Ultrasound-Assisted Polymorph Control in Reactive Crystallization of l-Glutamic Acid: Aiming for Consistently Producing Stable Form

Abstract

Polymorphic control in reactive crystallization remains a critical challenge due to the stochastic nature of nucleation and the competition between metastable and stable forms. This work aims to investigate the mechanisms controlling polymorphism in single-feed semibatch reactive crystallization and to develop strategies for reliably producing the stable form using l-glutamic acid (LGA) as a model compound. Unseeded and seeded experiments were performed under conventional and ultrasound-assisted conditions at high reactant concentrations. In unseeded systems, the use of ultrasound decreased induction times but did not eliminate the stochasticity of polymorphic outcomes. Compared with previously studied low-concentration systems yielding nearly pure metastable form, a higher concentration of reactant (sulfuric acid) may promote local supersaturation inhomogeneity, increasing the stochasticity of polymorphism. Seeded experiments showed that sufficient seed loading suppressed α-form nucleation and favored growth and secondary nucleation of β-form, though seeding at higher supersaturation required more seeds. Combining ultrasound with seeds significantly reduced the seed loading required and reproducibly produced, within the investigated repetitions, stable β-LGA crystals by enhancing secondary nucleation and overcoming the kinetic advantage of the metastable form. These findings provide deeper insight into the stochastic nucleation of the polymorphs and demonstrate ultrasound as a promising process-intensification tool for robustly producing the stable form during reactive crystallization.