This study addresses the performance of reverse antisolvent crystallization methods in controlling polymorphism of an active pharmaceutical ingredient (API). Preventing polymorphism is crucial because different polymorphic forms of the same compound can exhibit significantly different solubility, stability, and bioavailability, which may affect the drug's therapeutic performance and regulatory approval1. The API in consideration here is nitrofurantoin (NIFU), a WHO essential medicine used to treat urinary tract infections (UTIs). NIFU is used in pharmaceutical drug formulations in two different crystalline forms: monohydrate II and anhydrate β. The original antisolvent crystallization method using dimethyl sulfoxide (DMSO) and water produces undesired DMSO hemisolvate crystals. This polymorph must be transformed into monohydrate II or anhydrate β through solvent-mediated phase transformation or desolvation, introducing additional unit operations2, 3. Here we demonstrate that reverse antisolvent crystallization removes the need for these extra unit operations by favoring the formation of monohydrate II over DMSO hemisolvate. With the purpose of gaining a better understanding of the NIFU crystallization route, molecular dynamics (MD) simulations are used as a predictive tool to guide the experimental efforts by providing insights into polymorph stability predictions, solid-solid transitions, hydration and solvent effects, etc.
Experimental results conclude that the desired monohydrate II form can be obtained through reverse antisolvent crystallization with sufficiently large water to DMSO solution ratios. Filtration and washing steps are also determined to influence the form obtained, as excess drying leads to the formation of undesired DMSO hemisolvate. In addition, process analytical technology (PAT) is utilized to obtain mechanistic understanding of nitrofurantoin polymorphism.