Crystalline salts and polymorphs of a P2X3 antagonist
Inventors
Ibrahim, Prabha • Hawley, Ronald Charles • Ford, Anthony P. • Smith, Steven A.
Assignees
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Publication Number
US-11230533-B2
Publication Date
2022-01-25
Expiration Date
Abstract
Provided are novel salts and polymorphs of 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonamide, which are potentially useful for modulating a condition mediated by a P2X3 or P2X2/3 receptor. Also provided are pharmaceutical formulations and methods of administration and dosing of these salts and polymorphs to subjects in need thereof.
Core Innovation
The disclosure provides crystalline citrate Form B of 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonamide (Compound A), characterized by X-ray powder diffraction peaks at approximately 2θ values of 11.3, 16.2 and 23.0 degrees, and also by an XRPD set of peaks at approximately 5.7, 8.4, 11.3, 16.2, 18.8, 23.0 and 25.0 degrees. The solid forms are further supported by X-ray powder diffraction peak/d-spacing characterization and proton NMR composition ratios and stoichiometry, including drug:acid ratios such as 1:1 or 2:1.
The disclosure further provides crystalline tartrate Form F of Compound A, characterized by XRPD peaks at approximately 2θ values of 11.3, 18.7 and 22.7 degrees, with further refinements including additional XRPD peaks and complementary thermal behavior. The physical behavior of the crystalline salts is supported by thermal and moisture-related characterization including DSC, TGA, DVS and Karl Fischer analysis.
The crystalline citrate and tartrate forms are presented for improving aqueous solubility and physical stability relative to the free base, and are linked to use in pharmaceutical formulations and receptor-mediated conditions mediated by P2X3 or P2X2/3 receptors, including cough/urge to cough and respiratory symptoms.
Claims Coverage
The independent claim set covers three inventive features centered on specific XRPD-defined crystalline solid forms of Compound A. Additional scope further frames use as pharmaceutical compositions and modulation of P2X3 or P2X2/3 receptor-mediated conditions via administration of an effective amount.
Crystalline citrate Form B defined by XRPD peaks at 2θ≈11.3, 16.2, 23.0
Crystalline citrate Form B of 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonamide characterized by X-ray powder diffraction peaks at 2θ values of approximately 11.3, 16.2 and 23.0 degrees.
Crystalline citrate Form B defined by an XRPD peak set at 2θ≈5.7, 8.4, 11.3, 16.2, 18.8, 23.0, 25.0
A crystalline citrate Form B characterized by X-ray powder diffraction peaks at 2θ values of approximately 5.7, 8.4, 11.3, 16.2, 18.8, 23.0 and 25.0 degrees.
Crystalline tartrate Form F defined by XRPD peaks at 2θ≈11.3, 18.7, 22.7
A crystalline tartrate Form F of 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonamide characterized by X-ray powder diffraction peaks at 2θ values of approximately 11.3, 18.7 and 22.7 degrees.
Overall, the claim coverage is anchored in defining specific crystalline polymorphs of Compound A by XRPD peak positions, with narrower dependent scope additionally tying the forms to further XRPD constraints, proton NMR and thermal/moisture analyses, and to pharmaceutical compositions and receptor-mediated modulation via administration of an effective amount.
Stated Advantages
Improved aqueous solubility compared to the free base.
Improved physical stability versus the free base, including avoidance of deliquescence behavior.
Documented Applications
Pharmaceutical formulations/tablets including the crystalline citrate Form B or crystalline tartrate Form F, with dissolution and in vivo pharmacokinetics data described in the disclosure.
Modulating a condition mediated by P2X3 or P2X2/3 receptors by administering an effective amount of the crystalline citrate Form B or crystalline tartrate Form F to a subject in need thereof.
Therapeutic conditions mediated by P2X3/P2X2/3 receptor activity including cough/urge to cough and respiratory symptoms.
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