Crystal Forms of Enzalutamide and a Crystal Engineering Route to Drug Purification

The crystal forms of the active pharmaceutical ingredient enzalutamide, a drug used for the treatment of metastatic prostate cancer, have been investigated by X-ray, thermogravimetric analysis, and differential scanning calorimetry techniques. The single crystal structure of the anhydrous form R1 (marketed by Astellas) has been determined and compared with the powder diffraction data. Upon crystallization from MeOH and formic acid, a new solvate form called R2 has been discovered and characterized. The crystal structure of R2 contains voids that can host other small molecules such as formic acid, methanol, or water. Form R2 loses solvent at ca. 120–140 °C and recrystallizes into the stable unsolvated form R1. In the case of isopropyl alcohol, a solvate form R3 has also been obtained. R1 converts into R3 under slurry conditions in isopropyl alcohol. The structure of R3 has been determined from powder diffraction data. Importantly, while form R1 is easily contaminated with O-enzalutamide (the substitution impurity of S-enzalutamide) by forming stable solid solutions up to 50%, form R3 does not and can be used to easily purify the raw S-enzalutamide.