Mechanistic Insights into Additive-Mediated Habit Modification of 2-Hydroxynicotinic Acid via an Integrated...

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.