Crystal Morphology Manipulation of R-3HB Based on Theoretical Prediction and Growth Environment Control

To address the challenge of regulating the morphology of R-3-hydroxybutyric acid (R-3HB), this study employed experimental control and molecular dynamics (MD) simulations to investigate the influence of various crystallization environments on its crystal growth. Six typical solvent systems, such as acetone, methyl isobutyl ketone, ethyl acetate, pentyl acetate, methyl tert-butyl ether, and isopropanol, were selected for experimental research and simulation predictions. The results indicated that for five solvents, excluding isopropanol, the predictions from the occupancy model were more consistent with experimental observations. Conversely, for isopropanol, the modified attachment energy (MAE) model provided a reliable prediction of crystal morphology. Radial distribution functions (RDF) and molecular electrostatic potentials (MEP) analysis revealed that hydrogen bond interactions between the crystal face and solute molecules are generally stronger than those between solvent molecules and the crystal faces, thereby promoting the growth of specific crystal faces. Furthermore, diffusion coefficient analysis demonstrated that molecular mobility is governed by the combined effects of hydrogen bond and steric hindrance. Specifically, isopropanol exhibited restricted mobility due to its strong hydrogen bond donor capability, whereas acetone displays high diffusivity. Overall, the occupancy model, which incorporates solute-crystal face interactions, is essential for the accurate prediction of crystal morphology and provides a theoretical framework for solvent selection in the crystallization process of R-3HB.