Salts of 3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl) phenoxy]ethyli-1-benzofuran-2-carboxamide, related crystalline forms, method for preparing the same and pharmaceutical compositions containing the same
Inventors
GAILLARD, Marina • Letellier, Philippe
Assignees
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Publication Number
US-10898461-B2
Publication Date
2021-01-26
Expiration Date
Abstract
Described herein are salts of 3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide, in particular that of formula (I): wherein HA is naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, oxalic acid, benzenesulfonic acid, or sulfuric acid, or hydrates thereof, and crystalline forms thereof characterized by the powder X-ray diffraction diagram and the 13C CP/MAS NMR solid state spectrum. Also described are compositions, methods of use and preparation thereof.
Core Innovation
The disclosed crystalline salt forms are of abexinostat (3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide), including hydrates and polymorphs, where HA is selected from naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, oxalic acid, benzenesulfonic acid, or sulfuric acid. The document defines specific hydrogen sulfate forms including hydrogen sulfate hydrates such as hemipentahydrate and hemiheptahydrate. These crystalline salt forms are characterized as defined crystalline forms suitable for pharmaceutical use.
Each crystalline form is defined by powder X-ray diffraction (PXRD) and 13C CP/MAS solid-state NMR. The PXRD definition uses Bragg angle 2θ diffraction lines with a tolerance of ±0.2°. The 13C CP/MAS solid-state NMR characterization reports specified peak positions to define the solid-state form.
The disclosure provides crystallization concepts using a polar medium with the corresponding acid and optionally using seeding to obtain the crystalline salt form. It further reports that the disclosed crystalline salt forms enable improved industrial manufacturability and low hygroscopicity. Low hygroscopicity is supported by dynamic vapor sorption (DVS) mass variation thresholds, enabling stable pharmaceutical formulations. The document also includes characterization examples and example pharmaceutical tablet compositions using carrier excipients.
Claims Coverage
The independent claim covers one inventive feature: a crystalline form of an abexinostat salt defined by the acid component HA being benzenesulfonic acid and by a specified PXRD diffraction pattern with Bragg-angle 2θ lines within ±0.2°. Dependent claims refine the PXRD line set and define pharmaceutical compositions including the crystalline form with pharmaceutically acceptable carriers.
Crystalline abexinostat benzenesulfonate defined by specific PXRD lines
A crystalline form of an abexinostat salt according to formula (Ia) wherein HA is benzenesulfonic acid, and the crystalline form has a powder X-ray diffraction diagram exhibiting diffraction lines at Bragg angle 2θ of 8.08; 10.03; 13.63; 15.00; 16.19; 17.73; 17.90; 18.77; 19.77; 21.98; 22.45 (degrees, ±0.2° tolerance).
Overall, the claim set centers on a specific crystalline abexinostat salt form (HA = benzenesulfonic acid) characterized by a defined PXRD diffraction pattern, with dependents further specifying additional PXRD lines and pharmaceutical compositions with pharmaceutically acceptable carriers.
Stated Advantages
Improved industrial manufacturability.
Low hygroscopicity supported by DVS mass variation thresholds.
Enables stable pharmaceutical formulations.
Documented Applications
Pharmaceutical formulations, including pharmaceutical tablet compositions, comprising the defined crystalline form as the active ingredient with one or more pharmaceutically acceptable carriers.
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