Cocrystals of zileuton with enhanced physical stability

Abstract

Zileuton (ZIL) is an active oral inhibitor of the enzyme 5-lipoxygenase used for the maintenance treatment of asthma. Though ZIL was first approved by the United States FDA 20 years ago, structural knowledge of this active pharmaceutical ingredient (API) has been omitted. Here, we report the crystal structure of the commercially available anhydrous ZIL (form A) for the first time. It's also found that a monohydrate of ZIL (form H) can be formed when the compound is exposed to high relative humidity (RH) conditions. Such a phase change is not desired during manufacturing and storage, for the physicochemical and pharmacokinetic behaviours of ZIL may also be modified along with the solid state hydration. Cocrystallization experiments involving ZIL with nicotinamide (NIC) and isonicotinamide (ISO) were successfully performed and the obtained cocrystal forms, ZIL–NIC and ZIL–ISO, demonstrated superior phase stability against moisture. Additionally, all these ZIL forms were characterized by a variety of analytical methods, which provide plentiful information for the solid-state landscape of this important drug substance.