op5b00031_si_001.cif (345.02 kB)
Selection of a Suitable Physical Form and Development of a Crystallization Process for a PDE10A Inhibitor Exhibiting Enantiotropic Polymorphism
dataset
posted on 2015-12-18, 00:00 authored by Y.-H. Kiang, Eric A. Bercot, Qiong Wu, Jodi Liu, Robert
R. Milburn, Dawn E. Cohen, Christopher J. Borths, Robert E. Saw, Richard J. Staples, Carl Davis, Oliver
R. ThielAMG 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.
