Granted Patent B2

US 12,252,478 · App. 17/858,701 · Granted Mar 18, 2025

Inventors: Stephanie Kay Dodd (Ayer, MA); Arnaud Grandeury (Helfrantzkirch, FR); Emmanuel Suffert (Basel, CH); Evgenia Rousaki (Basel, CH)

Assignee: Novartis AG

C07D401/14A61K9/20C07B2200/13

Abstract

Claims (69)

1. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a crystalline form A of asciminib hydrochloride; and

(b) at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient, wherein the crystalline form A of asciminib hydrochloride is 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-Kalpha1,2 radiation having a wavelength of 0.1541 Å.

2. The pharmaceutical composition of claim 1 , wherein the crystalline form A of asciminib hydrochloride is 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-Kalpha1,2 radiation having a wavelength of 0.1541 Å.

3. The pharmaceutical composition of claim 1 , wherein the crystalline form A of asciminib hydrochloride is 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-Kalpha1,2 radiation having a wavelength of 0.1541 Å.

4. The pharmaceutical composition of claim 1 , wherein the crystalline form A of asciminib hydrochloride is 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-Kalpha1,2 radiation having a wavelength of 0.1541 Å.

5. The pharmaceutical composition of claim 1 , wherein the crystalline form A of asciminib hydrochloride is 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-Kalpha1,2 radiation having a wavelength of 0.1541 Å.

6. The pharmaceutical composition of claim 1 , wherein the crystalline form A of asciminib hydrochloride is 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.

7. The pharmaceutical composition of claim 1 , wherein the crystalline form A of asciminib hydrochloride is 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.

8. The pharmaceutical composition of claim 1 , wherein the crystalline form A of asciminib hydrochloride is characterized by having an x-ray powder diffraction pattern similar to FIG. 8 .

9. The pharmaceutical composition of claim 1 , wherein the crystalline form A of asciminib hydrochloride is 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 )

1.533

a (Å)

8.203(3)

b (Å)

11.116(3) 

c (Å)

12.627(4) 

beta (°)

97.711(12)

Z

2.

10. The pharmaceutical composition of claim 1 , wherein the crystalline form A of asciminib hydrochloride is 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.

11. The pharmaceutical composition of claim 1 in the form of a tablet.

12. The pharmaceutical composition of claim 11 wherein the tablet contains from about 5 to about 500 mg of crystalline form A of asciminib hydrochloride.

13. The pharmaceutical composition of claim 12 wherein the tablet contains between 10 mg to about 200 mg of crystalline form A of asciminib hydrochloride.

14. The pharmaceutical composition of claim 12 wherein the tablet contains between 25 mg to about 150 mg of crystalline form A of asciminib hydrochloride.

15. The pharmaceutical composition of claim 12 wherein the tablet contains crystalline form A of asciminib hydrochloride, in an amount of 20 mg, 40 mg, or 60 mg based on the weight of asciminib free base.

16. The pharmaceutical composition of claim 11 further comprising by percentage weight: 10-30% crystalline form A of asciminib hydrochloride, 60-80% of one or more fillers, 2-10% of one or more disintegrants; and 0.2-3% of one or more glidants.

17. The pharmaceutical composition of claim 11 further comprising an intra-granular phase, an extra-granular phase and a film-coating wherein said intra-granular phase comprises: crystalline form A of asciminib hydrochloride, lactose, Avicel PH101, HP-Cellulose low subst_40UM, Natrium-CMC XL, Aerosil 200 PH, and magnesium stearate; said extra-granular phase comprises lactose, Cellulose MK GR, Natrium-CMC XL, Aerosil 200 PH, and magnesium stearate; and said film-coating comprises one or more film-forming substances and can further comprise substances selected from plasticizers, intestinal lubricants, colorants and/or pigments.

18. The pharmaceutical composition of claim 11 further comprising an intra-granular phase, an extra-granular phase and a film-coating wherein: said intra-granular phase comprises, by percentage weight: about 22% crystalline form A of asciminib hydrochloride, about 33% of lactose, about 18% of Avicel PH101, about 5% of HP-Cellulose low subst_40UM, about 2% of Natrium-CMC XL, about 0.25% of Aerosil 200 PH, and about 0.5% of magnesium stearate.

19. The pharmaceutical composition of claim 18 wherein the extra-granular phase contains, by percentage weight: about 10% of lactose; about 5.6% of Cellulose MK GR, about 3% of Natrium-CMC XL, about 0.25% of Aerosil 200 PH, and about 1% of magnesium stearate; and the film-coating contains, by percentage weight: about 4.8% coating premix white; about 0.16% coating premix yellow; and about 0.008% coating premix red.

20. The pharmaceutical composition of claim 18 wherein the extra-granular phase contains, by percentage weight: about 10% of lactose; about 5.6% of Cellulose MK GR, about 3% of Natrium-CMC XL, about 0.25% of Aerosil 200 PH, and about 1% of magnesium stearate; and the film-coating contains contains, by percentage weight: about 8% coating premix white; about 0.02% coating premix red; and about 0.02% coating premix black.

21. A process for producing a pharmaceutical composition of claim 1 comprising:

(a) blending intra-granular phase ingredients: crystalline form A of asciminib hydrochloride, Avicel PH101, HP-Cellulose low subst_40UM, Natrium-CMC XL, Aerosil 200 PH and magnesium stearate;

(b) sieving, blending, roller compacting and milling the blended ingredients from step (a);

(c) blending the extra-granular phase ingredients: lactose, Cellulose MK GR, Natrium-CMC XL, Aerosil 200 PH and magnesium stearate;

(d) sieving the ingredients from step (c);

(e) blending the ingredients from step (b) and step (d);

(f) compressing the ingredients of step (e) into tablets and dedusting said tablets;

(g) forming a suspension of the film-coating: comprises purified water and a mixture of one or more coating premix selected from white, yellow, red and black; and

(h) film-coating the dedusted tablets of (f).

22. The pharmaceutical composition of claim 18 wherein the extra-granular phase contains, by percentage weight: about 10% of lactose; about 5.6% of Cellulose MK GR, about 3% of Natrium-CMC XL, about 0.25% of Aerosil 200 PH, and about 1% of magnesium stearate.

23. The pharmaceutical composition of claim 18 wherein the extra-granular phase contains, by percentage weight: about 10% of lactose; about 5.6% of Cellulose MK GR, about 3% of Natrium-CMC XL, about 0.25% of Aerosil 200 PH, and about 1% of magnesium stearate.

Assignments (9)