FORMULATIONS OF 3-(6-(1-(2,2-DIFLUOROBENZO[D][1,3]DIOXOL-5-YL) CYCLOPROPANECARBOXAMIDO)-3-METHYLPYRIDIN-2-YL)BENZOIC ACID
A pharmaceutical composition comprising Compound 1, (3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid), and at least one excipient selected from: a filler, a disintegrant, a surfactant, a binder, and a lubricant, the composition being suitable for oral administration to a patient in need thereof to treat a CFTR mediated disease such as Cystic Fibrosis. Processes of preparing pharmaceutical compositions comprising Compound 1 are also disclosed.
1 - 54 . (canceled)
55 . A continuous process for preparing a tablet comprising 3-(6-(1-(2,2-Difluorobenzo[d][1,3 ]dioxol-5-yl)cycl opropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (‘Compound 1’) Form I, comprising the steps of:
a) mixing Compound 1 Form I, 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; and
g) optionally coating the tablet from step f),
wherein the particle size of Compound 1 Form I is between 0.1 and 10 microns.
56 . The process of claim 55 , wherein the tablet comprises at least 30 wt % by weight of Compound 1 Form I.
57 . The process of claim 55 , wherein the particle size of Compound 1 Form I is between 1 micron and 5 microns.
58 . The process of claim 55 , wherein Compound 1 Form I has a particle size D50 of 2.0 microns.
59 . The process of claim 55 , wherein the tablet has a target friability of less than 1.0% after 400 revolutions.
60 . The process of claim 55 , wherein the tablet has a hardness of at least 5 kP.
61 . The process of claim 55 , 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.
62 . The process of claim 61 , 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.
63 . The process of claim 62 , wherein Compound 1 Form I is characterized by a peak having a 2θ value at 16.3 degrees in an X-ray powder diffraction.
64 . The process of claim 61 , 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.
65 . The process of claim 64 , wherein Compound 1 Form I is characterized by a peak having a 2θ value at 14.5 degrees in an X-ray powder diffraction.
66 . The process of claim 61 , 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.
67 . The process of claim 66 , wherein Compound 1 Form I is characterized by a peak having a 2θ value at 15.4 degrees in an X-ray powder diffraction.
68 . The process of claim 61 , wherein Compound 1 Form I is 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.
69 . The process of claim 61 , 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.
70 . The process of claim 55 , wherein Compound 1 Form I is characterized by one or more peaks having a 2θ value 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, all ±0.2 degrees, in an X-ray powder diffraction obtained using Cu K alpha radiation.
71 . The process of claim 55 , wherein Compound 1 Form I is characterized by one or more peaks having a 2θ value 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, all ±0.2 degrees, in an X-ray powder diffraction obtained using Cu K alpha radiation.
72 . The process of claim 55 , wherein Compound 1 Form I is characterized by a diffraction pattern substantially similar to that of FIG. 1 .
73 . The process of claim 55 , wherein Compound 1 Form I is characterized by a diffraction pattern substantially similar to that of FIG. 2 .
74 . The process of claim 55 , 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)°.
75 . The process of claim 55 , wherein the tablet further comprises N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.
76 . A tablet prepared by the process of claim 55 .
77 . A method of treating cystic fibrosis in a patient comprising administering a tablet prepared by the process of claim 55 .
78 . The method of claim 77 , wherein the patient has a F508Δ mutation.
79 . The method of claim 78 , wherein the patient is homozygous for F508Δ.