Mechanistic insight into the evaporative crystallization of two polymorphs of nitrofurantoin monohydrate

This study was conducted to gain a deeper understanding of the crystallization behavior of both known nitrofurantoin (NF) monohydrates (monohydrates I and II). NF monohydrate crystals were obtained by evaporative crystallization from a series of acetone–water mixtures. The water activity of each solution together with the solubility of NF was used for calculation of the NF supersaturation profiles during evaporative crystallization. The crystallization process for each solution was monitored in situ by optical and Raman microscopy. It was found that the fraction of the metastable monohydrate I in the final product increased with decreasing water fraction, suggesting that the nucleation rate of monohydrate I increases with decreasing water activity. In addition, the morphology of both monohydrate forms was affected by the water fraction in the solvent. The in situ images and Raman spectra taken during the evaporative crystallization from water–acetone mixture (0.67 mole fraction of water) demonstrated that the crystallization of the stable monohydrate II was encountered first, and the nucleation of the metastable monohydrate I happened afterwards at a reduced supersaturation level. This indicates that the crystal packing of the NF monohydrate from acetone–water solutions was affected by both supersaturation and water activity.