Crystalline salts or co-crystals of 2′,6-difluoro-5′-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b] [1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with phosphoric acid as GABAA positive allosteric modulators

1. A crystalline salt or co-crystal of 2′,6-difluoro-5′-[3-(1-hydroxy-1-methylethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with phosphoric acid of the following formula:

wherein the crystalline salt or co-crystal is Form A; and

wherein the crystalline salt or co-crystal is characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at angles (°2θ) of 6.4°±0.2°2θ, 7.5°±0.2°2θ, 10.2°±0.2°2θ, 12.7°±0.2°2θ, 13.3°±0.2°2θ, 14.5°±0.2°2θ, 16.0°±0.2°2θ, 17.1°±0.2°2θ, 17.4°±0.2°2θ, 17.9°±0.2°2θ, 18.5°±0.2°2θ, 19.1°±0.2°2θ, 19.7°±0.2°2θ, 20.3°±0.2°2θ, 20.9°±0.2°2θ, 21.5°±0.2°2θ, 22.6°±0.2°2θ, 23.7°±0.2°2θ, 26.2°±0.2°2θ, 26.7°±0.2°2θ, 26.9°±0.2°2θ, 27.5°±0.2 °2θ, 28.4°±0.2°2θ, 30.2°±0.2°2θ, and 32.1°±0.2°2θ, when measured using the parameters described in Table 1.

2. The crystalline salt or co-crystal of claim 1 , wherein the crystalline salt or co-crystal is further characterized by an X-ray powder diffraction pattern comprising at least three additional characteristic peaks at angles (°2θ) of 6.4°±0.2°2θ, 7.5°±0.2°2θ, 10.2°±0.2°2θ, 12.7°±0.2°2θ, 13.3°±0.2°2θ, 14.5°±0.2°2θ, 16.0°±0.2°2θ, 17.1°±0.2°2θ, 17.4°±0.2°2θ, 17.9°±0.2°2θ, 18.5°±0.2°2θ, 19.1°±0.2°2θ, 19.7°±0.2°2θ, 20.3°±0.2°2θ, 20.9°±0.2°2θ, 21.5°±0.2°2θ, 22.6°±0.2°2θ, 23.7°±0.2°2θ, 26.2°±0.2 °2θ, 26.7°±0.2°2θ, 26.9°±0.2°2θ, 27.5°±0.2°2θ, 28.4°±0.2°2θ, 30.2°±0.2°29, and 32.1°±0.2°29, when measured using the parameters described in Table 1.

3. The crystalline salt or co-crystal of claim 1 , wherein the crystalline salt or co-crystal is further characterized by an X-ray powder diffraction pattern comprising at least six additional characteristic peaks at angles (°2θ) of 6.4°±0.2°2θ, 7.5°±0.2°2θ, 10.2°±0.2°2θ, 12.7°±0.2°2θ, 13.3°±0.2°2θ, 14.5°±0.2°2θ, 16.0°±0.2°2θ, 17.1°±0.2°2θ, 17.4°±0.2°2θ, 17.9°±0.2°2θ, 18.5°±0.2°2θ, 19.1°±0.2°2θ, 19.7°±0.2°2θ, 20.3°±0.2°2θ, 20.9°±0.2°2θ, 21.5°±0.2°2θ, 22.6°±0.2°2θ, 23.7°±0.2°2θ, 26.2°±0.2 °2θ, 26.7°±0.2°2θ, 26.9°±0.2°2θ, 27.5°±0.2°2θ, 28.4°±0.2°2θ, 30.2°±0.2°2θ, and 32.1°±0.2°2θ, when measured using the parameters described in Table 1.

4. The crystalline salt or co-crystal of claim 1 , wherein the crystalline salt or co-crystal is further characterized by an X-ray powder diffraction pattern comprising at least nine additional characteristic peaks at angles (°2θ) of 6.4°±0.2°2θ, 7.5°±0.2°2θ, 10.2°±0.2°2θ, 12.7°±0.2°2θ, 13.3°±0.2°2θ, 14.5°±0.2°2θ, 16.0°±0.2°2θ, 17.1°±0.2°2θ, 17.4°±0.2°2θ, 17.9°±0.2°2θ, 18.5°±0.2°2θ, 19.1°±0.2°2θ, 19.7°±0.2°2θ, 20.3°±0.2°2θ, 20.9°±0.2°2θ, 21.5°±0.2°2θ, 22.6°±0.2°2θ, 23.7°±0.2°2θ, 26.2°±0.2 ‘2θ, 26.7°±0.2°2θ, 26.9°±0.2°2θ, 27.5°±0.2°2θ, 28.4°±0.2°2θ, 30.2°±0.2°2θ, and 32.1°±0.2°2θ, when measured using the parameters described in Table 1.

5. The crystalline salt or co-crystal of claim 1 , wherein the crystalline salt or co-crystal is further characterized by an X-ray powder diffraction pattern comprising at least twelve additional characteristic peaks at angles (°2θ) of 6.4°±0.2°2θ, 7.5°±0.2°2θ, 10.2°±0.2°2θ, 12.7°±0.2°2θ, 13.3°±0.2°2θ, 14.5°±0.2°2θ, 16.0°±0.2°2θ, 17.1°±0.2°2θ, 17.4°±0.2°2θ, 17.9°±0.2°2θ, 18.5°±0.2°2θ, 19.1°±0.2°2θ, 19.7°±0.2°2θ, 20.3°±0.2°2θ, 20.9°±0.2°2θ, 21.5°±0.2°2θ, 22.6°±0.2°2θ, 23.7°±0.2°2θ, 26.2°±0.2 ‘2θ, 26.7°±0.2°2θ, 26.9°±0.2°2θ, 27.5°±0.2°2θ, 28.4°±0.2°2θ, 30.2°±0.2°2θ, and 32.1°±0.2°2θ, and 32.1°±0.2°2θ, when measured using the parameters described in Table 1.

6. The crystalline salt or co-crystal of claim 1 , wherein the crystalline salt or co-crystal is further characterized by an X-ray powder diffraction pattern as shown in FIG. 1 , when measured using the parameters described in Table 1.

7. The crystalline salt or co-crystal of claim 1 , wherein the crystalline salt or co-crystal is further characterized by an X-ray powder diffraction pattern as shown in FIG. 19 , when measured using the parameters described in Table 1.

8. The crystalline salt or co-crystal of claim 1 , wherein the crystalline salt or co-crystal is further characterized by a differential scanning calorimetry thermogram with an endothermic peak at 205° C.

9. The crystalline salt or co-crystal of claim 1 , wherein the crystalline salt or co-crystal is further characterized by a differential scanning calorimetry thermogram as shown in FIG. 2 A .

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

11. The crystalline salt or co-crystal of claim 1 , wherein the crystalline salt or co-crystal is stable for at least a month at 40° C.

12. The crystalline salt or co-crystal of claim 1 , wherein the crystalline salt or co-crystal is characterized by the same stable X-ray powder diffraction pattern post-storage at 40° C. and 75% relative humidity for at least one week.

13. The crystalline salt or co-crystal of claim 1 , wherein the crystalline salt or co-crystal is characterized by the same stable X-ray powder diffraction pattern post-storage at 40° C. and 75% relative humidity for at least two weeks.

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

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

16. A therapeutic or prophylactic composition comprising the crystalline salt or co-crystal of claim 1 .

17. A process for preparing a crystalline salt or co-crystal of 2’,6-difluoro- 5′-[3-(1-hydroxy-1-methylethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with phosphoric acid of the following formula:

wherein the crystalline salt or co-crystal is Form A; and

wherein the crystalline salt or co-crystal is characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at angles (°2θ) of 6.4°±0.2°2θ, 7.5°±0.2°2θ, 10.2°±0.2°2θ, 12.7°±0.2°2θ, 13.3°±0.2°2θ, 14.5°±0.2°2θ, 16.0°±0.2°2θ, 17.1°±0.2°2θ, 17.4°±0.2°2θ, 17.9°±0.2°2θ, 18.5°±0.2°2θ, 19.1°±0.2°2θ, 19.7°±0.2°2θ, 20.3°±0.2°2θ, 20.9°±0.2°2θ, 21.5°±0.2°20, 22.6°±0.2°2θ, 23.7°±0.2°2θ, 26.2°±0.2°20, 26.7°±0.2°20, 26.9°±0.2°20, 27.5°±0.2 °20, 28.4°±0.2°20, 30.2°±0.2°2θ, and 32.1°±0.2°2θ, when measured using the parameters described in Table 1;

wherein the process comprises the following steps:

(1) obtaining 2′,6-difluoro-5′-[3-(1-hydroxy-1-methylethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile phosphate of the following formula:

and

(2) crystallizing the 2′,6-difluoro-5′-[3-(1-hydroxy-1-methylethyl)imidazo [1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile phosphate obtained above from a solution comprising at least one solvent selected from the group consisting of acetone, acetonitrile, dichloromethane, dimethylacetamide, dimethylformamide, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, methyl ethyl ketone, 2-methylbutanone, tetrahydrofuran, 2-methyltetrahydrofuran, and water, or a combination thereof.

18. The process of claim 17 , wherein the process further prepares a crystalline salt or co-crystal characterized by an X-ray powder diffraction pattern comprising at least three additional characteristic peaks at angles (°2θ) of 6.4°±0.2°2θ, 7.5°±0.2°2θ, 10.2°±0.2°20, 12.7°±0.2°2θ, 13.3°±0.2°20, 14.5°±0.2°2θ, 16.0°±0.2° a 17.1°±0.2° NI, 17.4°±0.2° 2 θ, 17.9°±0.2°2θ, 18.5°±0.2°2θ, 19.1°±0.2°2θ, 19.7°±0.2°2θ, 20.3°±0.2°2θ, 20.9°±0.2°2θ, 21.5°±0.2°2θ, 22.6°±0.2°2θ, 23.7°±0.2°2θ, 26.2°±0.2 °2θ, 26.7°±0.2°2θ, 26.9°±0.2°2θ, 27.5°±0.2°2θ, 28.4°±0.2°2θ, 30.2°±0.2°2θ, and 32.1°±0.2°2θ, when measured using the parameters described in Table 1.

19. The process of claim 17 , wherein the crystalline salt or co-crystal is further characterized by an X-ray powder diffraction pattern comprising at least six additional characteristic peaks at angles (°2θ) of 6.4°±0.2°2θ, 7.5°±0.2° 2 θ, 10.2°±0.2°2θ, 12.7°±0.2°2θ, 13.3°±0.2°2θ, 14.5°±0.2°2θ, 16.0°±0.2°2θ, 17.1°±0.2°2θ, 17.4°±0.2°2θ, 17.9°±0.2°2θ, 18.5°±0.2°2θ, 19.1°±0.2° 2 θ, 19.7°±0.2°2θ, 20.3°±0.2°2θ, 20.9°±0.2°2θ, 21.5°±0.2°2θ, 22.6°±0.2°2θ, 23.7°±0.2° a 26.2°±0.2° a 26.7°±0.2°2θ, 26.9°±0.2 °2θ, 27.5°±0.2°2θ, 28.4°±0.2° a 30.2°±0.2°2θ, and 32.1°±0.2° 2 θ, when measured using the parameters described in Table 1.

20. The process of claim 17 , wherein the crystalline salt or co-crystal is further characterized by an X-ray powder diffraction pattern comprising at least nine additional characteristic peaks at angles (°2θ) of 6.4°±0.2°2θ, 7.5°±0.2°2θ, 10.2°±0.2°2θ, 12.7°±0.2°2θ, 13.3°±0.2°2θ, 14.5°±0.2°2θ, 16.0°±0.2°2θ, 17.1°±0.2°2θ, 17.4°±0.2°2θ, 17.9°±0.2°2θ, 18.5°±0.2°20, 19.1°±0.2°20, 19.7°±0.2°2θ, 20.3°±0.2 ‘2θ, 20.9°±0.2°2θ, 21.5°±0.2°2θ, 22.6°±0.2°2θ, 23.7°±0.2°2θ, 26.2°±0.2°2θ, 26.7°±0.2°2θ, 26.9°±0.2°2θ, 27.5°±0.2°2θ, 28.4°±0.2°2θ, 30.2°±0.2°2θ, and 32.1°±0.2°2θ, when measured using the parameters described in Table 1.

21. The process of claim 17 , wherein the crystalline salt or co-crystal is further characterized by an X-ray powder diffraction pattern comprising at least twelve additional characteristic peaks at angles (°2θ) of 6.4°±0.2°2θ, 7.5°±0.2°2θ, 10.2°±0.2°2θ, 12.7°±0.2°2θ, 13.3°±0.2°2θ, 14.5°±0.2°2θ, 16.0°±0.2 ‘2θ, 17.1°±0.2°29, 17.4°±0.2°2θ, 17.9°±0.2°2θ, 18.5°±0.2°2θ, 19.1°±0.2°2θ, 19.7°±0.2°2θ, 20.3°±0.2°2θ, 20.9°±0.2°2θ, 21.5°±0.2°2θ, 22.6°±0.2°2θ, 23.7°±0.2°2θ, 26.2°±0.2°2θ, 26.7°±0.2°2θ, 26.9°±0.2°2θ, 27.5°±0.2°2θ, 28.4°±0.2°2θ, 30.2°±0.2°2θ, and 32.1°±0.2°2θ, and 32.1°±0.2°2θ, when measured using the parameters described in Table 1.

22. The process of claim 17 , wherein the crystalline salt or co-crystal is further characterized by an X-ray powder diffraction pattern as shown in FIG. 1 , when measured using the parameters described in Table 1.

23. The process of claim 17 , wherein the crystalline salt or co-crystal is further characterized by an X-ray powder diffraction pattern as shown in FIG. 19 , when measured using the parameters described in Table 1.