Crystallographic and Computational Analysis of Solid Form Landscape of Three Structurally Related Imidazolidine-2,4-dione Active Pharmaceutical Ingredients: Nitrofurantoin, Furazidin and Dantrolene

We present a crystallographic and computational study of three hydantoin-based active pharmaceutical ingredients nitrofurantoin, furazidin, and dantrolene aimed at identifying factors resulting in different propensities of these compounds to form polymorphs, hydrates, solvates, and solvate hydrates. This study is a continuation of our research towards understanding how small structural differences in closely related compounds affect their propensity to form different crystal phases, as all three compounds contain an imidazolidine-2,4-dione scaffold and a N-acyl hydrazone moiety and all form multiple crystalline phases. Crystallographic and computational analysis of the already known and newly obtained nitrofurantoin, furazidin and dantrolene crystal structures was performed by dissecting the properties of individual molecules and searching for the differences in tendency to form hydrogen bonding patterns and characteristic packing features. The propensity to form solvates was found to correlate with the relative packing efficiency of neat polymorphs and solvates and the ability of molecules to pack efficiently in several different ways. Additionally, the differences in propensity to form solvate-hydrates were attributed to the different stability of the hydrate phases.