Crystal Structures and the Solvent-Mediated Transformation of Erythromycin Acetone Solvate to Dihydrate during Batch Crystallization

The crystal structures of erythromycin solvates were investigated by XRPD. Dihydrate is orthorhombic, P212121 space group, and acetone solvate is monoclinic, P2 space group. The thermodynamic stability of two solvates in acetone aqueous solution from 35 to 50 °C were studied, indicating an enantiotropic system of solvent-mediated transformation that proceeds via the dissolution of the metastable phase and the subsequent nucleation and growth of the stable phase. In situ FBRM, off-line microscopy, and XRPD were used to examine the transformation behavior. Quantitatively, transformation kinetics at 50 °C was evaluated by the XRPD method. The effect of temperature and stirrer speed on transformation kinetics was also investigated by in situ FBRM. The results indicated that dissolution rate of metastable form is accelerated with the increase of temperature, inducing rapid nucleation of stable dihydrate and leading to small dominant chord length of final crystal products. Stirrer speed has a significant effect...