Crystalline forms of N-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide
The present invention describes specific crystalline forms of N-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5 -yl)pyridine-3-carboxamide. The present invention further relates to methods for preparing said crystalline forms, pharmaceutical compositions comprising said crystalline forms, and methods of using said crystalline forms and pharmaceutical compositions to treat disease.
1. Crystalline form A of asciminib hydrochloride characterized by having an x-ray powder diffraction pattern comprising reflections at 2-Theta angles of 12.6±0.2° , 18.9±0.2° and 20.9±0.2° , when measured at a temperature in the range of from 20 to 25° C. with Cu-Kalpha 1,2 radiation having a wavelength of 0.1541Å.
2. The crystalline form according to claim 1 characterized by having an x-ray powder diffraction pattern comprising reflections at 2-Theta angles of 12 . 6 ± 0 . 2 ° , 17 . 0 ± 0 . 2 ° , 18 . 9 ± 0 . 2 ° , 20 . 9 ± 0 . 2 ° and 32 . 5 ± 0 . 2 ° , when measured at a temperature in the range of from 20 to 25 ° C. with Cu-Kalpha 1,2 radiation having a wavelength of 0.1541Å.
3. The crystalline form according to claim 1 characterized by having an x-ray powder diffraction pattern comprising at least three 2 theta values selected from the group consisting of 8.5° ±0.2° , 9.5° ±0.2° , 11.8° ±0.2° , 12.3° ±0.2° , 12.6° ±0.2° , 13.9° ±0.2° , 14.8° ±0.2° , 15.9° ±0.2° , 16.5° ±0.2° , 17.0° ±0.2° , 17.6° ±0.2° , 18.9° ±0.2° , 19.1° ±0.2° , 19.8° ±0.2° , 20.4° ±0.2° , 20.9° ±0.2° , 21.2° ±0.2° , 22.4° ±0.2° , 22.7° ±0.2° , 23.9° ±0.2° , 24.3° ±0.2° , 24.8° ±0.2° , 25.0° ±0.2° , 25.9° ±0.2° , 26.8° ±0.2° , 27.0° ±0.2° , 28.3° ±0.2° , 28.6° ±0.2° , 28.9° ±0.2° , 29.8° ±0.2° , 30.5° ±0.2° , 31.3° ±0.2° , 31.5° ±0.2° , 31.8° ±0.2° , 32.1° ±0.2° , 32.5° ±0.2° , 32.9° ±0.2° , 33.6° ±0.2° , 34.0° ±0.2° , 34.6° ±0.2° , 35.0° ±0.2° , 35.6° ±0.2° , 36.3° ±0.2° and 38.8° ±0.2° , when measured at a temperature in the range of from 20 to 25° C. with Cu -Kalpha 1,2 radiation having a wavelength of 0.1541Å.
4. The crystalline form according to claim 1 characterized by having a differential scanning calorimetry curve comprising an endothermic peak having an onset temperature of 90° C., when measured at a heating rate of 2° C/min.
5. The crystalline form according to claim 1 characterized by having a thermogravimetric analysis curve showing a mass loss of not more than 3.3 weight % based on the weight of the crystalline form, when heated from 30 to 300° C. at a rate of 20° C/min.
6. The crystalline form according to claim 1 characterized by having an x-ray powder diffraction pattern comprising at least four 2 theta values selected from the group consisting of 8.5° ±0.2° , 9.5° ±0.2° , 11.8° ±0.2° , 12.3° ±0.2° , 12.6° ±0.2° , 13.9° ±0.2° , 14.8° ±0.2° , 15.9° ±0.2° , 16.5° ±0.2° , 17.0° ±0.2° , 17.6° ±0.2° , 18.9° ±0.2° , 19.1° ±0.2° , 19.8° ±0.2° , 20.4° ±0.2° , 20.9° ±0.2° , 21.2° ±0.2° , 22.4° ±0.2° , 22.7° ±0.2° , 23.9° ±0.2° , 24.3° ±0.2° , 24.8° ±0.2° , 25.0° ±0.2° , 25.9° ±0.2° , 26.8° ±0.2° , 27.0° ±0.2° , 28.3° ±0.2° , 28.6° ±0.2° , 28.9° ±0.2° , 29.8° ±0.2° , 30.5° ±0.2° , 31.3° ±0.2° , 31.5° ±0.2° , 31.8° ±0.2° , 32.1° ±0.2° , 32.5° ±0.2° , 32.9° ±0.2° , 33.6° ±0.2° , 34.0° ±0.2° , 34.6° ±0.2° , 35.0° ±0.2° , 35.6° ±0.2° , 36.3° ±0.2° and 38.8° ±0.2° , when measured at a temperature in the range of from 20 to 25° C. with Cu -Kalpha 1,2 radiation having a wavelength of 0.1541Å.
7. The crystalline form according to claim 1 characterized by having an x-ray powder diffraction pattern comprising at least five 2 theta values selected from the group consisting of 8.5° ±0.2° , 9.5° ±0.2° , 11.8° ±0.2° , 12.3° ±0.2° , 12.6° ±0.2° , 13.9° ±0.2° , 14.8° ±0.2° , 15.9° ±0.2° , 16.5° ±0.2° , 17.0° ±0.2° , 17.6° ±0.2° , 18.9° ±0.2° , 19.1° ±0.2° , 19.8° ±0.2° , 20.4° ±0.2° , 20.9° ±0.2° , 21.2° ±0.2° , 22.4° ±0.2° , 22.7° ±0.2° , 23.9° ±0.2° , 24.3° ±0.2° , 24.8° ±0.2° , 25.0° ±0.2° , 25.9° ±0.2° , 26.8° ±0.2° , 27.0° ±0.2° , 28.3° ±0.2° , 28.6° ±0.2° , 28.9° ±0.2° , 29.8° ±0.2° , 30.5° ±0.2° , 31.3° ±0.2° , 31.5° ±0.2° , 31.8° ±0.2° , 32.1° ±0.2° , 32.5° ±0.2° , 32.9° ±0.2° , 33.6° ±0.2° , 34.0° ±0.2° , 34.6° ±0.2° , 35.0° ±0.2° , 35.6° ±0.2° , 36.3° ±0.2° and 38.8° ±0.2° , when measured at a temperature in the range of from 20 to 25° C. with Cu -Kalpha 1,2 radiation having a wavelength of 0.1541Å.
8. The crystalline form according to claim 1 characterized by having an x-ray powder diffraction pattern similar to FIG. 8 .
9. Crystalline form A of asciminib hydrochloride characterized by the following unit cell parameters from x-ray diffraction data measured at 100K:
Space symmetry
Triclinic
Space group
P1
Cell Volume (Å 3 )
1053.6(6)
Crystal Density (g/cm 3 )
1
a (Å)
8.203(3)
b (Å)
11.116(3)
c (Å)
12.627(4)
beta (°)
97.711(12)
Z
2.
10. Crystalline form A of asciminib hydrochloride characterized by the following unit cell parameters from x-ray diffraction data measured at 298K:
Space symmetry
Triclinic
Space group
P1
Cell Volume (Å 3 )
1082.9(6)
Crystal Density (g/cm 3 )
1.491
a (Å)
8.245(3)
b (Å)
11.352(4)
c (Å)
12.697(4)
beta (°)
97.289(18)
Z
2.