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. A method of preparing a crystalline form of Compound I:
selected from:
a) preparing crystalline Form C of a potassium salt/co-crystal of Compound I, comprising stirring a potassium salt of Compound I with a solvent system comprising at least one source of water;
b) preparing crystalline Form A of a sodium salt of Compound I, comprising reacting Compound I with a sodium base;
c) preparing crystalline Form D of a sodium salt of Compound I, comprising heating a crystalline Form M or Form E of a sodium salt of Compound I at a temperature in a range from 280° C. to 300° C. under anhydrous conditions;
d) preparing crystalline Form M of a sodium salt of Compound I, comprising reacting Compound I with a sodium base in methanol;
e) preparing crystalline Form A of Compound I, comprising de-solvating at least one solvate of Compound I chosen from ethanol solvates of Compound I and methanol solvates of Compound I;
f) preparing crystalline Form E of a sodium salt of Compound I, comprising reacting Compound I with a sodium base in ethanol; and
g) preparing crystalline Form H of a sodium salt of Compound I, comprising de-solvating crystalline Form M or Form E of a sodium salt of Compound I or crystalline Form E of a sodium salt of Compound I in the presence of one source of water.
2. The method of claim 1 , wherein the crystalline Form C of a potassium salt/co-crystal of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta value chosen from 3.7±0.2, 7.0±0.2, 7.4±0.2, 8.7±0.2, 9.5±0.2, 11.4±0.2, 11.5±0.2, 12.4±0.2, and 16.0±0.2 degrees two-theta.
3. The method of claim 1 , wherein the crystalline Form C of a potassium salt/co-crystal of Compound I is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 7A .
4. The method of claim 1 , wherein the crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta value chosen from 4.7±0.2, 6.3±0.2, 11.1±0.2, and 12.6±0.2 degrees two-theta.
5. The method of claim 1 , wherein the crystalline Form A of a sodium salt of Compound I is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 8A .
6. The method of claim 1 , wherein the crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at 7.0±0.2, 9.8±0.2, and 16.0±0.2 degrees two-theta.
7. The method of claim 1 , wherein the crystalline Form D of a sodium salt of Compound I is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 9A .
8. The method of claim 1 , wherein the crystalline Form M of a sodium salt of Compound I has a monoclinic crystal system, a P 1 21 1 space group, and the following unit cell dimensions:
a=9.7434(2) Å α=90°
b=10.7467(2) Å β=95.5790(10°)
c=15.2452(3) Å γ=90°.
9. The method of claim 1 , wherein the crystalline Form A of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 5.5±0.2, 7.6±0.2, 15.1±0.2, 16.7±0.2, 18.9±0, and 19.6±0.2 degrees two-theta.
10. The method of claim 1 , wherein the crystalline Form A of Compound I is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 13A .
11. The method of claim 1 , wherein the crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta value chosen from 9.0±0.2, 11.4±0.2, 15.2±0.2, 16.3±0.2, 17.3±0.2, and 19.0±0.2 degrees two-theta.
12. The method of claim 1 , wherein the crystalline Form E of a sodium salt of Compound I is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 12A .
13. A crystalline form of Compound I prepared by the method of claim 1 , wherein the crystalline form is selected from:
a) crystalline Form C of a potassium salt/co-crystal of Compound I;
b) crystalline Form A of a sodium salt of Compound I;
c) crystalline Form D of a sodium salt of Compound I;
d) crystalline Form M of a sodium salt of Compound I;
e) crystalline Form A of Compound I;
f) crystalline Form E of a sodium salt of Compound I; and
g) crystalline Form H of a sodium salt of Compound I.