Polymorphic Forms of a Molecular Salt of Phenazopyridine with 3,5-Dihydroxybenzoic Acid: Crystal Structures, Theoretical Calculations, Thermodynamic Stability, and Solubility Aspects

The polymorphism of multicomponent crystals has not been studied as widely as that of single-component crystals. In this work, two polymorphic forms of a pharmaceutical salt of phenazopyridine with 3,5-dihydroxybenzoic acid in a 1:1 stoichiometry were successfully obtained and fully characterized by X-ray diffraction, thermal analysis, and dynamic vapor sorption measurement. The crystal structure study exhibited similarities and differences in H-bonding synthons, molecular conformations, and packing arrangements across two polymorphs. The solid-state density functional theory computations complemented by Bader analysis of the periodic electron density and Hirshfeld surface analysis were carried out to quantify the patterns of intermolecular interactions and the energies of crystal lattices for both forms. The combined experimental and theoretical method suggests that these two polymorphs are enantiotropically related. They exhibit different but significantly improved aqueous solubility.