Crystalline forms of N-(4-(4-(cyclopropymethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide
Inventors
Sizemore, Jacob P. • GUO, Liting • Mirmehrabi, Mahmoud • Su, Yeqing
Assignees
Solid State Pharma Inc • Crystal Pharmatech Co Ltd • Agios Pharmaceuticals Inc
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Publication Number
US-11254652-B2
Publication Date
2022-02-22
Expiration Date
Abstract
Provided herein are amorphous and crystalline hemisulfate salt forms of the formula (I). Also provided are pharmaceutical compositions comprising the amorphous and crystalline hemisulfate salt forms, methods for their manufacture, and uses thereof for treating conditions associated with pyruvate kinase such as e.g., pyruvate kinase deficiency.
Core Innovation
The disclosed invention provides crystalline Form A, a hemisulfate sesquihydrate salt of Compound 1, which is a pyruvate kinase R (PKR) allosteric activator. Crystalline Form A is characterized by x-ray powder diffraction peaks at 2θ angles of 9.9°, 15.8°, and 22.6°, each with a ±0.2° tolerance. The disclosure further provides powder x-ray diffraction, thermal-analysis, gravimetric, and dynamic vapor sorption data, including comparisons involving hemisuccinate forms, micronized and unmicronized forms, and the Compound 1 free base.
The disclosure describes pharmaceutical compositions, methods for preparing the crystalline form, and therapeutic applications for pyruvate kinase deficiency and other blood disorders. It reports high crystallinity, humidity and solvent stability, small particle size, and favorable pharmacokinetic properties, including higher exposure than the crystalline free base in rat studies. The technical problem addressed is not explicitly described in the patent.
Claims Coverage
The relevant claims include one independent claim, directed to one inventive feature: crystalline Form A of the specified compound.
Crystalline form A of the specified compound
The claim covers crystalline Form A of the specified compound, characterized by x-ray powder diffraction peaks at 2θ angles of 9.9°, 15.8°, and 22.6°, each with a ±0.2° tolerance.
The independent claim centers on crystalline Form A identified by the three specified diffraction peaks. Dependent claims further characterize the form, identify a solvate embodiment, and recite pharmaceutical or tablet compositions containing the form and a pharmaceutically acceptable carrier.
Stated Advantages
The form is reported to have high crystallinity.
The form is reported to have humidity and solvent stability, including stability under specified humidity and storage conditions.
The form is reported to have small particle size.
The form is reported to have favorable pharmacokinetic properties, such as plasma concentration profiles over time.
Rat studies report higher exposure for Form A than for the crystalline free base: AUC is 2.7–3.8-fold higher and Cmax is 1.6–2-fold higher.
Documented Applications
Therapeutic applications for pyruvate kinase deficiency (PKD) and other blood disorders.
Pharmaceutical or tablet compositions containing the crystalline form and a pharmaceutically acceptable carrier.
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