(670h) Thinking in Reverse: A Case Study to Control the Polymorphism of Nitrofurantoin During Crystallization

Nitrofurantoin (NIFU), a World Health Organization (WHO) essential medicine for the treatment of urinary tract infections, exhibits two pharmaceutically relevant polymorphs: anhydrous β and monohydrate II. As a purification method, an antisolvent crystallization process using dimethyl sulfoxide (DMSO) as the solvent and water as the antisolvent was developed. However, this process led to the formation of an undesired DMSO hemisolvate, which required an additional solvent-mediated transformation to obtain the target monohydrate II form.

In this study, we propose a practical approach to directly crystallize monohydrate II via reverse antisolvent addition, wherein the NIFU solution in DMSO is added to water to achieve a high water-to-DMSO ratio that thermodynamically favors the desired hydrate form. Both inline and offline characterization techniques, including a Blaze probe, Raman spectroscopy, X-ray diffraction, thermogravimetric analysis (TGA), and optical microscopy, were employed to monitor the crystallization pathway and verify solid-form purity. Molecular dynamics (MD) simulations aimed to provide DMSO-water, DMSO-NIFU, and NIFU-water interaction energies to gain mechanistic understanding of NIFU polymorphisms.

This integrated experimental–computational strategy provides a practical approach to control polymorphism and gain mechanistic understanding, ensuring process robustness and consistent formation of the desired form while eliminating the need for additional unit operations.