Liquid−Liquid Phase Separation-Controlled Polymorphism and Stoichiomorphism in the Pterostilbene-(E)-1,2-bis(pyridin-4-yl)ethene Cocrystal

Liquid−liquid phase separation (LLPS) can severely hinder controlled nucleation and crystal growth during cocrystallization, restricting access to phase-pure polymorphs and stoichiomorphs. During the cocrystallization of the Pterostilbene-(E)-1,2-bis(pyridin-4-yl)ethene (PTB-BPE) system, LLPS emerged as a major experimental barrier to crystal development. In situ microscopic observations revealed that strong PTB-solvent interactions under specific solvent environments promoted LLPS, thereby suppressing nucleation and crystal growth. This limitation was overcome through mechanochemical crystallization approaches combined with the ability of BPE to form stabilizing O−H···N hydrogen bond interactions with PTB. Systematic solvent modulation afforded four crystalline phases of PTB-BPE: Form I (plate, PTB/BPE = 1:0.5), Form II (needle, PTB/BPE = 1:0.5), and Form III (block, PTB/BPE = 2:1) as polymorphic forms, while Form IV (rod, PTB/BPE = 1:1.5) represents a distinct stoichiomorph. Mechanical pretreatment followed by slow evaporation enabled the formation of multiple solid forms; other mechanochemical routes predominantly yielded Form III, and slurry conversion selectively produced bulk Form IV. Single-crystal X-ray diffraction confirmed differences in packing, symmetry, and asymmetric unit composition among the forms. Lattice energy calculations and void analysis indicate comparable thermodynamic stability among the polymorphs, with Form III exhibiting strong intermolecular interactions and efficient packing within the PTB-BPE solid-form landscape.