Crystalline forms of CFTR modulators
Inventors
Shi, Yi • Gagnon, Kevin J. • Li, Jicong • Lu, Jennifer • Medek, Ales • Shrestha, Muna • Waldo, Michael • Zhang, Beili • Zwicker, Carl L • Anderson, Corey Don • Clemens, Jeremy J. • Cleveland, Thomas • Coon, Timothy Richard • Frieman, Bryan • Grootenhuis, Peter • Hadida Ruah, Sara Sabina • McCartney, Jason • Miller, Mark Thomas • Paraselli, Prasuna • Pierre, Fabrice • Swift, Sara E. • Zhou, Jinglan
Assignees
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Publication Number
US-12319693-B2
Publication Date
2025-06-03
Expiration Date
Abstract
Crystalline forms of Compound I: pharmaceutically acceptable salts thereof, and solvates and hydrates thereof are disclosed. Pharmaceutical compositions comprising the same, methods of treating cystic fibrosis using the same, and methods for making the same are also disclosed.
Core Innovation
The document describes solid-state forms of Compound I, including crystalline free forms, salts, solvates, hydrates, potassium salt hydrate forms B, C, and D, and an ammonia salt hydrate form A. Compound I calcium salt hydrate Form A is defined as a specific solid form characterized by an X-ray powder diffractogram having signals at 4.2±0.2 degrees two-theta, 18.0±0.2 degrees two-theta, and 19.7±0.2 degrees two-theta, and by a 13C solid state nuclear magnetic resonance spectrum with a peak at 17.0±0.2 ppm.
The disclosure further recites pharmaceutical compositions containing Compound I calcium salt hydrate Form A, including embodiments where at least 85% of the Compound I is Compound I calcium salt hydrate Form A and where one or more additional CFTR-modulating compounds are present. The document links Compound I to CFTR modulation for cystic fibrosis, including genotype groupings and combination-therapy frameworks.
In addition, a preparation approach is described for obtaining substantially crystalline Compound I calcium salt hydrate Form A. The disclosure also relates to characterization and differentiation of solid-state forms using XRPD peak positions, 13C ssNMR, reference figures, and similarity assessed by matching XRPD peak positions and corresponding diffractogram profiles.
Claims Coverage
The consolidated claims define Compound I calcium salt hydrate Form A by solid-state characterization and include pharmaceutical composition and cystic fibrosis treatment context. In total, the inventive features center on three characterization features and one composition/treatment feature.
X-ray powder diffractogram characterization of Compound I calcium salt hydrate Form A
Compound I calcium salt hydrate Form A is characterized by an XRPD having signals at 4.2±0.2 degrees two-theta, 18.0±0.2 degrees two-theta, and 19.7±0.2 degrees two-theta.
13C solid state NMR characterization of Compound I calcium salt hydrate Form A
Compound I calcium salt hydrate Form A is characterized by a 13C ssNMR spectrum with a peak at 17.0±0.2 ppm.
Pharmaceutical composition and cystic fibrosis treatment with Compound I calcium salt hydrate Form A
A pharmaceutical composition including Compound I calcium salt hydrate Form A, wherein at least 85% of the Compound I is Compound I calcium salt hydrate Form A, optionally with one or more additional CFTR-modulating compounds selected from Compound II, Compound III, Compound III-d, and Compound IV, for treatment of cystic fibrosis.
Overall, the claims coverage focuses on identifying Compound I calcium salt hydrate Form A through XRPD and 13C ssNMR constraints, and on its inclusion in pharmaceutical compositions for cystic fibrosis treatment.
Stated Advantages
Improved alternatives to previously reported amorphous forms.
Characterization and differentiation of Compound I salt hydrates using XRPD peak positions and reference figures.
Supports identification of specific solid-state forms via XRPD similarity assessment.
Provides a CFTR modulation rationale for cystic fibrosis, including genotype groupings.
Supports combination therapy frameworks using pharmaceutical compositions including Compound I with other CFTR modulators.
Documented Applications
Treatment of cystic fibrosis using Compound I forms, including crystalline free forms and calcium salt hydrate forms, alone or with CFTR modulators.
Administration of Compound I crystalline forms for cystic fibrosis genotypes including F508del-related mutations.
CFTR modulation in cystic fibrosis, including patient genotype groupings, using Compound I.
Combination therapy in cystic fibrosis using pharmaceutical compositions that include Compound I with other CFTR modulators selected from Compounds II, III/III-d, and IV.
Treatment of cystic fibrosis using a pharmaceutical composition that includes Compound I calcium salt hydrate Form A.
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