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.

AMG 579 (1) 是一种强效且选择性优异的磷酸二酯酶10（phosphodiesterase 10, PDE10A）抑制剂，被遴选进入临床开发用于精神分裂症的治疗。研究人员通过广泛的多晶型与盐筛选实验，发现了两种可用于后续开发的游离碱无水多晶型（晶型1与晶型2）。通过单晶X射线衍射研究，解析了这两种多晶型的晶体结构。晶型1与晶型2属于互变相关多晶型，二者的晶型转变温度介于190 ℃至210 ℃之间。完成全面表征并评估其质量属性后，研究人员选定在室温下热力学稳定性更优的晶型2用于临床开发。随后开发了针对晶型2的结晶工艺，并采用原位拉曼光谱作为过程分析技术（Process Analytical Technology, PAT）工具，对晶型状态进行监测与控制。借助该集成控制策略，成功制备得到多千克级别的目标晶型AMG 579。