Crystallization of Paracetamol via Liquid–Liquid Phase Separation: Solvent-Directed Polymorph Control through a Colloidal Soft Matter Phase

Understanding and controlling polymorphism in active pharmaceutical ingredients are essential for optimizing drug efficacy, stability, and manufacturing. In this study, we investigate the liquid–liquid phase transition (LLPT) and polymorph selection of paracetamol in ethanol–water binary solvents using a multitechnique approach, including transmission electron microscopy, dynamic light scattering (DLS), 1H NMR, UV–vis absorption spectroscopy, and atomistic molecular dynamics simulations. Our findings reveal that solvent composition critically modulates paracetamol’s self-assembly, yielding diverse colloidal morphologies such as pearl-necklace-like and fiber-like aggregates. These structures arise from a balance between hydrogen bonding and aromatic ring stacking, governed by ethanol-to-water ratios. At low ethanol content, strong paracetamol–water interactions are favorable, whereas higher ethanol concentrations favor paracetamol–ethanol binding and promote hydrogen bonding and aromatic ring stacking. This shift in solvent-mediated preferential interactions drives the formation of nucleation-competent aggregates, influencing crystal outcomes. Again, while crystallization under ethanol-rich conditions favors the monoclinic form I, introducing bulkier alcohols like benzyl alcohol enhances π-stacking and stabilizes the orthorhombic form II. A ternary phase diagram delineates the solvent-driven evolution from colloidal intermediates to crystalline phases. By linking solvent-mediated molecular interactions to colloidal behavior and polymorphic outcomes, this study offers a scalable and broadly applicable strategy for ambient-condition polymorph control─enabling rational crystal engineering across diverse pharmaceutical compounds.