Bulk nanobubbles as active nucleation sites during antisovent crystallization

Abstract

The control of crystallization is a critical yet challenging aspect of industrial processes, particularly in pharmaceuticals. In this work, we have hypothesized that remarkable stability of bulk nanobubbles may provide nucleation sites, control glycine crystal characteristics, and give high supersaturation regions for selective polymorph formation. The effect of different gaseous nanobubbles in various antisolvents were investigated. Nanobubbles were generated in the aqueous glycine solution by nanopore diffusion method. Our results indicate that nanobubbles influence crystal size distribution, with maximum reduction of 33 % in ethanol using oxygen nanobubbles. Nanobubbles also lead to more uniform crystals with an exclusive formation of the $\alpha$-polymorph. Gibbs free energy calculations show that nanobubbles decrease overall free energy, boosting nucleation rates. This action is attributed to glycine adsorption onto the negatively charged nanobubble surface. Overall, nanobubble technology proves to be a sustainable tool for regulating the crystallization process through efficient mixing of antisolvent and solute.