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.