[0213] 38.8 Differential Scanning Calorimetry (DSC)

[0254] DSC analysis was performed on a Discovery DSC 250 (TA Instruments, US). A weighed sample was placed in a DSC pinhole pan and the weight was accurately recorded. The sample was heated at 10°C / min to the final temperature.

[0214] 38.9 Dynamic Vapor Sorption (DVS)

[0255] DVS was determined using an IGA Sorp (Hiden Isochema, UK). Samples were tested in step mode over a full cycle of 0-90% RH. Analysis was performed in 10% RH increments.

[0215] 38.10 HPLC method

[0256] The HPLC methods for solubility and stability testing are shown in Table 26-5.

[0216] [Table 30]

[0217] Example 39 Characterization of the starting material (TPA023B free base)

[0257] One batch of TPA023B free base was used in Examples 38-48. Characterization results are shown in Figures 49 and 50. The XRPD pattern is shown in Figure 49; the PLM image shows irregular crystals; the TGA profile shows a 1.06% weight loss by 200°C; the DSC thermogram shows two overlapping endothermic peaks between 200 and 210°C; the purity of the free base is 97.8%. This batch of TPA023B is likely a mixture of free base form A and free base form C.

[0218] Example 40 Results of salt screening in 96-well plates

[0258] Following the procedure described in Example 38.1, 1 eq. or 0.5 eq. of 0.1 M acid (relative to H2SO4 acid) was added to the wells of a 96-well plate along with the free base solution. The solvents used are listed in Table 26-3. After drying, some solids appeared in the 96-well plate. One sample in each row of the 96-well plate was 1 It was analyzed by 1 H NMR and some solid samples were examined by PLM and XRPD.

[0219]

[0259] 1 H NMR spectra showed chemical shifts for the protons on the aromatic ring in the solid samples produced from reactions with HCl, H2SO4, HBr, methanesulfonic acid, p-toluenesulfonic acid, or benzenesulfonic acid compared to TPA023B free base. The sulfate salt sample was in crystalline form. The chloride and mesylate salt samples were mostly amorphous. The crystalline morphology of the maleate and acetate salt samples was consistent with the TPA023B free base starting material. The other samples were amorphous. XRPD results are shown in Figure 51.

[0220] Example 41 Preparation of TPA023B chloride

[0260] Seven experiments were performed to prepare TPA023B chloride, as shown in Table 27. The amount of HCl acid used in all seven experiments was 1 eq. relative to TPA023B free base. The XRPD patterns, NMR spectra, DSC / TGA thermograms, and DVS profiles of the samples are shown in Figures 52A-52F.

[0221] [Table 31]

[0222]

[0261] As shown in the XRPD patterns in Figure 52A, the TPA023B chloride sample prepared in THF / EtOH-1,4-dioxane exhibited XRPD pattern B (i.e., the sample is designated TPA023B chloride Form B), and the TPA023B chloride sample prepared in THF / EtOH-acetone exhibited XRPD pattern C (i.e., the sample is designated TPA023B chloride Form C).

[0223]

[0262] NMR results (Figures 52C-52D) indicated that TPA023B chloride Forms B and C had residual solvent. TGA (Figures 52E-52F) results indicated that TPA023B chloride Forms B and C had weight losses of approximately 8.6% and 4.6%, respectively, before 150°C (DSC: before melting point). The weight losses below the melting point indicated that the two crystalline forms of TPA023B chloride might be solvates. After slurrying in EA or heptane, TPA023B chloride Form C remained unchanged (see Figures 52G and 52H).

[0224] Example 42 Preparation of TPA023B sulfate

[0263] Five experiments were performed to prepare TPA023B sulfate, as shown in Table 28. The sulfate salt was prepared with H2SO4 and TPA023B free base (1:1 molar ratio). The XRPD patterns, DSC / TGS thermograms, and DVS profiles of the samples are shown in Figures 53A-53D.

[0225] [Table 32]

[0226]

[0264] XRPD results (Figure 53A) showed that TPA023B sulfate Form A was produced in THF-acetone, THF-EA, and THF / EtOH-EA. NMR results showed that TPA023B sulfate Form A prepared in THF-EA had THF and EA residues, while Form A prepared in THF / EtOH-EA had no residues. THF / EtOH was shown to be a good solvent for crystallization. TGA results (Figure 53C) showed that Form A showed little weight loss up to 150°C. DSC results (Figure 53C) showed that Form A had one endothermic peak at 192.27°C, indicating that Form A may be an anhydrous form.

[0227] Example 43 Preparation of TPA023B bromide

[0265] Three experiments were performed to prepare TPA023B bromide, as shown in Table 29. The salt was prepared with 1 eq. of HBr relative to TPA023B free base. The XRPD patterns of the samples are shown in Figure 54. No crystalline form of the TPA023B bromide salt was observed.

[0228] [Table 33]

[0229] Example 44 Preparation of TPA023B tosylate

[0266] Five experiments were performed to prepare TPA023B tosylate, as shown in Table 30. The tosylate salt was prepared with 1 eq. of p-toluenesulfonic acid relative to TPA023B free base. The XRPD pattern of the sample is shown in Figure 55. No crystalline form of TPA023B tosylate salt was observed.

[0230] [Table 34]

[0231] Example 45 Preparation of TPA023B mesylate

[0267] Two experiments were performed to prepare TPA023B mesylate, as shown in Table 31. The mesylate salt was prepared with 1 eq. of methylsulfonic acid relative to TPA023B free base. The XRPD pattern of the sample is shown in Figure 56. No crystalline form of TPA023B mesylate was observed.

[0232] [Table 35]

[0233] Example 46 Preparation of TPA023B besylate

[0268] Five experiments were performed to prepare TPA023B besylate, as shown in Table 32. The besylate salt was prepared with 1 eq. of benzenesulfonic acid relative to TPA023B free base. The XRPD patterns, NMR spectra, DSC / TGS thermograms, and DVS profiles of the samples are shown in Figures 57A-57G.

[0234] [Table 36]

[0235]

[0269] XRPD results (Figure 57A) showed that the crystalline form of all samples was the same, and they are designated as TPA023B besylate Form A. After being slurried in EA or heptane, Form A remained unchanged. NMR results (Figure 57C) showed that Form A had residual solvent. TGA results (Figure 57D) showed that Form A had a weight loss of approximately 5.15% before 150°C. DSC results (Figure 57D) showed that the two endothermic peaks of Form A overlapped with each other. This indicates that one crystalline form of TPA023B besylate was produced, which may be a solvate.

[0236] Example 47 Preparation of TPA023B phosphate

[0270] Five experiments were conducted to prepare TPA023B phosphate, as shown in Table 33. All phosphate salts produced were in crystalline form, and the crystalline form of the phosphate salt was not affected by increasing the molar ratio of phosphoric acid to TPA023B (see Figure 58).

[0237] [Table 37]

[0238] Example 48 Solid-state stability testing

[0271] As shown in Table 34, TPA-23B free base (Form A), TPA-23B sulfate (Form A), TPA-23B chloride (Form C), and TPA-23B besylate (Form A) were chemically stable under the test conditions. The purity of TPA-23B chloride improved under the test conditions; some impurities in the chloride salt were volatile and may have decomposed into non-UV-absorbing or volatile impurities or may not have been uniformly distributed during the test. XRPD results (Figures 59A-59D) indicate that the crystalline forms of TPA-23B free base, TPA-23B chloride, and TPA-23B sulfate remained unchanged during the test. After 7 days at 40 °C and 75% RH, three extra peaks at 15.8°, 17.4°, and 17.8° 2θ were observed for TPA-23B besylate, which may have been caused by impurities. The XRPD pattern of TPA-23B besylate with the extra peak was designated TPA-23B besylate form AI (see Figure 59D).

[0239] [Table 38]

[0240] Example 49 Annotated XRPD patterns

[0272] Additional annotated XRPD patterns measured using the parameters described in Example 38 are shown in Figures 60-63.

[0241] Example 50 Kilogram-scale preparation procedure for phosphate Form A

[0273] 2',6-Difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile (2.1 kg, 5.4 moles, 1.0 eq), acetone (42 L, 20 vol.), and water (672 mL, 0.32 vol.) were heated to 50±5°C with stirring. Concentrated phosphoric acid (85 wt%, 310 g, 2.7 moles, 0.50 eq.) was added over approximately 10 minutes. Additional concentrated phosphoric acid (85 wt%, 495 g, 4.3 moles, 0.80 eq.) was added over approximately 1 hour. The resulting mixture was stirred at 50±5°C for approximately 1 hour to give a dark, clear solution. The solution was filtered through a pad of diatomaceous earth (700 g) followed by an in-line 0.2 micron filter. Acetone (8.5 L, 4.0 Vol.) was removed by distillation, and anhydrous acetone (8.5 L, 4.0 Vol.) was added. This process was repeated two more times to form a yellow solid slurry. Acetone (8.5 L, 4.0 Vol.) was removed by distillation, and ethyl acetate (8.5 L, 4.0 Vol.) was added. This process was repeated two more times to obtain approximately 20 Vol of slurry, which was heated to 50±5°C. The resulting slurry was slowly cooled to 20-25°C and stirred overnight. The slurry was cooled to 0-5°C over 1 hour and stirred for 1 hour. The solid was collected by filtration, and the filter cake was washed with ethyl acetate (6.5 L, 3.0 Vol.). The filter cake was evaporated in vacuo at 25°C under a stream of N2 for 5 minutes. The resulting solution was dried for 2 hours under vacuum at 70°C under a stream of N2 for 21 hours to give 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 containing phosphoric acid (2.49 kg, 94.7% yield). The phosphoric acid content in the product was determined to be about 19.2% by ion chromatography. The XRPD pattern and DSC / TGA curves, measured using the parameters described in Example 38, are shown in Figure 64, Figure 65A, and Figure 65B, respectively.

[0242] Example 51 51.0 Phosphate Polymorph Screening

[0274] Representative solvents and materials used for polymorph screening include: ethanol (EtOH), isopropyl alcohol (IPA), methyl acetate (MAC), butyl acetate (BAC), trifluoroethanol, tetrahydrofuran (THF), acetonitrile (ACN), tert-butyl methyl ether (MTBE), diethyl ether (DEE), acetone, butanone (MEK), water, 1,4-dioxane (Diox), dichloromethane (DCM), ethyl acetate (EA), isopropyl acetate (IPAC), heptane (Hept), cyclohexane (CYH), dimethyl sulfoxide (DMSO), toluene, tert-amyl alcohol. Examples of suitable solvents include methylpropional, methylpropional, methylpropional (MDI), methylpropional (MMDI), methylpropional (MMPE ...

[0243] 51.1 Slow solvent evaporation at RT

[0275] Phosphate Form A was dissolved in a selected solvent. The solution was filtered and the filtrate was evaporated to dryness at room temperature (RT) in a working laboratory fume hood.

[0244] 51.2 Fast solvent evaporation at RT

[0276] Phosphate Form A was dissolved in a solvent and evaporative crystallization was carried out at RT or by rotary evaporation with a N purge. The solid was collected and analyzed.

[0245] 51.3 Slurry in a single solvent at RT

[0277] Phosphate Form A was added to a single solvent to form a suspension, which was then left stirring at RT for 4-9 days. Solid samples were collected by filtration and analyzed.

[0246] 51.4 Slurry in mixed solvent at RT

[0278] Phosphate Form A was added to the mixed solvent to form a suspension. The suspension was kept stirring at RT for 4-7 days. Solid samples were collected by filtration and analyzed.

[0247] 51.5 Slurry in a single solvent at 60°C

[0279] Phosphate Form A was added to various solvents to form suspensions. The suspensions were kept stirring at 60°C for 3-4 days. Solid samples were collected by filtration, stirred and then analyzed.

[0248] 51.6 Slurry in mixed solvent at 60°C

[0280] Phosphate Form A was added to the mixed solvent to form a suspension. The suspension was kept stirring at 60°C for 4-6 days. Solid samples were collected by filtration, stirred and then analyzed.

[0249] 51.7 Fast cooling crystallization

[0281] Phosphate Form A was weighed into a vial, and then the solvent of choice was added and heated to create a nearly clear solution. The suspension was filtered to obtain a saturated solution, which was immediately cooled to the final temperature (4°C or -20°C) and characterized.

[0250] 51.8 Slow Cooling Crystallization

[0282] Phosphate Form A was weighed into a vial, and then a solvent of choice was added with heating to create a nearly clear solution. The suspension was filtered to obtain a saturated solution, which was then kept in an oil bath and allowed to cool to RT. The resulting solid was characterized.

[0251] 51.9 Antisolvent Precipitation

[0283] Phosphate Form A was weighed into a vial and the solvent of choice was added to create a saturated solution. After filtration, the filtrate was slowly added to the antisolvent at RT or 50°C (or vice versa). Once precipitated, the product was characterized.

[0252] 51.10 Heat Treatment

[0284] The amorphous salt of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid was prepared by rapid evaporation of a saturated THF solution of phosphate Form A. Thermal treatment of the amorphous salt of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid was carried out using DSC from 25 °C to 160 °C with a ramp rate of 10 °C / min.

[0253] 51.11 Liquid Vapor Diffusion

[0285] Phosphate Form A was dissolved in a solvent. After filtration, the filtrate in the small vial was placed in a larger vial containing the antisolvent. The larger vial was left at RT for several days. Once precipitation occurred, the solid was collected and characterized.

[0254] 51.12 Solid-state vapor diffusion

[0286] Amorphous salts of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid were prepared by rapid evaporation and then placed in a small vial, which was then placed in a larger vial containing the solvent of choice. The larger vial was sealed and left at room temperature for 1 day. The sample was analyzed.

[0255] 51.13 Reactive Crystallization with Phosphoric Acid

[0287] Approximately 25 mg of free base Form H was dissolved or suspended in approximately 1 mL of the selected solvent. 1.1 eq. of phosphoric acid was then added and the suspension was stirred at RT for 7 h. The solid was isolated and characterized.

[0256] 51.14 Reactive crystallization using excess phosphoric acid

[0288] Approximately 30 mg of free base Form H was suspended in approximately 1 mL of acetone. Excess phosphoric acid (2 eq., 3 eq., and 4 eq., respectively) was then added and the suspension S was stirred for 4 hours at RT. The resulting products were characterized.

[0257] 51.15 Polymer-Induced Crystallization

[0289] Approximately 15 mg of phosphate Form A was dissolved in a selected solvent. Approximately 10% of the polymer was then added to the clear solution. The mixture was evaporated to dryness at RT. The solid was isolated and characterized.

[0258] 51.16 Mechanical Treatment

[0290] Phosphate Form A was placed in a mortar and ground at RT to find more crystalline forms.

[0259]

[0291] The amorphous salt of 2′,6-difluoro-5′-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid was manually ground with a small amount of solvent for several minutes, and then the sample was analyzed.

[0260] Analysis methods and conditions 51.17 Dynamic Vapor Sorption (DVS)

[0292] Moisture sorption / desorption data were collected with a Vsorp Dynamic Moisture Sorption Analyzer (ProUmid GmbH & Co. KG, Germany). Samples were placed in a tarred sample chamber and automatically weighed.

[0261] 51.18 Differential scanning calorimetry (DSC)

[0293] DSC was performed using a Discovery DSC 250 (TA Instruments, US). The sample was placed in an aluminum pinhole sealed pan and the weight was accurately recorded. The sample was then heated from 25°C to the final temperature at a rate of 10°C / min.

[0262] 51.19 Thermogravimetric analysis (TGA)

[0294] TGA was performed on a Discovery TGA 55 (TA Instruments, US). Samples were placed in open tarred aluminum pans, automatically weighed, and inserted into the TGA furnace. The samples were heated from ambient temperature to the final temperature at a rate of 10 °C / min.

[0263] 51.20 X-ray Powder Diffraction (XRPD)

[0295] PIXcel 1D Solid samples were examined using an X-ray diffractometer (PANalytic Empyrean) equipped with a detector. The tube voltage and current were 45 kV and 40 mA, respectively, and the samples were scanned from 3 to 40° 2θ with a step size of 0.013°.

[0264] [Table 39]

[0265] Example 52 Slow solvent evaporation at RT

[0296] Phosphate Form A was dissolved in a solvent of choice. The solution was filtered and the filtrate was run. Evaporation to dryness was allowed at room temperature in a laboratory fume hood. The results of the slow single solvent evaporation crystallization are summarized in Table 36.

[0266] [Table 40]

[0267] Example 53 Slow evaporative crystallization in mixed solvents

[0297] Slow evaporative crystallization was also performed using mixed solvents. No new phosphate forms were discovered in the solids produced by this method. Phosphate Form A dissociated to free base Form G in acetone-BAC, to free base Form A in acetone-isopropyl ether and acetone-DCM, and partially to free base Form F in ACN-MAC. The results are shown in Table 37.

[0268] [Table 41]

[0269] Example 54 Fast solvent evaporation at RT

[0298] Phosphate Form A was dissolved in a solvent, and evaporative crystallization was performed at room temperature with an N2 purge or by rotary evaporation, and the solid was collected. No new phosphate form was obtained by rapid evaporation. The phosphate partially dissociated to the free base in DMAC, 2-methyltetrahydrofuran, and DMAC-ACN upon fast solvent evaporation. The results are summarized in Table 38.

[0270] [Table 42]

[0271] Example 55 Slurry in a single solvent at RT

[0299] Phosphate Form A was added to a single solvent to form a suspension, which was stirred at RT for 4 to 9 days. Solid samples were collected. No new phosphate forms were obtained with solids prepared in this manner. Phosphate Form A dissociated to free base Form E in DMSO and partially to free base Form A in tert-amyl alcohol. Phosphate Form A plus free base Form E was obtained in butanol and isoamyl alcohol in a single solvent slurry at RT. The results are summarized in Table 39.

[0272] [Table 43]

[0273] Example 56 Slurry in mixed solvent at RT

[0300] Phosphate Form A was added to the mixed solvent to form a suspension. The suspension was stirred at RT for 4-7 days. Solid samples were collected by filtration. No new phosphate forms were obtained by this method. Phosphate Form A was dissociated to free base Form E in NMP-ethyl formate at RT and in DMAC-anisole. Free base Form A was obtained in DMAC-methylcyclohexane at RT. The results are summarized in Table 40.

[0274] [Table 44]

[0275] Example 57 Slurry in a single solvent at 60°C

[0301] Phosphate Form A was added to various solvents to form suspensions. The suspensions were stirred at 60°C for 3-4 days. Solid samples were collected by filtration. No new phosphate forms were obtained. Phosphate Form A dissociated to free base Form E in tert-amyl alcohol, butanol, isoamylol, IPA, and PEG200, and to free base Form C in EtOH. The results are summarized in Table 41.

[0276] [Table 45]

[0277] Example 58 Slurry in mixed solvent at 60°C

[0302] Phosphate Form A was added to the solvent mixture to form a suspension. The suspension was stirred at 60°C for 4-6 days. Solid samples were collected by filtration and analyzed. No new phosphate forms were obtained. Phosphate Form A dissociated to free base Form E in DMAC-anisole and DMAC-methylcyclohexane mixtures. The results are summarized in Table 42.

[0278] [Table 46]

[0279] Example 59 Antisolvent precipitation at RT

[0303] Phosphate Form A was weighed into a vial and the selected solvent was added to create a saturated solution. After filtration, the filtrate was slowly added to the respective antisolvent at RT, and then the procedure was reversed to add the antisolvent to the solution. Once precipitation occurred, the product was characterized. The solvent and antisolvent were selected according to the results of the solubility test. No new phosphate forms were obtained from the antisolvent precipitation. Phosphate Form A dissociated to free base Form E in DMF and to free base Form A in NMP-MTBE (antisolvent addition). Phosphate Form A was obtained with an additional minor peak in Diox / CYH, which may be due to dissociation of the phosphate. The results are shown in Table 43.

[0280] [Table 47]

[0281] Example 60 Antisolvent precipitation at 50 °C

[0304] Phosphate Form A was weighed into a vial and the solvent of choice was added to create a saturated solution. After filtration, the filtrate was slowly added to the antisolvent at 50°C, and then the procedure was reversed to add the antisolvent to the solution. Once precipitation occurred, the product was characterized. No new phosphate forms were obtained by antisolvent precipitation at 50°C under these conditions. Phosphate Form A dissociated or partially dissociated into free base Form A, free base Form E, and / or free base Form G in NMP-Hept, NMP / petroleum ether; THF-petroleum ether, and THF-methylcyclohexane solvent systems depending on the sequence of operations shown in Table 44.

[0282] [Table 48]

[0283] Example 61 Liquid Vapor Diffusion

[0305] Phosphate Form A was dissolved in the solvent. After filtration, the filtrate was transferred to a small vial and then placed inside a larger vial containing the antisolvent. This larger vial was left at RT for 6 days. Once precipitation occurred, the solid was collected and characterized. No new phosphate forms were obtained. The results are summarized in Table 45.

[0284] [Table 49]

[0285] Example 62 solid-vapor diffusion

[0306] Amorphous salts of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphate were prepared by rapid evaporation, then placed in a small vial inside a larger vial containing the solvent of choice. The larger vial was sealed and left at RT for 1 day. The sample was analyzed. Phosphate Form J was identified when using the solvent IPAC or EA for solid-vapor diffusion, as seen in Figure 71. The results are shown in Table 46.

[0286] [Table 50]

[0287] Example 63 Rapid cooling crystallization

[0307] Phosphate Form A was added to a vial and heated until nearly in solution. The suspension was filtered to obtain a saturated solution and immediately cooled to the final temperature (4°C or -20°C). The resulting solid was characterized. Phosphate Form A or a clear solution was obtained from the fast-cooling crystallization. Phosphate Form A dissociated in butanol and isoamyl alcohol in the fast-cooling crystallization. A new free base pattern K was found in the isoamyl alcohol fast-cooling crystallization. The results are summarized in Table 47.

[0288] [Table 51]

[0289] Example 64 Slow Cooling Crystallization

[0308] Phosphate Form A was weighed into a vial and a selected solvent was added with heating to create a nearly clear solution. The suspension was filtered to obtain a saturated solution, kept in an oil bath, and allowed to cool naturally to RT. The resulting solid was characterized. Phosphate Form A dissociated in butanol and isoamyl alcohol during slow cooling crystallization. No new phosphate forms were obtained. The results are summarized in Table 48.

[0290] [Table 52]

[0291] Example 65 Reactive crystallization using 1.1Eq phosphoric acid

[0309] Free base Form H was dissolved or suspended in approximately 1 mL of the selected solvent. 1.1 eq. of phosphoric acid was then added, and the suspension was stirred at RT for 7 h. The solid was isolated and characterized. No new phosphate forms were obtained in reactive crystallization under this method. A mixture of free base Form H and phosphate Form A was obtained from CYH and Hept, likely due to the very low solubility of free base Form H and phosphoric acid in CYH and Hept. The results are summarized in Table 49.

[0292] [Table 53]

[0293] Example 66 Reactive crystallization using excess phosphoric acid

[0310] The free base Form H was suspended in approximately 1 mL of acetone. An excess of phosphoric acid was then added and the suspension was stirred for 4 hours at RT. The product was characterized. Only phosphate Form A was obtained. The results are shown in Table 50.

[0294] [Table 54]

[0295] Example 67 Polymer-induced crystallization

[0311] Phosphate Form A was dissolved in a selected solvent, approximately 10% polymer was added, and then evaporative crystallization was carried out at RT. No new phosphate form was obtained. Phosphate Form A dissociated in MEK, likely caused by water adsorption during evaporation. The results are shown in Table 51.

[0296] [Table 55]

[0297] Example 68 Slurries of phosphate form A at various water contents

[0312] Phosphate Form A was suspended in acetone with different water contents. The suspensions were stirred at RT for several hours. The solids were isolated and analyzed. Phosphate Form A remained unchanged when the water content was ≦3.5% wt. The phosphate dissociated when the water content was ≧4% wt. in acetone at RT. The results are summarized in Table 52.

[0298] [Table 56]

[0299] Example 69 Mechanical Treatment

[0313] Phosphate Form A was manually ground for 5 min and the sample was examined by XRPD. The crystalline form was unchanged after grinding.

[0300]

[0314] The amorphous salt of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid was prepared by rapid evaporation and manually in a few minutes using a small amount of solvent. The resulting XPRD can be seen in Figure 72. Phosphate Form J (low crystallinity) was obtained by grinding the amorphous sample with small amounts of ACN and EA separately.

[0301] Example 70 Heat Treatment

[0315] Amorphous salts of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid were prepared by rapid evaporation for thermal treatment. A sample of the amorphous salt of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid was heated to 160 °C by DSC. No clear glass transition was observed, and a recrystallization peak was observed at approximately 120 °C. Analysis of the sample revealed that phosphate Form A was obtained. Thus, the amorphous salt of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid crystallized to phosphate form A after thermal treatment.

[0302] Example 71

[0316] The phosphate salt of TPA023B was dissolved in THF and then rotary evaporated to give an amorphous salt of TPA023B containing phosphoric acid, which was recrystallized in a desiccator at room temperature to give phosphate Form J. This specification includes the disclosure of the following inventions. [Item 1] A crystalline form of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing sulfuric acid, wherein the crystalline form has the following characteristics: (a) an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 61 when measured using the parameters set forth in Table 26-4; (b) an XRPD pattern having at least three characteristic peak positions at values ​​selected from the group consisting of about 6.1, 10.9, 11.3, 11.8, 12.2, 13.8, 14.8, 16.1, 16.8, 17.3, 17.9, 18.3, 19.2, 19.6, 21.4, 21.8, 22.8, 23.6, 24.4, 25.4, 27.2, 29.9, 30.5, 31.5, 32.6, 33.9, and 39.1±0.2 degrees two-theta when measured using the parameters set forth in Table 26-4; (c) Differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 53C; (d) DSC thermogram with an endothermic peak at approximately 192°C; (e) stable at about 40°C for at least 3 days; and (f) Stable for at least 3 days at approximately 60°C A crystalline form having at least one of the following: [Item 2] The crystalline form described in Item 1, which provides an XRPD pattern substantially identical to that shown in Figure 61, when measured using the parameters set forth in Table 26-4. [Item 3] When measured using the parameters listed in Table 26-4, approximately 6.1, 10.9, 11.3, 11.8, 12.2, 13.8, 14.8, 16.1, 16.8, 17.3, 17.9, 18.3, 19.2, 19.6, 21.4, 21.8, 22.8, 2. The crystalline form of claim 1, wherein the crystalline form provides an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, or all values ​​selected from the group consisting of 23.6, 24.4, 25.4, 27.2, 29.9, 30.5, 31.5, 32.6, 33.9, and 39.1±0.2 degrees two-theta. [Item 4] The crystalline form of item 1, which provides an XRPD pattern having characteristic peak positions of at least six values ​​selected from the group consisting of about 6.1, 10.9, 11.3, 11.8, 12.2, 13.8, 14.8, 16.1, 16.8, 17.3, 17.9, 18.3, 19.2, 19.6, 21.4, 21.8, 22.8, 23.6, 24.4, 25.4, 27.2, 29.9, 30.5, 31.5, 32.6, 33.9, and 39.1±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. [Item 5] The crystalline form of item 1, which provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.1, 10.9, 12.2, 16.1, 16.8, 21.4, 21.8, 25.4, and 27.2±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. [Item 6] The crystalline form of item 1, which provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.1, 12.2, 16.1, 21.8, 24.4, and 25.4±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. [Item 7] A characteristic peak of all values ​​selected from the group consisting of about 6.1, 12.2, and 21.8 ± 0.2 degrees 2-theta when measured using the parameters set forth in Table 26-4. Item 1, the crystalline form of which provides an XRPD pattern having the position. [Item 8] The crystalline form of item 1, which provides a DSC thermogram substantially identical to that shown in Figure 53C. [Item 9] The crystalline form according to Item 1, which provides a DSC thermogram with an endothermic peak at about 192°C. [Item 10] The crystalline form according to Item 1, which is stable at about 40°C for at least one month. [Item 11] The crystalline form of item 1, which provides a substantially identical XRPD pattern after storage at 40°C and 75% RH for at least 3 days. [Item 12] The crystalline form according to Item 1, which is a salt. [Item 13] The crystalline form according to Item 1, which is a cocrystal. [Item 14] A crystalline form of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing hydrochloric acid, wherein the crystalline form has the following characteristics: (a) an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 63 when measured using the parameters set forth in Table 26-4; (b) an XRPD pattern having characteristic peak positions of at least three, at least nine, at least six, or all values ​​selected from the group consisting of about 6.3, 11.7, 12.8, 14.1, 15.1, 16.5, 17.6, 18.8, 19.3, 20.6, 21.8, 23.2, 24.3, 25.7, 26.5, 26.9, 28.5, 30.3, 32.2, 32.7, and 33.5±0.2 degrees two-theta when measured using the parameters set forth in Table 26-4; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that labeled Chloride Form C in Figure 52F; (d) DSC thermogram with an endothermic peak at approximately 179°C; (e) a substantially identical XRPD pattern after storage at 40°C and 75% RH for at least 3 days; and (f) Substantially identical XRPD patterns after storage at 60°C and 75% RH for at least 3 days A crystalline form having at least one of the following: [Item 15] The crystalline form of item 14, which provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.3, 11.7, 12.8, 16.5, 17.6, and 21.8±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. [Item 16] The crystalline form of item 14, which provides an XRPD pattern having characteristic peak positions of all values ​​selected from the group consisting of about 11.7, 12.8, and 21.8±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. [Item 17] A group consisting of approximately 6.6, 7.5, 9.6, 10.3, 13.3, 13.8, 14.5, 15.4, 15.9, 16.5, 17.3, 17.8, 19.5, 20.3, 22.3, 23.2, 23.7, 26.1, 26.9, 27.9, 29.0, 31.1, and 35.8 ± 0.2 degrees 2-theta when measured using the parameters listed in Table 26-4. 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 E, providing an X-ray powder diffraction (XRPD) pattern having characteristic peak positions of at least three values ​​selected from: [Item 18] The crystalline form of item 17, which provides an XRPD pattern having characteristic peak positions of all values ​​selected from the group consisting of about 7.5, 9.6, and 10.3±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. [Item 19] 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 F, providing 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, 7.7, 8.1, 9.2, 10.9, 12.3, 13.1, 14.0, 14.2, 15.2, 15.4, 15.7, 16.3, 17.2, 17.8, 19.4, 19.9, 21.0, 22.9, 26.7, and 27.6±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. [Item 20] The crystalline form of item 19, which provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 7.7, 8.1, and 13.1±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. [Item 21] 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 G, 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 6.3, 7.5, 8.0, 11.7, 12.0, 12.8, 13.3, 14.1, 14.8, 15.3, 17.2, 18.0, 19.2, 19.6, 21.5, 23.2, 23.8, 25.9, 26.6, 27.7, and 32.4±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. [Item 22] The crystalline form of item 21, which provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.3, 8.0, and 13.3±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. [Item 23] Form H of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl) methyl]propanol, 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, 7.9, 9.4, 10.9, 12.7, 13.4, 14.0, 14.3, 14.6, 16.0, 16.3, 18.0, 19.2, 19.7, 20.1, 21.2, 24.1, 25.7, 26.9, and 28.0±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. -Crystalline polymorphs of imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile. [Item 24] The crystalline form of item 23, which provides an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, or all values ​​selected from the group consisting of about 7.9, 12.7, and 14.0±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. [Item 25] (a) Chloride salts that provide XRPD patterns substantially identical to those shown in Figure 62; and Call (b) a besylate salt that provides an XRPD pattern substantially identical to the XRPD pattern labeled besylate Form A shown in Figure 57A. A crystalline form of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile selected from the group consisting of: [Item 26] A crystalline form of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid, wherein the crystalline form has the following characteristics: (a) an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 67, when measured using the parameters set forth in Table 35; (b) an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.3, 7.4, 10.1, 12.6, 13.2, 14.0, 15.7, 17.0, 17.3, 18.0, 19.0, 20.2, 20.7, 26.4, 27.2, and 27.5±0.2 degrees two-theta when measured using the parameters set forth in Table 35; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 69; (d) a DSC thermogram with an endothermic peak at approximately 200°C; and (e) DSC thermogram showing an endothermic peak with an onset temperature of approximately 197°C. A crystalline form having at least one of the following: [Item 27] ​​The crystalline form of Item 26, which provides an XRPD pattern having characteristic peak positions of at least three, at least six, or all values ​​selected from the group consisting of about 6.3, 13.2, 14.0, 15.7, 17.0, 17.3, 18.0, 19.0, 20.2, 20.7, and 26.4±0.2 degrees two-theta, when measured using the parameters set forth in Table 35. [Item 28] The crystalline form of item 26, which provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.3, 17.0, and 19.0±0.2 degrees two-theta, when measured using the parameters set forth in Table 35. [Item 29] The crystalline form according to Item 26, which is a salt or a co-crystal. [Item 30] A therapeutic or preventive composition comprising the compound according to any one of Items 1 to 29. [Item 31] A method for treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in any one of Items 1 to 29, or a composition described in Item 30. [Item 32] The method described in Item 31, wherein the disease or disorder is associated with α2 / α3 GABAA receptors. [Item 33] The method according to Item 31, 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. [Item 34] A disease or disorder in a subject in need of treatment. 29. A compound for use in treating a patient suffering from atopic dermatitis, the compound being a compound according to any one of items 1 to 29. There is a compound. [Item 35] A method for preparing a crystalline form of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid, 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; Including, The method wherein the crystalline form provides an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 64, when measured using the parameters set forth in Table 26-4. [Item 36] The method of Item 35, wherein the crystalline form provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.5, 7.6, 10.2, 13.4, 14.0, 14.4, 15.4, 16.0, 16.2, 17.2, 17.5, 17.8, 18.6, 19.2, 19.8, 20.4, 20.9, 21.6, 23.5, 26.2, 26.6, 27.4, 28.3, 29.0, 30.2, and 32.7±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. [Item 37] The method of Item 35, wherein the crystalline form provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.5, 13.4, 14.0, 15.4, 17.2, 17.5, and 26.6±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. [Item 38] The method of Item 35, wherein the crystalline form provides an XRPD pattern having characteristic peak positions of all values ​​selected from the group consisting of about 6.5, 14.4, 16.0, 18.6, 19.2, 21.6, and 26.6±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4. [Item 39] The method according to Item 35 or 36, wherein at least 500 grams of the crystalline form is prepared. [Item 40] The method according to Item 35 or 36, wherein the solution comprises ethyl acetate, acetone, water, or any mixture thereof. [Item 41] The method according to Item 35 or 36, further comprising a step of removing water.

Claims

1. 1. A crystalline form of 2′,6-difluoro-5′-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing sulfuric acid, wherein the crystalline form has the following characteristics: (a) an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 61, when measured using the parameters set forth in Table 26-4; (b) an XRPD pattern having at least three characteristic peak positions at values ​​selected from the group consisting of about 6.1, 10.9, 11.3, 11.8, 12.2, 13.8, 14.8, 16.1, 16.8, 17.3, 17.9, 18.3, 19.2, 19.6, 21.4, 21.8, 22.8, 23.6, 24.4, 25.4, 27.2, 29.9, 30.5, 31.5, 32.6, 33.9, and 39.1±0.2 degrees two-theta when measured using the parameters set forth in Table 26-4; (c) a differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 53C; (d) DSC thermogram with an endothermic peak at about 192°C; (e) stable at about 40°C for at least 3 days; and (f) Stable at about 60°C for at least 3 days A crystalline form having at least one of the following:

2. 61. The crystalline form of claim 1, which provides an XRPD pattern substantially identical to that shown in Figure 61 when measured using the parameters set forth in Table 26-4.

3. 2. The crystalline form of claim 1, wherein the crystalline form provides an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, or all values ​​selected from the group consisting of about 6.1, 10.9, 11.3, 11.8, 12.2, 13.8, 14.8, 16.1, 16.8, 17.3, 17.9, 18.3, 19.2, 19.6, 21.4, 21.8, 22.8, 23.6, 24.4, 25.4, 27.2, 29.9, 30.5, 31.5, 32.6, 33.9, and 39.1±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4.

4. 2. The crystalline form of claim 1, wherein the crystalline form provides an XRPD pattern having characteristic peak positions of at least six values ​​selected from the group consisting of about 6.1, 10.9, 11.3, 11.8, 12.2, 13.8, 14.8, 16.1, 16.8, 17.3, 17.9, 18.3, 19.2, 19.6, 21.4, 21.8, 22.8, 23.6, 24.4, 25.4, 27.2, 29.9, 30.5, 31.5, 32.6, 33.9, and 39.1±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4.

5. 2. The crystalline form of claim 1, wherein the crystalline form provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.1, 10.9, 12.2, 16.1, 16.8, 21.4, 21.8, 25.4, and 27.2±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4.

6. 2. The crystalline form of claim 1, which provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.1, 12.2, 16.1, 21.8, 24.4, and 25.4±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4.

7. Characteristic peaks of all values ​​selected from the group consisting of about 6.1, 12.2, and 21.8±0.2 degrees 2-theta when measured using the parameters set forth in Table 26-4 10. The crystalline form of claim 1, providing an XRPD pattern having positions.

8. 53C. The crystalline form of claim 1, which provides a DSC thermogram substantially identical to that shown in FIG. 53C.

9. 10. The crystalline form of claim 1, which provides a DSC thermogram with an endothermic peak at about 192°C.

10. 10. The crystalline form of claim 1, which is stable at about 40°C for at least one month.

11. 10. The crystalline form of claim 1, which provides a substantially identical XRPD pattern after storage at 40°C and 75% RH for at least 3 days.

12. The crystalline form of claim 1 which is a salt.

13. 10. The crystalline form of claim 1 which is a co-crystal.

14. 1. A crystalline form of 2′,6-difluoro-5′-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with hydrochloric acid, wherein the crystalline form has the following characteristics: (a) an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 63, when measured using the parameters set forth in Table 26-4; (b) an XRPD pattern having characteristic peak positions of at least three, at least nine, at least six, or all values ​​selected from the group consisting of about 6.3, 11.7, 12.8, 14.1, 15.1, 16.5, 17.6, 18.8, 19.3, 20.6, 21.8, 23.2, 24.3, 25.7, 26.5, 26.9, 28.5, 30.3, 32.2, 32.7, and 33.5±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that labeled Chloride Form C in Figure 52F; (d) DSC thermogram with an endothermic peak at about 179°C; (e) substantially identical XRPD patterns after storage at 40° C. and 75% RH for at least 3 days; and (f) Substantially identical XRPD pattern after storage at 60°C and 75% RH for at least 3 days A crystalline form having at least one of the following:

15. 15. The crystalline form of claim 14, which provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.3, 11.7, 12.8, 16.5, 17.6, and 21.8±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4.

16. 15. The crystalline form of claim 14, which provides an XRPD pattern having characteristic peak positions of all values ​​selected from the group consisting of about 11.7, 12.8, and 21.8±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4.

17. A group consisting of about 6.6, 7.5, 9.6, 10.3, 13.3, 13.8, 14.5, 15.4, 15.9, 16.5, 17.3, 17.8, 19.5, 20.3, 22.3, 23.2, 23.7, 26.1, 26.9, 27.9, 29.0, 31.1, and 35.8±0.2 degrees 2-theta when measured using the parameters set forth in Table 26-4. A crystalline polymorph of Form E of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile, providing an X-ray powder diffraction (XRPD) pattern having characteristic peak positions of at least three values ​​selected from the group consisting of:

18. 18. The crystalline form of claim 17, which provides an XRPD pattern having characteristic peak positions of all values ​​selected from the group consisting of about 7.5, 9.6, and 10.3±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4.

19. 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 F, 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, 7.7, 8.1, 9.2, 10.9, 12.3, 13.1, 14.0, 14.2, 15.2, 15.4, 15.7, 16.3, 17.2, 17.8, 19.4, 19.9, 21.0, 22.9, 26.7, and 27.6±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4.

20. 20. The crystalline form of claim 19, which provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 7.7, 8.1, and 13.1±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4.

21. A crystalline polymorph of Form G of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile, providing an X-ray powder diffraction (XRPD) pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.3, 7.5, 8.0, 11.7, 12.0, 12.8, 13.3, 14.1, 14.8, 15.3, 17.2, 18.0, 19.2, 19.6, 21.5, 23.2, 23.8, 25.9, 26.6, 27.7, and 32.4±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4.

22. 22. The crystalline form of claim 21, providing an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.3, 8.0, and 13.3±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4.

23. 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 H, 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, 7.9, 9.4, 10.9, 12.7, 13.4, 14.0, 14.3, 14.6, 16.0, 16.3, 18.0, 19.2, 19.7, 20.1, 21.2, 24.1, 25.7, 26.9, and 28.0±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4.

24. 24. The crystalline form of claim 23, which provides an XRPD pattern having characteristic peak positions of at least three, at least six, at least nine, or all values ​​selected from the group consisting of about 7.9, 12.7, and 14.0±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4.

25. (a) the chloride salt, which provides an XRPD pattern substantially identical to that shown in Figure 62; and Call (b) a besylate salt that provides an XRPD pattern substantially identical to the XRPD pattern labeled besylate Form A shown in Figure 57A. A crystalline form of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile selected from the group consisting of:

26. 1. A crystalline form of 2′,6-difluoro-5′-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid, wherein the crystalline form has the following characteristics: (a) an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 67, when measured using the parameters set forth in Table 35; (b) an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.3, 7.4, 10.1, 12.6, 13.2, 14.0, 15.7, 17.0, 17.3, 18.0, 19.0, 20.2, 20.7, 26.4, 27.2, and 27.5±0.2 degrees two-theta when measured using the parameters set forth in Table 35; (c) a differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 69; (d) a DSC thermogram with an endothermic peak at about 200°C; and (e) DSC thermogram showing an endothermic peak with an onset temperature at approximately 197°C. A crystalline form having at least one of the following:

27. 27. The crystalline form of claim 26, which provides an XRPD pattern having characteristic peak positions of at least three, at least six, or all values ​​selected from the group consisting of about 6.3, 13.2, 14.0, 15.7, 17.0, 17.3, 18.0, 19.0, 20.2, 20.7, and 26.4±0.2 degrees two-theta, when measured using the parameters set forth in Table 35.

28. 27. The crystalline form of claim 26, which provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.3, 17.0, and 19.0±0.2 degrees two-theta, when measured using the parameters set forth in Table 35.

29. 27. The crystalline form of claim 26, which is a salt or a co-crystal.

30. A therapeutic or prophylactic composition comprising a compound according to any one of claims 1 to 29.

31. 31. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 29, or a composition of claim 30.

32. 32. The method of claim 31, wherein the disease or disorder is associated with α2 / α3 GABAA receptors.

33. 32. The method of claim 31, 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.

34. 30. A compound for use in treating a disease or disorder in a subject in need thereof, wherein the compound is a compound according to any one of claims 1 to 29. There is a compound.

35. 1. A method for preparing a crystalline form of 2′,6-difluoro-5′-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile containing phosphoric acid, 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. Including, The method wherein the crystalline form provides an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 64, when measured using the parameters set forth in Table 26-4.

36. 36. The method of claim 35, wherein the crystalline form provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.5, 7.6, 10.2, 13.4, 14.0, 14.4, 15.4, 16.0, 16.2, 17.2, 17.5, 17.8, 18.6, 19.2, 19.8, 20.4, 20.9, 21.6, 23.5, 26.2, 26.6, 27.4, 28.3, 29.0, 30.2, and 32.7±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4.

37. 36. The method of claim 35, wherein the crystalline form provides an XRPD pattern having characteristic peak positions of at least three values ​​selected from the group consisting of about 6.5, 13.4, 14.0, 15.4, 17.2, 17.5, and 26.6±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4.

38. 36. The method of claim 35, wherein the crystalline form provides an XRPD pattern having characteristic peak positions of all values ​​selected from the group consisting of about 6.5, 14.4, 16.0, 18.6, 19.2, 21.6, and 26.6±0.2 degrees two-theta, when measured using the parameters set forth in Table 26-4.

39. 37. The method of claim 35 or 36, wherein at least 500 grams of the crystalline form is prepared.

40. 37. The method of claim 35 or 36, wherein the solution comprises ethyl acetate, acetone, water, or any mixture thereof.

41. 37. The method of claim 35 or 36, including the step of removing water.

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