Methods for making and using endoxifen
The present disclosure provides industrially scalable methods of making (Z)-endoxifen or a salt thereof, crystalline forms of endoxifen, 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 free base of a compound of Formula (III):
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 free base of a compound of Formula (III):
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 free base of a compound of Formula (III):
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 free base of a compound of Formula (III):
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 free base of a compound of Formula (III):
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 free base of a compound of Formula (III):
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 , further comprising less than 1% (Z)-endoxifen impurities.
74 . The enteric oral formulation of claim 71 , further comprising less than 0.5% (Z)-endoxifen impurities.
75 . 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.
76 . 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.
77 . 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.
78 . 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.
79 . The enteric oral formulation of claim 71 , wherein the enteric oral formulation has a water activity (Aw) of less than 0.9.
80 . 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.
81 . 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.
82 . 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.
83 . The enteric oral formulation of claim 82 , 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.
84 . The enteric oral formulation of claim 71 , comprising 0.01 mg to 200 mg of (Z)-endoxifen.
85 . 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 free base of a compound of Formula (III):
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.
86 . The method of claim 85 , wherein the enteric oral formulation has an aerobic bacterial plate count of not more than 20,000 g/mL.
87 . The method of claim 85 , wherein the enteric oral formulation has a water content of not more than 1.0% as tested by Method Ic of USP 921.
88 . The method of claim 85 , wherein the enteric oral formulation has a water activity (Aw) of less than 0.9.
89 . The method of claim 85 , wherein the enteric oral formulation has a residue on ignition of not more than 0.1% as tested by a method of USP 281.
90 . The method of claim 85 , wherein the enteric oral formulation has a heavy metal content of not more than 20 ppm as tested by Method II of USP 231.
91 . The method of claim 85 , 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.
92 . The method of claim 85 , 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.
93 . The method of claim 85 , wherein the enteric oral formulation further comprises less than 2% (Z)-endoxifen impurities.
94 . The method of claim 85 , wherein the enteric oral formulation further comprises less than 1% (Z)-endoxifen impurities.
95 . The method of claim 85 , wherein the enteric oral formulation further comprises less than 0.5% (Z)-endoxifen impurities.
96 . The method of claim 85 , wherein the (Z)-endoxifen is stable for at least 9 months at 5° C. and 25° C. at 60% relative humidity.
97 . The method of claim 85 , wherein the (Z)-endoxifen is stable for at least 3 months at 40° C. at 75% relative humidity.
98 . The method of claim 85 , 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.
99 . The method of claim 98 , 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.
100 . The method of claim 85 , wherein the enteric oral formulation comprises 0.01 mg to 200 mg of (Z)-endoxifen.