Selection of a Suitable Physical Form and Development of a Crystallization Process for a PDE10A Inhibitor Exhibiting Enantiotropic Polymorphism

AMG 579 (1) is a potent and selective phosphodiesterase 10 (PDE10A) inhibitor selected for clinical development for the treatment of schizophrenia. Extensive polymorph and salt screening identified two free-base anhydrous polymorphs (Form 1 and Form 2) that are viable for further development. Crystal structures of these two polymorphs were determined by single-crystal X-ray study. Form 1 and Form 2 are enantiotropically related with the transition temperature between 190 and 210 °C. After full characterization, quality attributes were evaluated, and Form 2, the thermodynamically more stable form at room temperature, was selected for clinical development. A crystallization process for Form 2 was developed, and in situ Raman spectroscopy was used as a PAT tool to monitor and control the physical form. Use of this integrated control strategy allowed access to multikilogram quantities of AMG 579 in the desired form.