Cocrystallization of paracetamol with p-anisic acid yields distinct polymorphic forms exhibiting enhanced dissolution, antioxidant, and antibacterial properties

The diversity of molecular conformations plays a decisive role in directing polymorphic nucleation and cocrystal formation. Using paracetamol (PARA) and p‑anisic acid (pAn) as a model system, we demonstrate how conformational landscapes govern cocrystallization outcomes. Distinct polymorphic forms were obtained and comprehensively characterized by SCXRD, PXRD, SEM, DSC, and FTIR. Structural analysis revealed that Form I is stabilized by robust O–H···O hydrogen bonds, whereas Form II relies on weaker C–H···O and C–H···π interactions. Hirshfeld surface mapping and PIXEL energy calculations confirmed conformational diversity and distinct stabilization motifs. Both polymorphic cocrystals exhibited significantly enhanced solubility and dissolution compared with pure PARA, translating into improved bioavailability. Biological assays further demonstrated superior antioxidant and antibacterial activities, arising from the synergistic interplay between PARA and pAn. These findings highlight how the balance between conformational flexibility and intermolecular forces dictates polymorphic behavior, offering mechanistic insights into the strategic design of pharmaceutical cocrystals with optimized physicochemical and therapeutic performance.