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

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journal contribution
posted on 18.12.2015, 00:00 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. Thiel
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.

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