Crystalline salts and polymorphs of a P2X3 antagonist

Inventors

Ibrahim, Prabha • Hawley, Ronald Charles • Ford, Anthony P. • Smith, Steven A.

Assignees

Afferent Pharmaceuticals Inc

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 describes crystalline citrate forms of 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonamide (Compound A), including a crystalline free base Form A and multiple crystalline salt polymorphs. The citrate salt polymorphs include citrate salt Form A (anhydrous 1:1) and citrate salt Form B (monohydrate 1:1). Each crystalline form is characterized by analytical signatures including XRPD peak positions, proton NMR stoichiometry, and thermal and vapor sorption behavior.

The crystalline forms are further characterized by reported thermal and vapor sorption behavior using DSC, TGA, and DVS, with information including hygroscopicity and behavior under high relative humidity. The disclosure states that these crystalline citrate forms exhibit stability and solubility improvements compared to the free base, and describes specific proton NMR stoichiometry for the salt forms.

The disclosure connects the crystalline citrate forms of Compound A to pharmaceutical use for modulating P2X3- and/or P2X2/3-mediated conditions. Respiratory symptoms are identified, including cough and urge to cough, as conditions addressed by modulation using the crystalline forms. Pharmaceutical formulations and examples are described for tablets containing Compound A with tartaric or citric acid, including reported in vivo dog pharmacokinetic and dissolution data.

Claims Coverage

The provided independent claims (three total) each define a crystalline citrate Form A of Compound A based on specific XRPD peak positions, using different subsets or combinations of 2θ values. Across the independent claims, the core inventive constraint is an XRPD-defined crystalline citrate Form A, with one independent claim adding an additional XRPD peak at approximately 26.3 degrees.

Overall claim coverage is directed to a crystalline citrate Form A of Compound A where the material is identified by XRPD peak positions, with the independent claims differing in which 2θ peak set is required (11.7/16.2; 11.7/16.2/21.1; or 11.7/16.2/21.1/26.3). The included dependent claim information further indicates receptor-mediated modulation and cough-related condition selection, but the independent-claim scope itself is centered on the XRPD-defined crystalline form.

Stated Advantages

Documented Applications