Crystalline forms OF N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide
Inventors
Dodd, Stephanie Kay • Grandeury, Arnaud • SUFFERT, Emmanuel • ROUSAKI, Evgenia
Assignees
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Publication Number
US-12252479-B2
Publication Date
2025-03-18
Expiration Date
Abstract
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.
Core Innovation
The disclosure relates to crystalline forms and pharmaceutical uses of asciminib, including crystalline form A of asciminib hydrochloride. Crystalline form A is characterized by an x-ray powder diffraction pattern comprising reflections at defined 2-Theta angles measured at 20 to 25 C with Cu-Kalpha1,2 radiation having a wavelength of 0.1541 A.
The disclosure further describes additional solid-state modifications, including a free base crystalline form A and hydrochloride crystalline forms A and B, as well as a trihydrate modification H_A. It also identifies multiple solvates, including solvates S_A to S_D corresponding to methanol, 1-propanol, ethanol, and acetone.
Thermal characterization and x-ray powder diffraction based definitions are used to define and distinguish these forms. The document includes statements on enantiotropic relationship and transition behavior between hydrochloride forms A and B, and conversion to the trihydrate at low pH.
The document includes statements on non-hygroscopicity and intrinsic dissolution, along with dog pharmacokinetic food-effect comparisons. In these comparisons, exposure differences (AUCinf) are reported for amorphous solid dispersion versus crystalline form A, and for hydrochloride salt formulation versus solid dispersion.
Claims Coverage
The provided content includes one independent claim. It covers a therapeutically effective administration method directed to an ABL1/BCR-ABL1-mediated disorder using crystalline form A of asciminib hydrochloride, with the crystalline form defined by specific XRPD reflections measured at a defined temperature and radiation condition.
Treating ABL1/BCR-ABL1-mediated disorder with crystalline form A asciminib hydrochloride
A method for treating an ABL1/BCR-ABL1-mediated disorder by administering to a patient in need a therapeutically effective amount of a crystalline form A of asciminib hydrochloride.
XRPD-defined crystalline form A characterization
Crystalline form A is characterized by 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 20 to 25 C with Cu-Kalpha1,2 radiation having a wavelength of 0.1541 Å.
The core inventive coverage is the therapeutic treating method for an ABL1/BCR-ABL1-mediated disorder using a therapeutically effective amount of asciminib hydrochloride crystalline form A, where the crystalline form is defined by specified XRPD reflections under defined measurement conditions.
Stated Advantages
Non-hygroscopicity.
Intrinsic dissolution data.
Positive food effect in dog pharmacokinetics for the crystalline formulation relative to solid dispersion, with exposure differences reported by AUCinf.
Documented Applications
Treating an ABL1/BCR-ABL1-mediated disorder by administering crystalline form A of asciminib hydrochloride.
Treating an ABL1/BCR-ABL1-mediated cancer selected from chronic myeloid leukemia and acute lymphoblastic leukemia.
Food-effect pharmacokinetic comparison in dogs between amorphous solid dispersion and crystalline form A, and between hydrochloride salt formulation and solid dispersion, reporting AUCinf exposure differences.
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