Mechanistic Insights into Additive-Mediated Habit Modification of 2-Hydroxynicotinic Acid via an Integrated Experimental–Computational Framework

Crystal habit profoundly influences the downstream processability of the final product in industrial crystallization, yet its rational control remains challenging. Herein, an integrated experimental-computational framework was employed to elucidate additive-mediated habit modification of 2-hydroxynicotinic acid (2-HNA). Controlled cooling crystallization experiments reveal a systematic transformation from highly anisotropic needle-like crystals in pure water (aspect ratio ≈ 16:1) to rod- and block-like morphologies (≈5:2) in the presence of additives, following a clear habit-modification efficiency hierarchy: PVP > PEG > CTAB ≈ SDS > INA > water. Meanwhile, mechanistic insight was obtained using a coupled attachment energy-molecular dynamics-modified attachment energy (AE-MD-MAE) framework, which demonstrates that habit evolution originates from additive-crystal surface interactions governed by two synergistic mechanisms: (i) thermodynamic stabilization, whereby additives reduce the attachment energy of reactive surfaces, particularly (011), and (10-1), and (ii) kinetic inhibition, characterized by suppressed surface diffusion and prolonged residence of additives on these surfaces. Collectively, these effects establish a unified causal chain linking intrinsic surface descriptors and additive recognition to face-specific growth inhibition, thereby enabling a transferable, mechanistically grounded workflow for crystal habit control in crystallization process development.