Claims for Patent: 10,174,074

Summary for Patent: 10,174,074

Title:	Salts and polymorphs of SCY-078
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.
Inventor(s):	Zhang; Yi (Suzhou, CN)
Assignee:	SCYNEXIS, INC. (Research Triangle Park, NC)
Application Number:	14/995,593
Patent Claims:	1. A pharmaceutically acceptable salt of compound 1: ##STR00003## 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.degree. 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.degree. 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.degree. C. and 80% relative humidity as determined by DVS. 4. A citrate salt of compound 1: ##STR00004## 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.degree. C. 12. The citrate salt of claim 5, wherein the Type A is stable for at least 1 week when stored at 25.degree. 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.degree. 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.degree. 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: ##STR00005## 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 .mu.m 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: ##STR00006## 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 .mu.m 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: ##STR00007## 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 4 hours, (d) at 4 hours, a 0.5 mL aliquot is taken from the tube and centrifuged, and (e) resulting supernatant is filtered through a 0.45 .mu.m 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. 38. The salt of claim 37, wherein the filtered resulting supernatant contains compound 1 at a concentration of at least 4 mg/mL. 39. A pharmaceutically acceptable salt of compound 1: ##STR00008## 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 4 hours, (d) at 4 hours, a 0.5 mL aliquot is taken from the tube and centrifuged, and (e) resulting supernatant is filtered through a 0.45 .mu.m 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 5 mg/mL. 40. The salt of claim 39, wherein the filtered resulting supernatant contains compound 1 at a concentration of from 4 mg/mL to 5 mg/mL. 41. A pharmaceutically acceptable salt of compound 1: ##STR00009## 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 phosphate buffer at pH 6.0, (b) the tube is capped, (c) the tube is stirred on a rolling incubator at 25 rpm at room temperature for 4 hours, (d) at 4 hours, a 0.5 mL aliquot is taken from the tube and centrifuged, and (e) resulting supernatant is filtered through a 0.45 .mu.m 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. 42. The salt of claim 41, wherein the filtered resulting supernatant contains compound 1 at a concentration of at least 4 mg/mL. 43. A pharmaceutically acceptable salt of compound 1: ##STR00010## 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 phosphate buffer at pH 6.0, (b) the tube is capped, (c) the tube is stirred on a rolling incubator at 25 rpm at room temperature for 4 hours, (d) at 4 hours, a 0.5 mL aliquot is taken from the tube and centrifuged, and (e) resulting supernatant is filtered through a 0.45 .mu.m 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 5 mg/mL. 44. The salt of claim 43, wherein the filtered resulting supernatant contains compound 1 at a concentration of from 4 mg/mL to 5 mg/mL. 45. A pharmaceutically acceptable salt of compound 1: ##STR00011## 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 phosphate buffer at pH 6.0, (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 .mu.m 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 4.5 mg/mL. 46. The salt of claim 45, wherein the filtered resulting supernatant contains compound 1 at a concentration of at least 7 mg/mL. 47. A pharmaceutically acceptable salt of compound 1: ##STR00012## 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 phosphate buffer at pH 6.0, (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 .mu.m 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 4.5 mg/mL to 8 mg/mL. 48. The salt of claim 47, wherein the filtered resulting supernatant contains compound 1 at a concentration of from 7 mg/mL to 8 mg/mL. 49. A pharmaceutically acceptable salt of compound 1: ##STR00013## wherein when: (a) 50 mg of the pharmaceutically acceptable salt of compound 1 is placed into a 4 mL plastic centrifuge tube along with 1.7 mL of SGF media, (b) the tube is capped, (c) the tube is stirred on a rolling incubator at 25 rpm at room temperature for 1 hour, (d) at 1 hour, a 0.5 mL aliquot is taken from the tube and centrifuged, and (e) resulting supernatant is filtered through a 0.45 .mu.m 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 16 mg/mL. 50. The salt of claim 49, wherein the filtered resulting supernatant contains compound 1 at a concentration of at least 17 mg/mL. 51. The salt of claim 49, wherein the filtered resulting supernatant contains compound 1 at a concentration of at least 18 mg/mL. 52. The salt of claim 49, wherein the filtered resulting supernatant contains compound 1 at a concentration of at least 20 mg/mL. 53. A pharmaceutically acceptable salt of compound 1: ##STR00014## wherein when: (a) 50 mg of the pharmaceutically acceptable salt of compound 1 is placed into a 4 mL plastic centrifuge tube along with 1.7 mL of SGF media, (b) the tube is capped, (c) the tube is stirred on a rolling incubator at 25 rpm at room temperature for 1 hour, (d) at 1 hour, a 0.5 mL aliquot is taken from the tube and centrifuged, and (e) resulting supernatant is filtered through a 0.45 .mu.m 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 17 mg/mL to 21 mg/mL. 54. The salt of claim 53, wherein the filtered resulting supernatant contains compound 1 at a concentration of from 18 mg/mL to 21 mg/mL. 55. The salt of claim 53, wherein the filtered resulting supernatant contains compound 1 at a concentration of from 20 mg/mL to 21 mg/mL. 56. A pharmaceutically acceptable salt of compound 1: ##STR00015## wherein when: (a) 50 mg of the pharmaceutically acceptable salt of compound 1 is placed into a 4 mL plastic centrifuge tube along with 1.7 mL of FaSSIF media, (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 .mu.m 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 17 mg/mL. 57. The salt of claim 56, wherein the filtered resulting supernatant contains compound 1 at a concentration of at least 22 mg/mL. 58. A pharmaceutically acceptable salt of compound 1: ##STR00016## wherein when: (a) 50 mg of the pharmaceutically acceptable salt of compound 1 is placed into a 4 mL plastic centrifuge tube along with 1.7 mL of FaSSIF media, (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 .mu.m 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 17 mg/mL to 22 mg/mL. 59. The salt of claim 58, wherein the filtered resulting supernatant contains compound 1 at a concentration of from 21 mg/mL to 22 mg/mL. 60. A pharmaceutically acceptable salt according to any of claims 31, 34, 37, 39, 41, 43, 45, 47, 49, 53, 56, and 58 having a water sorption of not greater than 7% at 25.degree. C. and 80% relative humidity as determined by DVS. 61. A pharmaceutically acceptable salt according to claim 60 having a water sorption of from 2% to 7% at 25.degree. C. and 80% relative humidity as determined by DVS. 62. The salt of claim 61, wherein the water sorption is from 3% to 7% at 25.degree. C. and 80% relative humidity as determined by DVS. 63. The salt of claim 61, wherein the water sorption is from 6% to 7% at 25.degree. C. and 80% relative humidity as determined by DVS. 64. The citrate salt of claim 5, wherein the Type A has an XRPD pattern comprising peaks at d-spacings of 11.86, 6.71, and 5.90 Angstroms. 65. The citrate salt of claim 5, wherein the Type A has an XRPD pattern comprising peaks at degrees 2 theta of 7.45, 13.19, and 15.02. 66. A pharmaceutically acceptable salt according to any of claims 31, 34, 37, 39, 41, 43, 45, 47, 49, 53, 56, and 58, wherein the salt is selected from citrate, hippurate, mesylate, and fumarate. 67. A pharmaceutically acceptable salt according to any of claims 31, 34, 37, 39, 41, 43, 45, 47, 49, 53, 56, and 58, wherein the pharmaceutically acceptable salt of compound 1 has a chemical purity of at least 99%. 68. A method of preparing a pharmaceutical composition for injection, comprising dissolving the pharmaceutically acceptable salt of claim 4 in a pharmaceutically acceptable carrier. 69. The method of claim 68, wherein the step of dissolving the pharmaceutically acceptable salt in the pharmaceutically acceptable carrier takes less than 24 hours. 70. A method of preparing a pharmaceutical composition for injection, comprising dissolving the pharmaceutically acceptable salt of claim 31 in a pharmaceutically acceptable carrier. 71. The method of claim 70, wherein the step of dissolving the pharmaceutically acceptable salt in the pharmaceutically acceptable carrier takes less than 24 hours. 72. A pharmaceutical composition comprising the pharmaceutically acceptable salt of claim 1 and a pharmaceutically acceptable carrier. 73. A method of preparing a pharmaceutical composition, comprising combining the pharmaceutically acceptable salt of claim 1 and a pharmaceutically acceptable carrier. 74. A pharmaceutical composition made by a process comprising combining the pharmaceutically acceptable salt of claim 1 and a pharmaceutically acceptable carrier. 75. A pharmaceutical composition comprising the pharmaceutically acceptable salt of claim 5 and a pharmaceutically acceptable carrier. 76. A pharmaceutical composition made by a process comprising dissolving the pharmaceutically acceptable salt of claim 5 in a pharmaceutically acceptable carrier. 77. A method of preparing a pharmaceutical composition, comprising combining the pharmaceutically acceptable salt of claim 5 and a pharmaceutically acceptable carrier. 78. A pharmaceutical composition made by a process comprising combining the pharmaceutically acceptable salt of claim 5 and a pharmaceutically acceptable carrier.