Salts and polymorphs of SCY-078

Patent metadata

Field	Value
Publication number	US-10174074-B2
Application number	US-201614995593-A
Country	US
Kind code	B2
Filing date	Jan 14, 2016
Priority date	Jan 19, 2015
Publication date	Jan 8, 2019
Grant date	Jan 8, 2019

Abstract

SCY-078 is a glucan synthase inhibitor with antimicrobial activity. Novel salts and polymorph forms of SCY-078 are disclosed herein. The disclosure also relates to pharmaceutical compositions, methods of use, and methods of preparing the novel salts and polymorphs of SCY-078.

First claim

The invention claimed is:

1. A pharmaceutically acceptable salt of compound 1:

wherein the salt is selected from citrate, hippurate, mesylate, and fumarate, and wherein the pharmaceutically acceptable salt of compound 1 has a water sorption of from 2% to 7% at 25° C. and 80% relative humidity as determined by DVS.

2. The salt of claim 1 , wherein the pharmaceutically acceptable salt of compound 1 has a water sorption of from 3% to 7% at 25° C. and 80% relative humidity as determined by DVS.

3. The salt of claim 1 , wherein the pharmaceutically acceptable salt of compound 1 has a water sorption of from 6% to 7% at 25° C. and 80% relative humidity as determined by DVS.

4. A citrate salt of compound 1:

wherein the citrate salt of compound 1 comprises at least one of Type A, Type B, Type E, Type F, Type M, Type N, Type O, Type Q, Type R, and Type S citrate crystal forms.

5. The citrate salt of claim 4 , wherein the citrate salt of compound 1 comprises Type A.

6. The citrate salt of claim 4 , wherein the citrate salt of compound 1 consists essentially of Type A.

7. The citrate salt of claim 4 , wherein the citrate salt of compound 1 comprises at least 98% Type A.

8. The citrate salt of claim 4 , wherein the citrate salt of compound 1 comprises at least 99% Type A.

9. The citrate salt of claim 5 , wherein the Type A has an XRPD pattern comprising peaks at d-spacings of 11.86, 7.70, 7.09, 6.71, 5.90, and 5.29 Angstroms.

10. The citrate salt of claim 5 , wherein the Type A has an XRPD pattern comprising peaks at degrees 2 theta of 7.45, 11.49, 12.49, 13.19, 15.02, and 16.75.

11. The citrate salt of claim 5 , wherein the Type A is stable for at least 1 week when stored at 60° C.

12. The citrate salt of claim 5 , wherein the Type A is stable for at least 1 week when stored at 25° C. and 60% relative humidity.

13. The citrate salt of claim 5 , wherein the Type A is stable for at least 1 week when stored at 40° C. and 75% relative humidity.

14. The citrate salt of claim 5 , wherein the Type A has an equilibrium solubility of 38 mg/mL in non-buffered water at room temperature.

15. The citrate salt of claim 5 , wherein the Type A has an approximate solubility of from 40 mg/mL to 42 mg/mL at room temperature in at least one solvent selected from methanol, isopropyl alcohol, acetic acid, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, n-methyl-2-pyrrolidone, dimethyl sulfoxide, and dimethylacetamide.

16. The citrate salt of claim 5 , wherein the Type A has a kinetic solubility of 4 mg/mL at 4 hours in dextrose buffer at pH 5.5.

17. The citrate salt of claim 5 , wherein the Type A has a kinetic solubility of 8 mg/mL at 24 hours in dextrose buffer at pH 5.5.

18. The citrate salt of claim 5 , wherein the Type A has a kinetic solubility of 5 mg/mL at 4 hours in phosphate buffer at pH 6.0.

19. The citrate salt of claim 5 , wherein the Type A has a kinetic solubility of 8 mg/mL at 24 hours in phosphate buffer at pH 6.0.

20. The citrate salt of claim 5 , wherein the Type A has a kinetic solubility of 21 mg/mL at 1 hour in SGF media.

21. The citrate salt of claim 5 , wherein the Type A has a kinetic solubility of 4 mg/mL at 24 hours in FeSSIF media.

22. The citrate salt of claim 5 , wherein the Type A has a kinetic solubility of 10 mg/mL at 1 hour in FaSSIF media.

23. The citrate salt of claim 5 , wherein the Type A has a kinetic solubility of 21 mg/mL at 4 hours in FaSSIF media.

24. The citrate salt of claim 5 , wherein the Type A has a water sorption of 6% at 25° C. and 80% relative humidity as determined by DVS.

25. A pharmaceutical composition comprising the pharmaceutically acceptable salt of claim 4 and a pharmaceutically acceptable carrier.

26. A method of preparing a pharmaceutical composition for injection, comprising dissolving the pharmaceutically acceptable salt of claim 1 in a pharmaceutically acceptable carrier.

27. The method of claim 26 , wherein the step of dissolving the pharmaceutically acceptable salt in the pharmaceutically acceptable carrier takes less than 24 hours.

28. A pharmaceutical composition made by dissolving the pharmaceutically acceptable salt of claim 4 in a pharmaceutically acceptable carrier.

29. The pharmaceutical composition of claim 28 , wherein the pharmaceutical composition is suitable for injection into a human.

30. The pharmaceutical composition of claim 28 , wherein the pharmaceutical composition is suitable for intravenous injection into a human.

31. A pharmaceutically acceptable salt of compound 1:

wherein when:
(a) 15 mg of the pharmaceutically acceptable salt of compound 1 is placed into a 4 mL plastic centrifuge tube along with 1.7 mL of dextrose buffer at pH 5.5,
(b) the tube is capped,
(c) the tube is stirred on a rolling incubator at 25 rpm at room temperature for 24 hours,
(d) at 24 hours, a 0.5 mL aliquot is taken from the tube and centrifuged, and
(e) resulting supernatant is filtered through a 0.45 μm centrifuge filtration tube at 8,000 rpm at room temperature for 30 minutes,
the filtered resulting supernatant contains compound 1 at a concentration of at least 2 mg/mL.

32. The salt of claim 31 , wherein the filtered resulting supernatant contains compound 1 at a concentration of at least 4 mg/mL.

33. The salt of claim 31 , wherein the filtered resulting supernatant contains compound 1 at a concentration of at least 8 mg/mL.

34. A pharmaceutically acceptable salt of compound 1:

wherein when:
(a) 15 mg of the pharmaceutically acceptable salt of compound 1 is placed into a 4 mL plastic centrifuge tube along with 1.7 mL of dextrose buffer at pH 5.5,
(b) the tube is capped,
(c) the tube is stirred on a rolling incubator at 25 rpm at room temperature for 24 hours,
(d) at 24 hours, a 0.5 mL aliquot is taken from the tube and centrifuged, and
(e) resulting supernatant is filtered through a 0.45 μm centrifuge filtration tube at 8,000 rpm at room temperature for 30 minutes,
the filtered resulting supernatant contains compound 1 at a concentration of from 2 mg/mL to 9 mg/mL.

35. The salt of claim 34 , wherein the filtered resulting supernatant contains compound 1 at a concentration of from 4 mg/mL to 9 mg/mL.

36. The salt of claim 34 , wherein the filtered resulting supernatant contains compound 1 at a concentration of from 8 mg/mL to 9 mg/mL.

37. A pharmaceutically acceptable salt of compound 1:

wherein when:
(a) 15 mg of the pharmaceutically acceptable salt of compound 1 is placed into a 4 mL plastic centrifuge tube along with 1.7 mL of dextrose buffer at pH 5.5,
(b) the tube is

Assignees

• Zhang Yi
• Scynexis Inc

Inventors

• Zhang Yi

Classifications

• A61P31/10

  Antimycotics · CPC title

• C07C59/265

  Citric acid · CPC title

• C07J71/0005 Primary

  Oxygen-containing hetero ring · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title