Methods for making and using endoxifen
The present disclosure provides industrially scalable methods of making (Z)-endoxifen or a salt thereof, crystalline forms of endoxifin, and compositions comprising them. The present disclosure also provides methods for treating hormone-dependent breast and hormone-dependent reproductive tract disorders.
1. An enteric oral formulation comprising a compound of Formula (III):
or a pharmaceutically acceptable salt thereof,
wherein:
at least 90% by weight of the compound of Formula (III) is (Z)-endoxifen; and
the enteric oral formulation has an aerobic bacterial plate count of not more than 20,000 g/mL.
2. The enteric oral formulation of claim 1 , further comprising less than 2% (Z)-endoxifen impurities.
3. The enteric oral formulation of claim 1 , further comprising less than 1% (Z)-endoxifen impurities.
4. The enteric oral formulation of claim 1 , further comprising less than 0.5% (Z)-endoxifen impurities.
5. The enteric oral formulation of claim 1 , wherein the (Z)-endoxifen is stable for at least 9 months at 5° C. and 25° C. at 60% relative humidity.
6. The enteric oral formulation of claim 1 , wherein the (Z)-endoxifen is stable for at least 3 months at 40° C. at 75% relative humidity.
7. The enteric oral formulation of claim 1 , wherein the enteric oral formulation has a water content of not more than 1.0% as tested by Method Ic of USP 921.
8. The enteric oral formulation of claim 1 , wherein the enteric oral formulation has a water activity (Aw) of less than 0.9.
9. The enteric oral formulation of claim 1 , wherein the enteric oral formulation has a residue on ignition of not more than 0.1% as tested by a method of USP 281.
10. The enteric oral formulation of claim 1 , wherein the enteric oral formulation has a heavy metal content of not more than 20 ppm as tested by Method II of USP 231.
11. The enteric oral formulation of claim 1 , wherein the enteric oral formulation has: a methanol content of not more than 3000 ppm; a tetrahydrofuran content of not more than 720 ppm; an isopropanol content of not more than 5000 ppm; an ethyl acetate content of not more than 5000 ppm; a n-Heptane content of not more than 5000 ppm; and an ethanol content of not more than 5000 ppm, as tested by a validated HPLC method.
12. The enteric oral formulation of claim 1 , wherein the compound of Formula (III) is in a crystalline form which is Form I, characterized by an x-ray powder diffraction pattern comprising major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3° two theta.
13. The enteric oral formulation of claim 12 , wherein the x-ray powder diffraction pattern further comprises at least one peak selected from 16.0±0.3°, 18.8±0.3° and 26.5±0.3° two theta.
14. The enteric oral formulation of claim 1 , comprising 0.01 mg to 200 mg of (Z)-endoxifen.
15. An enteric oral formulation comprising a compound of Formula (III):
or a pharmaceutically acceptable salt thereof,
wherein:
at least 90% by weight of the compound of Formula (III) is (Z)-endoxifen; and
the enteric oral formulation has a water content of not more than 1.0% as tested by Method Ic of USP 921.
16. The enteric oral formulation of claim 15 , further comprising less than 2% (Z)-endoxifen impurities.
17. The enteric oral formulation of claim 15 , further comprising less than 1% (Z)-endoxifen impurities.
18. The enteric oral formulation of claim 15 , further comprising less than 0.5% (Z)-endoxifen impurities.
19. The enteric oral formulation of claim 15 , wherein the (Z)-endoxifen is stable for at least 9 months at 5° C. and 25° C. at 60% relative humidity.
20. The enteric oral formulation of claim 15 , wherein the (Z)-endoxifen is stable for at least 3 months at 40° C. at 75% relative humidity.
21. The enteric oral formulation of claim 15 , wherein the enteric oral formulation has an aerobic bacterial plate count of not more than 20,000 g/mL.
22. The enteric oral formulation of claim 15 , wherein the enteric oral formulation has a water activity (Aw) of less than 0.9.
23. The enteric oral formulation of claim 15 , wherein the enteric oral formulation has a residue on ignition of not more than 0.1% as tested by a method of USP 281.
24. The enteric oral formulation of claim 15 , wherein the enteric oral formulation has a heavy metal content of not more than 20 ppm as tested by Method II of USP 231.
25. The enteric oral formulation of claim 15 , wherein the enteric oral formulation has: a methanol content of not more than 3000 ppm; a tetrahydrofuran content of not more than 720 ppm; an isopropanol content of not more than 5000 ppm; an ethyl acetate content of not more than 5000 ppm; a n-Heptane content of not more than 5000 ppm; and an ethanol content of not more than 5000 ppm, as tested by a validated HPLC method.
26. The enteric oral formulation of claim 15 , wherein the compound of Formula (III) is in a crystalline form which is Form I, characterized by an x-ray powder diffraction pattern comprising major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3° two theta.
27. The enteric oral formulation of claim 26 , wherein the x-ray powder diffraction pattern further comprises at least one peak selected from 16.0±0.3°, 18.8±0.3° and 26.5±0.3° two theta.
28. The enteric oral formulation of claim 15 , comprising 0.01 mg to 200 mg of (Z)-endoxifen.
29. An enteric oral formulation comprising a compound of Formula (III):
or a pharmaceutically acceptable salt thereof,
wherein:
at least 90% by weight of the compound of Formula (III) is (Z)-endoxifen; and
the enteric oral formulation has a water activity (Aw) of less than 0.9.
30. The enteric oral formulation of claim 29 , further comprising less than 2% (Z)-endoxifen impurities.
31. The enteric oral formulation of claim 29 , further comprising less than 1% (Z)-endoxifen impurities.
32. The enteric oral formulation of claim 29 , further comprising less than 0.5% (Z)-endoxifen impurities.
33. The enteric oral formulation of claim 29 , wherein the (Z)-endoxifen is stable for at least 9 months at 5° C. and 25° C. at 60% relative humidity.
34. The enteric oral formulation of claim 29 , wherein the (Z)-endoxifen is stable for at least 3 months at 40° C. at 75% relative humidity.
35. The enteric oral formulation of claim 29 , wherein the enteric oral formulation has an aerobic bacterial plate count of not more than 20,000 g/mL.
36. The enteric oral formulation of claim 29 , wherein the enteric oral formulation has a water content of not more than 1.0% as tested by Method Ic of USP 921.
37. The enteric oral formulation of claim 29 , wherein the enteric oral formulation has a residue on ignition of not more than 0.1% as tested by a method of USP 281.
38. The enteric oral formulation of claim 29 , wherein the enteric oral formulation has a heavy metal content of not more than 20 ppm as tested by Method II of USP 231.
39. The enteric oral formulation of claim 29 , wherein the enteric oral formulation has: a methanol content of not more than 3000 ppm; a tetrahydrofuran content of not more than 720 ppm; an isopropanol content of not more than 5000 ppm; an ethyl acetate content of not more than 5000 ppm; a n-Heptane content of not more than 5000 ppm; and an ethanol content of not more than 5000 ppm, as tested by a validated HPLC method.
40. The enteric oral formulation of claim 29 , wherein the compound of Formula (III) is in a crystalline form which is Form I, characterized by an x-ray powder diffraction pattern comprising major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3° two theta.
41. The enteric oral formulation of claim 40 , wherein the x-ray powder diffraction pattern further comprises at least one peak selected from 16.0±0.3°, 18.8±0.3° and 26.5±0.3° two theta.
42. The enteric oral formulation of claim 29 , comprising 0.01 mg to 200 mg of (Z)-endoxifen.
43. An enteric oral formulation comprising a compound of Formula (III):
or a pharmaceutically acceptable salt thereof,
wherein:
at least 90% by weight of the compound of Formula (III) is (Z)-endoxifen; and
the enteric oral formulation has a residue on ignition of not more than 0.1% as tested by a method of USP 281.
44. The enteric oral formulation of claim 43 , further comprising less than 2% (Z)-endoxifen impurities.
45. The enteric oral formulation of claim 43 , further comprising less than 1% (Z)-endoxifen impurities.
46. The enteric oral formulation of claim 43 , further comprising less than 0.5% (Z)-endoxifen impurities.
47. The enteric oral formulation of claim 43 , wherein the (Z)-endoxifen is stable for at least 9 months at 5° C. and 25° C. at 60% relative humidity.
48. The enteric oral formulation of claim 43 , wherein the (Z)-endoxifen is stable for at least 3 months at 40° C. at 75% relative humidity.
49. The enteric oral formulation of claim 43 , wherein the enteric oral formulation has an aerobic bacterial plate count of not more than 20,000 g/mL.
50. The enteric oral formulation of claim 43 , wherein the enteric oral formulation has a water content of not more than 1.0% as tested by Method Ic of USP 921.
51. The enteric oral formulation of claim 43 , wherein the enteric oral formulation has a water activity (Aw) of less than 0.9.
52. The enteric oral formulation of claim 43 , wherein the enteric oral formulation has a heavy metal content of not more than 20 ppm as tested by Method II of USP 231.
53. The enteric oral formulation of claim 43 , wherein the enteric oral formulation has: a methanol content of not more than 3000 ppm; a tetrahydrofuran content of not more than 720 ppm; an isopropanol content of not more than 5000 ppm; an ethyl acetate content of not more than 5000 ppm; a n-Heptane content of not more than 5000 ppm; and an ethanol content of not more than 5000 ppm, as tested by a validated HPLC method.
54. The enteric oral formulation of claim 43 , wherein the compound of Formula (III) is in a crystalline form which is Form I, characterized by an x-ray powder diffraction pattern comprising major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3° two theta.
55. The enteric oral formulation of claim 54 , wherein the x-ray powder diffraction pattern further comprises at least one peak selected from 16.0±0.3°, 18.8±0.3° and 26.5±0.3° two theta.
56. The enteric oral formulation of claim 43 , comprising 0.01 mg to 200 mg of (Z)-endoxifen.
57. An enteric oral formulation comprising a compound of Formula (III):
or a pharmaceutically acceptable salt thereof,
wherein:
at least 90% by weight of the compound of Formula (III) is (Z)-endoxifen; and
the enteric oral formulation has a heavy metal content of not more than 20 ppm as tested by Method II of USP 231.
58. The enteric oral formulation of claim 57 , further comprising less than 2% (Z)-endoxifen impurities.
59. The enteric oral formulation of claim 57 , further comprising less than 1% (Z)-endoxifen impurities.
60. The enteric oral formulation of claim 57 , further comprising less than 0.5% (Z)-endoxifen impurities.
61. The enteric oral formulation of claim 57 , wherein the (Z)-endoxifen is stable for at least 9 months at 5° C. and 25° C. at 60% relative humidity.
62. The enteric oral formulation of claim 57 , wherein the (Z)-endoxifen is stable for at least 3 months at 40° C. at 75% relative humidity.
63. The enteric oral formulation of claim 57 , wherein the enteric oral formulation has an aerobic bacterial plate count of not more than 20,000 g/mL.
64. The enteric oral formulation of claim 57 , wherein the enteric oral formulation has a water content of not more than 1.0% as tested by Method Ic of USP 921.
65. The enteric oral formulation of claim 57 , wherein the enteric oral formulation has a water activity (Aw) of less than 0.9.
66. The enteric oral formulation of claim 57 , wherein the enteric oral formulation has a residue on ignition of not more than 0.1% as tested by a method of USP 281.
67. The enteric oral formulation of claim 57 , wherein the enteric oral formulation has: a methanol content of not more than 3000 ppm; a tetrahydrofuran content of not more than 720 ppm; an isopropanol content of not more than 5000 ppm; an ethyl acetate content of not more than 5000 ppm; a n-Heptane content of not more than 5000 ppm; and an ethanol content of not more than 5000 ppm, as tested by a validated HPLC method.
68. The enteric oral formulation of claim 57 , wherein the compound of Formula (III) is in a crystalline form which is Form I, characterized by an x-ray powder diffraction pattern comprising major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3° two theta.
69. The enteric oral formulation of claim 68 , wherein the x-ray powder diffraction pattern further comprises at least one peak selected from 16.0±0.3°, 18.8±0.3° and 26.5±0.3° two theta.
70. The enteric oral formulation of claim 57 , comprising 0.01 mg to 200 mg of (Z)-endoxifen.
71. An enteric oral formulation comprising a compound of Formula (III):
or a pharmaceutically acceptable salt thereof,
wherein:
at least 90% by weight of the compound of Formula (III) is (Z)-endoxifen; and
the enteric oral formulation has a methanol content of not more than 3000 ppm; a tetrahydrofuran content of not more than 720 ppm; an isopropanol content of not more than 5000 ppm; an ethyl acetate content of not more than 5000 ppm; a n-Heptane content of not more than 5000 ppm; and an ethanol content of not more than 5000 ppm, as tested by a validated HPLC method.
72. The enteric oral formulation of claim 71 , further comprising less than 2% (Z)-endoxifen impurities.
73. The enteric oral formulation of claim 71 , wherein the (Z)-endoxifen is stable for at least 9 months at 5° C. and 25° C. at 60% relative humidity.
74. The enteric oral formulation of claim 71 , wherein the (Z)-endoxifen is stable for at least 3 months at 40° C. at 75% relative humidity.
75. The enteric oral formulation of claim 71 , wherein the enteric oral formulation has an aerobic bacterial plate count of not more than 20,000 g/mL.
76. The enteric oral formulation of claim 71 , wherein the enteric oral formulation has a water content of not more than 1.0% as tested by Method Ic of USP 921.
77. The enteric oral formulation of claim 71 , wherein the enteric oral formulation has a water activity (Aw) of less than 0.9.
78. The enteric oral formulation of claim 71 , wherein the enteric oral formulation has a residue on ignition of not more than 0.1% as tested by a method of USP 281.
79. The enteric oral formulation of claim 71 , wherein the enteric oral formulation has a heavy metal content of not more than 20 ppm as tested by Method II of USP 231.
80. The enteric oral formulation of claim 71 , wherein the compound of Formula (III) is in a crystalline form which is Form I, characterized by an x-ray powder diffraction pattern comprising major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3° two theta.
81. The enteric oral formulation of claim 80 , wherein the x-ray powder diffraction pattern further comprises at least one peak selected from 16.0±0.3°, 18.8±0.3° and 26.5±0.3° two theta.
82. The enteric oral formulation of claim 71 , comprising 0.01 mg to 200 mg of (Z)-endoxifen.
83. A method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an enteric oral formulation comprising a compound of Formula (III):
or a pharmaceutically acceptable salt thereof,
wherein:
at least 90% by weight of the compound of Formula (III) is (Z)-endoxifen; and
the enteric oral formulation has one or more of the following properties:
(a) an aerobic bacterial plate count of not more than 20,000 g/mL;
(b) a water content of not more than 1.0% as tested by Method Ic of USP 921;
(c) a water activity (Aw) of less than 0.9;
(d) a residue on ignition of not more than 0.1% as tested by a method of USP 281;
(e) a heavy metal content of not more than 20 ppm as tested by Method II of USP 231; and
(f) a methanol content of not more than 3000 ppm, a tetrahydrofuran content of not more than 720 ppm, an isopropanol content of not more than 5000 ppm, an ethyl acetate content of not more than 5000 ppm, a n-Heptane content of not more than 5000 ppm, and an ethanol content of not more than 5000 ppm, as tested by a validated HPLC method.
84. The method of claim 83 , wherein the enteric oral formulation has an aerobic bacterial plate count of not more than 20,000 g/mL.
85. The method of claim 83 , wherein the enteric oral formulation has a water content of not more than 1.0% as tested by Method Ic of USP 921.
86. The method of claim 83 , wherein the enteric oral formulation has a water activity (Aw) of less than 0.9.
87. The method of claim 83 , wherein the enteric oral formulation has a residue on ignition of not more than 0.1% as tested by a method of USP 281.
88. The method of claim 83 , wherein the enteric oral formulation has a heavy metal content of not more than 20 ppm as tested by Method II of USP 231.
89. The method of claim 83 , wherein the enteric oral formulation has a methanol content of not more than 3000 ppm; a tetrahydrofuran content of not more than 720 ppm; an isopropanol content of not more than 5000 ppm; an ethyl acetate content of not more than 5000 ppm; a n-Heptane content of not more than 5000 ppm; and an ethanol content of not more than 5000 ppm, as tested by a validated HPLC method.
90. The method of claim 83 , wherein the enteric oral formulation has each of the following properties:
(a) an aerobic bacterial plate count of not more than 20,000 g/mL;
(b) a water content of not more than 1.0% as tested by Method Ic of USP 921;
(c) a water activity (Aw) of less than 0.9;
(d) a residue on ignition of not more than 0.1% as tested by a method of USP 281;
(e) a heavy metal content of not more than 20 ppm as tested by Method II of USP 231; and
(f) a methanol content of not more than 3000 ppm, a tetrahydrofuran content of not more than 720 ppm, an isopropanol content of not more than 5000 ppm, an ethyl acetate content of not more than 5000 ppm, a n-Heptane content of not more than 5000 ppm, and an ethanol content of not more than 5000 ppm, as tested by a validated HPLC method.
91. The method of claim 83 , wherein the enteric oral formulation further comprises less than 2% (Z)-endoxifen impurities.
92. The method of claim 83 , wherein the enteric oral formulation further comprises less than 1% (Z)-endoxifen impurities.
93. The method of claim 83 , wherein the enteric oral formulation further comprises less than 0.5% (Z)-endoxifen impurities.
94. The method of claim 83 , wherein the (Z)-endoxifen is stable for at least 9 months at 5° C. and 25° C. at 60% relative humidity.
95. The method of claim 83 , wherein the (Z)-endoxifen is stable for at least 3 months at 40° C. at 75% relative humidity.
96. The method of claim 83 , wherein the compound of Formula (III) is in a crystalline form which is Form I, characterized by an x-ray powder diffraction pattern comprising major peaks at 16.8±0.3°, 17.1±0.3°, and 21.8±0.3° two theta.
97. The method of claim 96 , wherein the x-ray powder diffraction pattern further comprises at least one peak selected from 16.0±0.3°, 18.8±0.3° and 26.5±0.3° two theta.
98. The method of claim 83 , wherein the enteric oral formulation comprises 0.01 mg to 200 mg of (Z)-endoxifen.