CRYSTAL FORMS OF AMINO LIPIDS

• US 20200131116A1
• Filed: 03/15/2018
• Published: 04/30/2020
• Est. Priority Date: 03/15/2017
• Status: Active Grant

• Current Assignee: Moderna TX, Inc. (Moderna, Inc.)
• Original Assignee: Moderna TX, Inc. (Moderna, Inc.)
• Inventors: ALMARSSON, Orn, CHEUNG, Eugene
• Granted Patent: US 11,203,569 B2
• Time in Patent Office: Days
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07C 227/16 by reactions not involving the amino or carboxyl groups
• CPC Class Codes: C07C 229/12 to carbon atoms of acyclic carbon skeletons
• CPC Class Codes: C07C 229/16 to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
• CPC Class Codes: C07C 229/24 having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
• CPC Class Codes: C07C 55/07 Salts thereof
• CPC Class Codes: C07C 65/03 monocyclic and having all hydroxy or O-metal groups bound to the ring

Abstract

Provided herein are novel solid forms of each of four compounds: (1) heptadecan-9-yl 8-((2-hydroxyethyl)amino)octanoate (“Compound 1”), (2) heptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6-(undecyloxy)hexyl)amino)octanoate (“Compound 2”), (3) heptadecan-9-yl 8-((2-hydroxyethyl)(8-(nonyloxy)-8-oxooctyl)amino)octanoate (“Compound 3”), and (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate (“MC3”), and related compositions and methods.

Claims

1. A salt or cocrystal of heptadecan-9-yl 8-((2-hydroxyethyl)amino)octanoate (“

Compound 1”

), heptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6-(undecyloxy)hexyl)amino)octanoate (“

Compound 2”

), or heptadecan-9-yl 8-((2-hydroxyethyl)(8-(nonyloxy)-8-oxooctyl)amino)octanoate (“

Compound 3”

), the salt or cocrystal of Compound 1, 2, or 3 having a melting point of about 50°

C. or greater.

5. The salt or cocrystal of any one of the preceding claims, wherein the stoichiometry of Compound 1 and the compound is within the range of from about 1:

0.2 to 1;

5 or from about 1;

0.5 to 1;

2.

6. The salt or cocrystal of any one of the preceding claims, wherein the stoichiometry of Compound 1 and the compound is about 1:

1.

7. The salt or cocrystal of any one of the preceding claims, being an anhydrate, a solvate, or a hydrate.

8. The salt or cocrystal of any one of the preceding claims, which is 4-hydroxybenzoate of Compound 1, having an X-ray powder diffraction pattern obtained using Cu Kα

radiation, comprising two, three, or more characteristic peaks expressed in degrees 2-theta (+1-0.2) selected from the group consisting of 4.5, 6.8, 9.1, and 11.4.

9. The salt or cocrystal of claim 8, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having two, three, four, or more characteristic peaks expressed in degrees 2-theta (+/−

0.2) selected from the group consisting of 4.5, 6.8, 9.1, 11.4, and 13.7.

10. The salt or cocrystal of claim 8, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having characteristic peaks expressed in degrees 2-theta (+/−

0.2) at 4.5, 6.8, 9.1, 11.4, 13.7, 18.3, 20.1, and 20.6.

11. The salt or cocrystal of claim 8, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having at least eight characteristic peaks expressed in degrees 2-theta (+/−

0.2), selected from the group consisting of 4.5, 6.8, 9.1, 11.4, 13.7, 16.0, 18.3, 20.1, and 20.6.

12. The salt or cocrystal of claim 8, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having at least nine characteristic peaks expressed in degrees 2-theta (+/−

0.2), selected from the group consisting of 4.5, 6.8, 9.1, 11.4, 13.7, 16.0, 16.6, 18.3, 20.1, and 20.6.

13. The salt or cocrystal of claim 8, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having at least ten characteristic peaks expressed in degrees 2-theta (+/−

0.2), selected from the group consisting of 4.5, 6.8, 9.1, 11.4, 13.7, 16.0, 16.6, 18.3, 20.1, 20.6, and 21.5.

14. The salt or cocrystal of any one of the preceding claims, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having peaks with 2-theta values substantially in accordance with FIG. 1.

15. The salt or cocrystal of any one of the preceding claims, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having peaks with 2-theta values substantially in accordance with the table below.

16. The salt or cocrystal of any one of the preceding claims, wherein the salt or cocrystal exhibits a differential scanning calorimetry thermogram showing a primary endotherm expressed in units of °

C. at a temperature of 103+/−

2°

C.

17. The salt or cocrystal of claim 16, wherein the salt or cocrystal exhibits a differential scanning calorimetry thermogram showing a second primary endotherm expressed in units of °

C. at a temperature of 68+/−

2°

C.

18. The salt or cocrystal of any one of the preceding claims, wherein the salt or cocrystal exhibits a differential scanning calorimetry thermogram substantially in accordance with the DSC profile shown in FIG. 3.

19. The salt or cocrystal of any one of the preceding claims, wherein said salt or cocrystal is substantially free of impurities.

20. The salt or cocrystal of any one of the preceding claims, wherein said salt or cocrystal is a crystalline solid substantially free of other crystalline forms of the salt or cocrystal.

21. The salt or cocrystal of claim 20, wherein said other crystalline forms of the salt or cocrystal comprises Polymorph B of 4-hydroxybenzoate of Compound 1.

36. The salt or cocrystal of any one of the preceding claims, wherein the stoichiometry of Compound 3 and the compound is within the range of from about 1:

0.2 to 1;

5 or from about 1;

0.5 to 1;

2.

37. The salt or cocrystal of any one of the preceding claims, wherein the stoichiometry of Compound 3 and the compound is about 1:

1.

38. The salt or cocrystal of any one of the preceding claims, being an anhydrate, a solvate, or a hydrate.

39. The salt or cocrystal of any one of the preceding claims, which is trimesate of Compound 3, having an X-ray powder diffraction pattern obtained using Cu Kα

radiation, comprising two, three, or more characteristic peaks expressed in degrees 2-theta (+/−

0.2) selected from the group consisting of 6.2, 10.8, 16.5, and 26.7.

40. The salt or cocrystal of claim 39, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having characteristic peaks expressed in degrees 2-theta (+/−

0.2) at 6.2, 10.8, 16.5, and 26.7.

41. The salt or cocrystal of claim 39, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having at least five characteristic peaks expressed in degrees 2-theta (+/−

0.2), selected from the group consisting of 6.2, 10.8, 12.4, 16.5, 18.7, 22.5 and 26.7.

42. The salt or cocrystal of claim 39, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having at least six characteristic peaks expressed in degrees 2-theta (+/−

0.2), selected from the group consisting of 6.2, 10.8, 12.4, 16.5, 18.7, 22.5 and 26.7

43. The salt or cocrystal of any one of the preceding claims, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having peaks with 2-theta values substantially in accordance with FIG. 48.

44. The salt or cocrystal of any one of the preceding claims, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having peaks with 2-theta values substantially in accordance with the table below.

45. The salt or cocrystal of any one of the preceding claims, wherein the salt or cocrystal exhibits a differential scanning calorimetry thermogram showing a primary endotherm expressed in units of °

C. at a temperature of 305+/−

2°

C.

46. The salt or cocrystal of claim 44, wherein the salt or cocrystal exhibits a differential scanning calorimetry thermogram showing a second primary endotherm expressed in units of °

C. at a temperature of 240+/−

2°

C.

47. The salt or cocrystal of any one of the preceding claims, wherein the salt or cocrystal exhibits a differential scanning calorimetry thermogram substantially in accordance with the DSC profile shown in FIG. 49.

48. The salt or cocrystal of any one of the preceding claims, wherein said salt or cocrystal is substantially free of impurities.

49. The salt or cocrystal of any one of the preceding claims, wherein said salt or cocrystal is a crystalline solid substantially free of other crystalline forms of the salt or cocrystal.

50. The salt or cocrystal of claim 48, wherein said other crystalline forms of the salt or cocrystal comprises Polymorph A of trimesate of Compound 3.

51. A method of preparing the salt or cocrystal of any one of the preceding claims, comprising:

combining Compound 1 with a compound selected from the group consisting of 4-hydroxybenzoic acid, oxalic acid, trimellitic acid, orotic acid, trimesic acid, and sulfuric acid;

or combining Compound 2 with a compound selected from the group consisting of trimesic acid, (−

)-2,3-dibenzoyl-L-tartaric acid, 4-acetamido benzoic acid, (+)-L-tartaric acid, and methanesulfonic acid;

or combining Compound 3 with trimesic acid.

52. The method of claim 51 comprising the steps of:

a) dissolving Compound 1, Compound 2, or Compound 3 in a solvent to obtain a solution;

b) combining the compound with the solution;

c) precipitating or crystallizing the salt or cocrystal from the solution; and

d) collecting the salt or cocrystal.

53. The method of claim 52, wherein the solvent comprises an aprotic solvent.

54. The method of claim 52, wherein the solvent comprises a nonpolar aprotic solvent.

55. The method of claim 52, wherein the solvent is n-Heptane, ethyl acetate, toluene, or cyclohexane.

56. The method of any one of claims 52-55, wherein one or more of the solutions of steps a) or b) is heated.

57. The method of any one of claims 52-56, wherein the molar ratio of Compound 1, Compound 2, or Compound 3 and the compound is about 1:

1.

61. The salt or cocrystal of any one of the preceding claims, wherein the stoichiometry of MC3 and the compound is within the range of from about 1:

0.5 mol/mol to 1;

2 mol/mol.

62. The salt or cocrystal of any one of the preceding claims, wherein the stoichiometry of MC3 and the compound is about 1:

1.2 mol/mol, about 1;

1.1 mol/mol, or about 1;

1.5 mol/mol).

63. The salt or cocrystal of any one of the preceding claims, being an anhydrate, a solvate, or a hydrate.

64. The salt or cocrystal of any one of the preceding claims, having an X-ray powder diffraction pattern obtained using Cu Kα

radiation, comprising two, three, or more characteristic peaks expressed in degrees 2-theta (+/−

0.2) selected from the group consisting of 5.2, 7.8, 20.9, and 23.6.

65. The salt or cocrystal of any one of the preceding claims, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having two, three, four, or more characteristic peaks expressed in degrees 2-theta (+/−

0.2) selected from the group consisting of 5.2, 7.8, 10.4, 20.9, and 23.6.

66. The salt or cocrystal of any one of the preceding claims, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta (+/−

0.2) at 5.2, 7.8, 10.4, 18.3, 20.9, 23.6, and 26.2.

67. The salt or cocrystal of any one of the preceding claims, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having at least seven characteristic peaks expressed in degrees 2-theta (+/−

0.2), selected from the group consisting of 5.2, 7.8, 9.7, 10.4, 18.3, 20.9, 23.6, and 26.2.

68. The salt or cocrystal of any one of the preceding claims, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having at least nine characteristic peaks expressed in degrees 2-theta (+/−

0.2), selected from the group consisting of 5.2, 7.8, 9.7, 10.4, 11.5, 13.0, 18.3, 20.9, 23.6, and 26.2.

69. The salt or cocrystal any one of the preceding claims, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having peaks with 2-theta values substantially in accordance with FIG. 52.

70. The salt or cocrystal of any one of the preceding claims, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having peaks with 2-theta values substantially in accordance with the table below.

71. The salt or cocrystal any one of the preceding claims, wherein the salt or cocrystal exhibits a differential scanning calorimetry thermogram showing a primary endotherm expressed in units of °

C. at a temperature of 184+/−

2°

C.

72. The salt or cocrystal of any one of the preceding claims, wherein the salt or cocrystal exhibits a differential scanning calorimetry thermogram showing a primary endotherm expressed in units of °

C. at a temperature of 186+/−

2°

C.

73. The salt or cocrystal of claim 72, wherein the salt or cocrystal exhibits a differential scanning calorimetry thermogram showing a second primary endotherm expressed in units of °

C. at a temperature of 90+/−

2°

C.

74. The salt or cocrystal of any one of the preceding claims, wherein the salt or cocrystal exhibits a differential scanning calorimetry thermogram substantially in accordance with the DSC profile shown in FIG. 53.

75. The salt or cocrystal any one of the preceding claims, wherein the salt or cocrystal exhibits a differential scanning calorimetry thermogram substantially in accordance with the DSC profile shown in FIG. 54.

76. The salt or cocrystal of any one of the preceding claims, having an X-ray powder diffraction pattern obtained using Cu Kα

radiation, comprising two, three, or more characteristic peaks expressed in degrees 2-theta (+/−

0.2) selected from the group consisting of 4.8, 19.4, 24.3, and 26.8.

77. The salt or cocrystal of any one of the preceding claims, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having two, three, four, or more characteristic peaks expressed in degrees 2-theta (+/−

0.2) selected from the group consisting of 4.8, 19.4, 24.3, 26.8, and 29.3.

78. The salt or cocrystal of any one of the preceding claims, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having two, three, four, or more characteristic peaks expressed in degrees 2-theta (+/−

0.2) selected from the group consisting of 4.8, 5.4, 7.2, 9.7, 19.4, 24.3, 26.8, and 29.3.

79. The salt or cocrystal of any one of the preceding claims, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having characteristic peaks expressed in degrees 2-theta (+/−

0.2) at 4.8, 5.4, 7.2, 9.7, 19.4, 24.3, 26.8, and 29.3.

80. The salt or cocrystal of any one of the preceding claims, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having at least seven characteristic peaks expressed in degrees 2-theta (+/−

0.2), selected from the group consisting of 4.8, 5.4, 7.2, 9.7, 12.1, 19.4, 21.9, 24.3, 26.8, and 29.3.

81. The salt or cocrystal of any one of the preceding claims, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having at least nine characteristic peaks expressed in degrees 2-theta (+1-0.2), selected from the group consisting of 4.8, 5.4, 7.2, 9.7, 12.1, 14.5, 17.0, 19.4, 21.9, 24.3, 26.8, 29.3, and 31.8.

82. The salt or cocrystal any one of the preceding claims, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having peaks with 2-theta values substantially in accordance with FIG. 59.

83. The salt or cocrystal any one of the preceding claims, wherein the salt or cocrystal exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having peaks with 2-theta values substantially in accordance with the table below.

84. The salt or cocrystal any one of the preceding claims, wherein the salt or cocrystal exhibits a differential scanning calorimetry thermogram substantially in accordance with the DSC profile shown in FIG. 60.

85. The salt or cocrystal of any one of the preceding claims, wherein said salt or cocrystal is substantially free of impurities.

86. The salt or cocrystal of any one of the preceding claims, wherein said salt or cocrystal is a crystalline solid substantially free of other crystalline forms of the salt or cocrystal.

87. The salt or cocrystal of claim 86, wherein said other crystalline forms of the salt or cocrystal comprises Polymorph B of trimesate of MC3.

88. The salt or cocrystal of claim 86, wherein said other crystalline forms of the salt or cocrystal comprises Polymorph A of trimesate of MC3.

89. A method of preparing the salt or cocrystal of any one of the preceding claims, comprising:

combining MC3 with trimesic acid.

90. The method of claim 89, comprising the steps of:

a) combining MC 3 with trimesic acid;

b) dissolving the combination of MC3 and trimesic acid in a solvent to obtain a solution;

c) precipitating or crystallizing the salt or cocrystal from the solution; and

d) collecting the salt or cocrystal.

91. The method of claim 90, wherein the solvent comprises an aprotic solvent.

92. The method of claim 90, wherein the solvent comprises a nonpolar aprotic solvent.

93. The method of claim 90, wherein the solvent is ethyl acetate, toluene, or cyclohexane.

94. The method of any one of claims 90-93, wherein one or more of the solutions of steps a) or b) is heated.

2. A salt or cocrystal of heptadecan-9-yl 8-((2-hydroxyethyl)amino)octanoate (“

Compound 1”

) and a compound selected from the group consisting of 4-hydroxybenzoic acid, oxalic acid, trimellitic acid, orotic acid, trimesic acid, and sulfuric acid.

3. The salt or cocrystal of claim 2, wherein the compound is 4-hydroxybenzoic acid.

4. The salt or cocrystal of claim 2, wherein the compound is oxalic acid.

22. A salt or cocrystal of heptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6-(undecyloxy)hexyl)amino)octanoate (“

Compound 2”

) and a compound selected from the group consisting of trimesic acid, (−

)-2,3-dibenzoyl-L-tartaric acid, 4-acetamido benzoic acid, (+)-L-tartaric acid, and methanesulfonic acid.

23. The salt or cocrystal of claim 22, wherein the stoichiometry of Compound 2 and the compound is within the range of from about 1:

0.2 mol/mol to 1;

5 mol/mol or from about 1;

0.5 mol/mol to 1;

2 mol/mol.

24. The salt or cocrystal of claim 22, wherein the stoichiometry of Compound 2 and the compound is about 1:

1 mol/mol.

25. The salt or cocrystal of any one of claims 22-24, being an anhydrate, a solvate or a hydrate.

26. The salt or cocrystal of any one of claims 22-25, which exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having peaks with 2-theta values substantially in accordance with FIG. 36, 38, 40, 42, or 44.

27. The salt or cocrystal of any one of claims 22-26, wherein the salt or cocrystal exhibits a differential scanning calorimetry thermogram substantially in accordance with the DSC profile shown in FIG. 37, 39, 41, 43, or 45.

28. A salt or cocrystal of heptadecan-9-yl 8-((2-hydroxyethyl)(8-(nonyloxy)-8-oxooctyl)amino)octanoate (“

Compound 3”

) and trimesic acid.

29. The salt or cocrystal of claim 28, wherein the stoichiometry of Compound 3 and the compound is within the range of from about 1:

0.2 mol/mol to 1;

5 mol/mol or from about 1;

0.5 mol/mol to 1;

2 mol/mol.

30. The salt or cocrystal of claim 28, wherein the stoichiometry of Compound 3 and the compound is about 1:

1 mol/mol.

31. The salt or cocrystal of any one of claims 28-30, being an anhydrate.

32. The salt or cocrystal of any one of claims 28-31, which exhibits an X-ray powder diffraction pattern obtained using Cu Kα

radiation, having peaks with 2-theta values substantially in accordance with FIG. 46.

33. The salt or cocrystal of any one of claims 28-32, wherein the salt or cocrystal exhibits a differential scanning calorimetry thermogram substantially in accordance with the DSC profile shown in FIG. 47.

34. A salt or cocrystal of heptadecan-9-yl 8-((2-hydroxyethyl)(8-(nonyloxy)-8-oxooctyl)amino)octanoate (“

Compound 3”

), the salt or cocrystal of Compound 3 having a melting point of about 300°

C. or greater.

35. A salt or cocrystal of heptadecan-9-yl 8-((2-hydroxyethyl)(8-(nonyloxy)-8-oxooctyl)amino)octanoate (“

Compound 3”

) and trimesic acid.

58. A salt or cocrystal of (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate (“

MC3”

), the salt or cocrystal of MC3 having a melting point of about 50°

C. or greater.

59. The salt or cocrystal of claim 58, having a melting point of 180°

C. or greater.

60. A salt or cocrystal of (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate (“

MC3”

) and trimesic acid.