Crystalline forms and compositions of CFTR modulators
Crystalline Forms of Compound I: and pharmaceutically acceptable salts thereof are disclosed. Pharmaceutical compositions comprising the same, methods of treating cystic fibrosis using the same, and methods for making the same are also disclosed.
1. Crystalline Form B of a potassium salt of Compound I:
characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 5.8±0.2, 8.2±0.2, 9.6±0.2, 10.2±0.2, 13.8±0.2, 15.1±0.2, 16.3±0.2, 17.2±0.2, and 19.1±0.2.
2. Crystalline Form B of a potassium salt of Compound I:
having a unit cell characterized by three edges of 9.0±0.2A, 11.5±0.2A, and 31.0±0.2A.
3. A method of preparing crystalline Form B of a potassium salt of Compound I of claim 1 or claim 2 , comprising reacting Compound I with a potassium base.
4. A pharmaceutical composition comprising:
(a) 50 mg to 600 mg of crystalline Form B of a potassium salt of Compound I of claim 1 or claim 2 :
(b) a first solid dispersion comprising 25 mg to 125 mg of Compound II:
and 10 wt % to 30 wt % of a polymer relative to the total weight of the first solid dispersion; and
(c) a second solid dispersion comprising 5 mg to 300 mg of Compound III or Compound III-d:
and 10 wt % to 30 wt % of a polymer relative to the total weight of the second solid dispersion.
5. The pharmaceutical composition of claim 4 , wherein the composition comprises:
(a) 15 wt % to 45 wt % of crystalline Form B of a potassium salt of Compound I of claim 1 or claim 2 relative to the total weight of the pharmaceutical composition;
(b) 5 wt % to 20 wt % of a first solid dispersion relative to the total weight of the pharmaceutical composition,
wherein the first solid dispersion comprises 70 wt % to 90 wt % of Compound II relative to the total weight of the first solid dispersion and 10 wt % to 30 wt % of a polymer relative to the total weight of the first solid dispersion; and
(c) 10 wt % to 40 wt % of a second solid dispersion relative to the total weight of the pharmaceutical composition, wherein the second solid dispersion comprises 70 wt % to 90 wt % of Compound III or Compound III-d relative to the total weight of the second solid dispersion, and 10 wt % to 30 wt % of a polymer relative to the total weight of the second solid dispersion.
6. The pharmaceutical composition of claim 4 , wherein the composition comprises:
(a) 20 wt % to 35 wt % of crystalline Form B of a potassium salt of Compound I of claim 1 or claim 2 relative to the total weight of the pharmaceutical composition;
(b) 5 wt % to 20 wt % of a first solid dispersion relative to the total weight of the pharmaceutical composition, wherein the first solid dispersion comprises 70 wt % to 90 wt % of Compound II relative to the total weight of the first solid dispersion, and 10 wt % to 30 wt % of a polymer relative to the total weight of the first solid dispersion; and
(c) 20 wt % to 40 wt % of a second solid dispersion relative to the total weight of the pharmaceutical composition, wherein the second solid dispersion comprises 70 wt % to 90 wt % of Compound III relative to the total weight of the second solid dispersion, and 10 wt % to 30 wt % of a polymer relative to the total weight of the second solid dispersion.
7. The pharmaceutical composition of claim 4 , wherein at least one of the first or second solid dispersions is a spray-dried dispersion.
8. The pharmaceutical composition of claim 4 , comprising 100 mg to 250 mg of crystalline Form B of a potassium salt of Compound I of claim 1 or claim 2 .
9. The pharmaceutical composition of claim 4 , wherein the first solid dispersion comprises 25 mg to 100 mg of Compound II.
10. The pharmaceutical composition of claim 4 , wherein the second solid dispersion comprises 25 mg to 175 mg of Compound III or Compound III-d.
11. The pharmaceutical composition of claim 4 , comprising 100 mg to 250 mg of crystalline Form B of a potassium salt of Compound I of claim 1 or claim 3 ; and wherein the first solid dispersion comprises 25 mg to 75 mg of Compound II and the second solid dispersion comprises 50 mg to 100 mg of Compound III or Compound III-d.
12. The pharmaceutical composition of claim 11 , comprising 100 mg to 150 mg of crystalline Form B of a potassium salt of Compound I of claim 1 or claim 2 , and wherein the first solid dispersion comprises 50 mg of Compound II and the second solid dispersion comprises 75 mg or 150 mg of Compound II or 100 mg of Compound III-d.
13. The pharmaceutical composition of claim 4 , wherein the composition comprises:
(a) 115 mg to 140 mg of crystalline Form B of a potassium salt of Compound I of claim 1 or claim 2 ;
(b) 60 mg to 65 mg of a first solid dispersion comprising 80 wt % Compound II relative to the total weight of the first solid dispersion, and 20 wt % of a hypromellose relative to the total weight of the first solid dispersion; and
(c) 90 mg to 95 mg of a second solid dispersion comprising 80 wt % of Compound III relative to the total weight of the second solid dispersion, 0.5 wt % of sodium lauryl sulfate relative to the total weight of the second solid dispersion, and 19.5 wt % of a hypromellose acetate succinate to the total weight of the second solid dispersion;
(d) 120 mg to 135 mg of a microcrystalline cellulose;
(e) 15 mg to 25 mg of a croscarmellose sodium; and
(f) 2 mg to 6 mg of magnesium stearate.
14. The pharmaceutical composition of claim 4 selected from:
(a)
weight % based on the
total weight of
Component
composition
crystalline Form B of a potassium salt of
20-45 wt %
Compound I of claim 1 or claim 3
solid dispersion containing 80% Compound II,
5-20 wt %
20% hypromellose
solid dispersion containing 80% Compound III,
10-30 wt %
19.5% hypromellose acetate succinate,
and 0.5% sodium lauryl sulfate
(b)
weight % based on the
total weight of
Component
composition
crystalline Form B of a potassium salt of
15-45 wt %
Compound I of claim 1 or claim 2
solid dispersion containing 80% Compound II,
5-20 wt %
20% hypromellose
solid dispersion containing 80% Compound III or
10-40 wt %
Compound III-d, 19.5% hypromellose acetate
succinate, and 0.5% sodium lauryl sulfate
microcrystalline cellulose
5-50 wt %
croscarmellose sodium (CCS)
1-10 wt %
optionally magnesium stearate in an amount of 0.01 wt %-2 wt % based on the total weight of composition
(c)
weight % based on the
total weight of
Component
composition
crystalline Form B of a potassium salt of
15-45 wt %
Compound I of claim 1 or claim 2
solid dispersion containing 80% Compound II,
5-20 wt %
20% hypromellose
solid dispersion containing 80% Compound III or
10-40 wt %
Compound III-d, 19.5% hypromellose acetate
succinate, and 0.5% sodium lauryl sulfate
microcrystalline cellulose
5-50 wt %
croscarmellose sodium (CCS)
1-10 wt %
magnesium stearate
0.05-2 wt %
(d)
weight % based on the
total weight of
Component
composition
crystalline Form B of a potassium salt of
15-35 wt %
Compound I of claim 1 or claim 2
solid dispersion containing 80% Compound II,
5-20 wt %
20% hypromellose
solid dispersion containing 80% Compound III,
20-40 wt %
19.5% hypromellose acetate succinate, and 0.5%
sodium lauryl sulfate
microcrystalline cellulose
20-40 wt %
croscarmellose sodium (CCS)
1-10 wt %
magnesium stearate
0.05-2 wt %
(e)
weight % based on the
total weight of
Component
composition
crystalline Form B of a potassium salt of
20-40 wt %
Compound I of claim 1 or claim 2
solid dispersion containing 80% Compound II,
5-20 wt %
20% hypromellose
solid dispersion containing 80% Compound III,
10-25 wt %
19.5% hypromellose acetate succinate, and 0.5%
sodium lauryl sulfate
microcrystalline cellulose
20-40 wt %
croscarmellose sodium (CCS)
1-10 wt %
magnesium stearate
0.05-2 wt %
(f)
weight % based on the
total weight of
Component
composition
crystalline Form B of a potassium salt of
25-35 wt %
Compound I of claim 1 or claim 2
solid dispersion containing 80% Compound II,
10-20 wt %
20% hypromellose
solid dispersion containing 80% Compound III,
15-25 wt %
19.5% hypromellose acetate succinate, and 0.5%
sodium lauryl sulfate
microcrystalline cellulose
25-35 wt %
croscarmellose sodium (CCS)
2-7 wt %
magnesium stearate
0.05-2 wt %
(g)
weight % based on the
total weight of
Component
composition
crystalline Form B of a potassium salt of
27-32 wt %
Compound I of claim 1 or claim 2
solid dispersion containing 80% Compound II,
12-17 wt %
20% hypromellose
solid dispersion containing 80% Compound III,
18-23 wt %
19.5% hypromellose acetate succinate, and 0.5%
sodium lauryl sulfate
microcrystalline cellulose
25-35 wt %
croscarmellose sodium (CCS)
3-6 wt %
magnesium stearate
0.05-1.5 wt %
(h)
weight % based on the
total weight of
Component
composition
crystalline Form B of a potassium salt of
25-40 wt %
Compound I of claim 1 or claim 2
solid dispersion containing 80% Compound II,
7-15 wt %
20% hypromellose
solid dispersion containing 80% Compound III-d,
15-35 wt %
19.5% hypromellose acetate succinate, and 0.5%
sodium lauryl sulfate
microcrystalline cellulose
25-35 wt %
croscarmellose sodium (CCS)
2-5 wt %
magnesium stearate
0.05-1.5 wt %
(i)
weight % based on the
total weight of
Component
composition
crystalline Form B of a potassium salt of
15-40 wt %
Compound I of claim 1 or claim 2
solid dispersion containing 80% Compound II,
5-20 wt %
20% hypromellose
solid dispersion containing 80% Compound III-d,
20-40 wt %
19.5% hypromellose acetate succinate, and 0.5%
sodium lauryl sulfate
microcrystalline cellulose
10-50 wt %
croscarmellose sodium (CCS)
2-7 wt %
optionally magnesium stearate in an amount of 0.01 wt %-2 wt % based on the total weight of composition
(j)
weight % based on the
total weight of
Component
composition
crystalline Form B of a potassium salt of
20-30 wt %
Compound I of claim 1 or claim 2
solid dispersion containing 80% Compound II,
8-18 wt %
20% hypromellose
solid dispersion containing 80% Compound III-d,
20-30 wt %
19.5% hypromellose acetate succinate, and 0.5%
sodium lauryl sulfate
microcrystalline cellulose
20-30 wt %
croscarmellose sodium (CCS)
2-5 wt %
optionally magnesium stearate in an amount of 0.01 wt %-1.5 wt % based on the total weight of composition
and (k)
weight % based on the
total weight of
Component
composition
crystalline Form B of a potassium salt of
22-32 wt %
Compound I of claim 1 or claim 2
solid dispersion containing 80% Compound II,
10-20 wt %
20% hypromellose
solid dispersion containing 80% Compound III-d,
20-30 wt %
19.5% hypromellose acetate succinate, and 0.5%
sodium lauryl sulfate
microcrystalline cellulose
20-30 wt %
croscarmellose sodium (CCS)
2-5 wt %
optionally magnesium stearate in an amount of 0.01 wt %-1.5 wt % based on the total weight of composition
15. The pharmaceutical composition of claim 4 , wherein the composition is in the form of a single tablet comprising:
(a) 50 mg to 140 mg of a crystalline Form B of a potassium salt of Compound I of claim 1 or claim 3 ;
(b) 25 mg to 65 mg of a first solid dispersion comprising 80 wt % Compound II relative to the total weight of the first solid dispersion, and 20 wt % of a hypromellose relative to the total weight of the first solid dispersion; and
(c) 75 mg to 200 mg of a second solid dispersion comprising 80 wt % of Compound III relative to the total weight of the second solid dispersion, 0.5 wt % of sodium lauryl sulfate relative to the total weight of the second solid dispersion; and 19.5 wt % of a hypromellose acetate succinate to the total weight of the second solid dispersion
(d) 60 mg to 150 mg of a microcrystalline cellulose;
(e) 5 mg to 25 mg of a croscarmellose sodium; and
(f) 1 mg to 6 mg of magnesium stearate.
16. The pharmaceutical composition of claim 4 , wherein the composition is in the form of a single tablet comprising:
(a) 100 mg to 250 mg of a crystalline Form B of a potassium salt of Compound I of claim 1 or claim 2 ;
(b) 30 mg to 65 mg of a first solid dispersion comprising 80 wt % Compound II relative to the total weight of the first solid dispersion, and 20 wt % of a hypromellose relative to the total weight of the first solid dispersion; and
(c) 75 mg to 200 mg of a second solid dispersion comprising 80 wt % of Compound III relative to the total weight of the second solid dispersion, 0.5 wt % of sodium lauryl sulfate relative to the total weight of the second solid dispersion; and 19.5 wt % of a hypromellose acetate succinate to the total weight of the second solid dispersion;
(d) 85 mg to 215 mg of a microcrystalline cellulose;
(e) 10 mg to 30 mg of a croscarmellose sodium; and
(f) 1 mg to 7 mg of magnesium stearate.
17. The pharmaceutical composition of claim 4 , wherein the composition is in the form of a single tablet comprising:
(a) 100 mg to 215 mg of crystalline Form B of a potassium salt of Compound I of claim 1 or claim 3 ;
(b) 30 mg to 65 mg of a first solid dispersion comprising 80 wt % Compound II relative to the total weight of the first solid dispersion, and 20 wt % of a hypromellose relative to the total weight of the first solid dispersion; and
(c) 50 mg to 300 mg of a second solid dispersion comprising 80 wt % of Compound III-d relative to the total weight of the second solid dispersion, 0.5 wt % of sodium lauryl sulfate relative to the total weight of the second solid dispersion; and 19.5 wt % of a hypromellose acetate succinate to the total weight of the second solid dispersion;
(d) 85 mg to 215 mg of a microcrystalline cellulose;
(e) 10 mg to 30 mg of a croscarmellose sodium; and
(f) 1 mg to 7 mg of magnesium stearate.
18. The pharmaceutical composition of claim 4 , wherein the composition is in the form of a single tablet comprising:
(a) 55 mg to 300 mg of a crystalline Form B of a potassium salt of Compound I of claim 1 or claim 2 ;
(b) 30 mg to 130 mg of a first solid dispersion comprising 80 wt % Compound II relative to the total weight of the first solid dispersion, and 20 wt % of a hypromellose relative to the total weight of the first solid dispersion; and
(c) 50 mg to 300 mg of a second solid dispersion comprising 80 wt % of Compound III-d relative to the total weight of the second solid dispersion, 0.5 wt % of sodium lauryl sulfate relative to the total weight of the second solid dispersion; and 19.5 wt % of a hypromellose acetate succinate to the total weight of the second solid dispersion
(d) 60 mg to 300 mg of a microcrystalline cellulose;
(e) 7 mg to 25 mg of a croscarmellose sodium; and
(f) optionally 0.05 mg to 6 mg of magnesium stearate.
19. A method of treating cystic fibrosis in a patient comprising orally administering to the patient one or more of the pharmaceutical compositions of claim 4 .
20. The method of claim 19 , wherein one or more of the pharmaceutical compositions are administered once daily or twice daily.
21. The method of claim 19 , wherein said patient has cystic fibrosis is chosen from patients with F508del/minimal function genotypes, patients with F508del/F508del genotypes, patients with F508del/gating genotypes, and patients with F508del/residual function genotypes.
22. The pharmaceutical composition of claim 4 , wherein the composition comprises:
(a) about 128 mg of crystalline Form B of a potassium salt of Compound I of claim 1 or claim 2 ;
(b) about 63 mg of a first solid dispersion comprising 80 wt % Compound H relative to the total weight of the first solid dispersion, and 20 wt % of a hypromellose relative to the total weight of the first solid dispersion; and
(c) about 94 mg of a second solid dispersion comprising 80 wt % of Compound III relative to the total weight of the second solid dispersion, 0.5 wt % of sodium lauryl sulfate relative to the total weight of the second solid dispersion; and 19.5 wt % of a hypromellose acetate succinate to the total weight of the second solid dispersion.
23. The pharmaceutical composition of claim 22 , wherein the pharmaceutical composition is a single tablet.