Insight into Crystallization Mechanisms of Polymorphic Hydrate Systems

Polymorphic anhydrate systems have been well studied but until now little attention has been paid to polymorphic hydrate systems. The incorporation of water molecules can complicate the whole polymorphic system and thus impede the control of the crystallization process. In this work, nitrofurantoin monohydrate polymorphs which have the same chemical composition and molar ratio of water but different crystal packing arrangements, have been investigated. The metastable nitrofurantoin monohydrate was found to be difficult to crystallize, where both evaporative and cooling crystallization failed in its production. The possible phase conversion of the nitrofurantoin hydrate polymorphic system was also investigated in a liquid-assisted ball milling process. High-energy solids, e.g., amorphous and cocrystals, have often been created during high-energy ball milling. Metastable nitrofurantoin monohydrate, however, was again not observed during the whole milling process, in contrast to another polymorphic hydrate system, namely niclosamide. During milling of niclosamide anhydrate in ethyl acetate-water mixture the metastable niclosamide monohydrate was formed immediately upon milling (2 min). Under further milling, the metastable niclosamide hydrate started converting to the stable niclosamide hydrate (from 30 min onwards).