Investigation of Solid-State Forms between p-Aminosalicylic Acid and Adenine: Exploring Salts, Cocrystals and their Polymorphism

This study investigates the polymorphic behavior of multi-component adducts formed between p-aminosalicylic acid (PAS), a second-line anti-tuberculosis drug, and adenine (ADE), a hydrogen bond-rich coformer. Given a ΔpKa of 2.2 between PAS and ADE, within the salt–cocrystal uncertainty region, three distinct solid-state forms (an anhydrous and two hydrates) were synthesized via solvent-tuned liquid-assisted grinding and solution evaporation. Comprehensive characterization was performed using solid-state NMR, FT-IR and Raman spectroscopy, X-ray diffraction (SCXRD and PXRD), DSC, TGA, and in vitro dissolution tests. Results revealed significant differences in structure, hydrogen-bonding networks, and thermal properties among the forms, with PAS:ADE stoichiometries of 3:2 for the anhydrous form and 1:1 for the hydrated forms. These findings demonstrate the critical role of solvent and stoichiometry in directing adduct formation and polymorphism, offering insights for optimizing drug formulation and expanding intellectual property strategies in pharmaceutical development.