Granted Patent B2

US 12,508,231 · App. 17/174,764 · Granted Dec 30, 2025

Inventor: Marinus Jacobus Verwijs (Framingham, MA)

Assignee: Vertex Pharmaceuticals Incorporated

A61K9/28A61J3/10A61K9/1623A61K9/1652A61K9/2054A61K9/2077A61K9/2866A61K31/443A61K31/47A61K31/4709A61K45/06

Abstract

Claims (35)

1 . A continuous process for preparing a tablet comprising 3-(6-(1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (‘Compound 1’) Form I, comprising the steps of:

a) mixing Compound 1 Form I milled to a particle size between 1 and 5 microns, a filler, and a disintegrant in a blender to form a blend;

b) preparing a granulation solution with water, a binder, and a surfactant;

c) feeding the blend from step a) into a continuous twin screw granulator while adding the granulation solution from step b) to produce granules;

d) drying the granules from step c) and milling them;

e) blending the milled granules from step d) with a filler, disintegrant, and lubricant to form a blend;

f) compressing the blend from step e) into a tablet, wherein the tablet comprises:

i. 30-55 wt % of Compound 1 Form I by weight of the composition;

ii. about 20 wt % to about 55 wt % of the filler by weight of the composition, wherein the filler is microcrystalline cellulose;

iii. about 1.5 wt % to about 7.5 wt % of the disintegrant by weight of the composition, wherein the disintegrant is croscarmellose sodium;

iv. about 0.2 wt % to about 5 wt % of the surfactant by weight of the composition, wherein the surfactant is sodium lauryl sulfate;

v. about 1 wt % to about 10 wt % of the binder by weight of the composition, wherein the binder is polyvinylpyrrolidone; and

vi. about 0.5 wt % to about 4.5 wt % of the lubricant by weight of the composition, wherein the lubricant is magnesium stearate;

g) optionally coating the tablet from step f).

2 . The process of claim 1 , wherein Compound 1 Form I has a particle size D50 of 2.0 microns.

3 . The process of claim 1 , wherein the tablet has a target friability of less than 1.0% after 400 revolutions.

4 . The process of claim 1 , wherein the tablet has a hardness of at least 5 kP.

5 . The process of claim 1 , wherein Compound 1 Form I is characterized by one or more peaks within one or more 2θ ranges, selected from 15.2 to 15.6 degrees; 16.1 to 16.5 degrees; and 14.3 to 14.7 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation.

6 . The process of claim 5 , wherein Compound 1 Form I is characterized by a peak within the range of 16.1 to 16.5 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation.

7 . The process of claim 6 , wherein Compound 1 Form I is characterized by a peak having a 2θ value at 16.3 degrees in an X-ray powder diffraction.

8 . The process of claim 1 , wherein Compound 1 Form I is characterized by a peak within the range of 14.3 to 14.7 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation.

9 . The process of claim 8 , wherein Compound 1 Form I is characterized by a peak having a 2θ value at 14.5 degrees in an X-ray powder diffraction.

10 . The process of claim 1 , wherein Compound 1 Form I is characterized by a peak within the range of 15.2 to 15.6 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation.

11 . The process of claim 10 , wherein Compound 1 Form I is characterized by a peak having a 2θ value at 15.4 degrees in an X-ray powder diffraction.

12 . The process of claim 5 , wherein Compound 1 Form I is further characterized by a peak within the range of 17.6 to 18.0 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation.

13 . The process of claim 5 , wherein Compound 1 Form I is further characterized by a peak within the range of 7.6 to 8.0 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation.

14 . The process of claim 1 , wherein Compound 1 Form I is characterized by one or more peaks having a 2θ value, ±0.2 degrees, selected from 14.41 degrees, 14.64 degrees, 15.23 degrees, 16.11 degrees, 17.67 degrees, 19.32 degrees, 21.67 degrees, 23.40 degrees, 23.99 degrees, 26.10 degrees, and 28.54 degrees, in an X-ray powder diffraction obtained using Cu K alpha radiation.

15 . The process of claim 1 , wherein Compound 1 Form I is characterized by one or more peaks having a 2θ value, ±0.2 degrees, selected from 7.83 degrees; 14.51 degrees; 14.78 degrees; 15.39 degrees; 16.26 degrees; 16.62 degrees; 17.81 degrees; 21.59 degrees; 23.32 degrees; 24.93 degrees; and 25.99 degrees, in an X-ray powder diffraction obtained using Cu K alpha radiation.

16 . The process of claim 1 , wherein Compound 1 Form I is characterized by a diffraction pattern substantially similar to that of FIG. 1 .

17 . The process of claim 1 , wherein Compound 1 Form I is characterized by a diffraction pattern substantially similar to that of FIG. 2 .

18 . The process of claim 1 , wherein Compound 1 Form I is characterized as a monoclinic crystal system in P2 1 /n space group with the following unit cell dimensions: a=4.9626(7) Å, b=12.299(2) Å, c=33.075 (4) Å, β=93.938(9)°.

19 . A tablet prepared by the process of claim 1 .

20 . A method of treating cystic fibrosis in a patient comprising administering a tablet prepared by the process of claim 1 .

21 . The method of claim 20 , wherein the patient has a ΔF508 CFTR mutation.

22 . The method of claim 21 , wherein the patient is homozygous for the ΔF508 CFTR mutation.

Assignments (2)

Continuity (9)

References Cited (400)