Crystalline solid forms of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, processes for making, and methods of use
Inventors
Aftab, Dana T. • GUZ, NATHAN • Lau, Stephen • Hamill, Noel • WALKER, Tracy • Galbraith, Jana • Yau, Simon • Shah, Khalid
Assignees
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Publication Number
US-11724986-B2
Publication Date
2023-08-15
Expiration Date
Abstract
The invention relates to novel crystalline solid forms of the chemical compound N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (Compound 1), and solvates thereof, including hydrates, that are useful for the treatment of cancer. Also disclosed are pharmaceutical compositions comprising the crystalline solid forms and processes for making the crystalline solid forms, as well as methods of using them for the treatment of cancer, particularly thyroid cancer, prostate cancer, hepatocellular cancer, renal cancer, and non-small cell lung carcinoma. The crystalline solid forms can be used to make the L-malate salt of cabozantinib.
Core Innovation
The disclosure relates to crystalline solid forms of Compound 1, defined as N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide. It provides crystalline solid forms including free base and hydrates/solvates, with x-ray powder diffraction characterization reported for multiple named forms. The document describes each crystalline solid form by its solid-state physical properties and corresponding analytical results.
A key form identified in the disclosure is Compound 1 in Form XXX, which is characterized by an x-ray powder diffraction pattern (CuKα) comprising peaks at 7.2, 7.5, 10.0, 12.0, 12.4, 13.5, 15.8, and 19.8 (±2θ) at room temperature, together with additional characterization data. The document also reports that other named forms exhibit different solid-state behaviors, including water/solvent loss and hygroscopicity or sorption observations.
The disclosure further states that the crystalline solid forms can be used in pharmaceutical compositions for treating cancer, and it provides context for dosing and formulation use cases. It additionally notes that the solid forms can be used to prepare the L-malate salt of cabozantinib, and that the described solid forms and their properties support therapeutic use across multiple cancer types.
Claims Coverage
The partial claims provided include one independent claim (clm-00001) defining a specific crystalline solid form and its XRPD peak characterization. The dependent claims refine identification by reference to a specific pattern and extend coverage to pharmaceutical compositions and formulations.
Crystalline solid form of Compound 1 in Form XXX defined by an XRPD peak list (CuKα) at room temperature
The crystalline solid form is Compound 1 in Form XXX, wherein Form XXX is characterized by an x-ray powder diffraction pattern (CuKα) comprising peaks at 7.2, 7.5, 10.0, 12.0, 12.4, 13.5, 15.8, and 19.8 (±2θ) at room temperature.
XRPD characterization matching a referenced figure/pattern
The crystalline solid form of Compound 1 is characterized by an x-ray powder diffraction pattern (CuKα) matching the pattern shown in FIG. 21.
Pharmaceutical composition containing a therapeutically effective dose with a pharmaceutically acceptable carrier
A pharmaceutical composition includes a therapeutically effective dose of a substantially pure crystalline solid form of compound 1 together with a pharmaceutically acceptable carrier.
Pharmaceutical formulation with specified excipients and, in one embodiment, an Opadry Yellow film coating composition
A pharmaceutical formulation comprises Compound 1 Form XXX combined with specified percentages of excipients and, in one embodiment, an Opadry Yellow film coating including HPMC 2910/hypromellose 6 cp, titanium dioxide, triacetin, and iron oxide yellow, with Compound 1 Form XXX amounts fixed or within stated ranges and/or specified as a theoretical quantity per unit dose.
Overall, the claim coverage centers on identifying Compound 1 Form XXX by a specified XRPD (CuKα) peak list at room temperature, optionally tying the identification to a referenced figure pattern, and then applying the substantially pure Form XXX in pharmaceutical compositions and specific formulations.
Stated Advantages
Enables characterization and identification of Compound 1 Form XXX by an XRPD peak list at room temperature.
Supports use of substantially pure crystalline solid forms of Compound 1 in pharmaceutical compositions for treating cancer.
Documented Applications
Treating cancer using pharmaceutical compositions containing a therapeutically effective dose of substantially pure Compound 1 crystalline solid form(s).
Preparing the L-malate salt of cabozantinib using the described solid forms.
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