The invention of robust and reliable liquid chromatography (LC) methods is critical to developing process understanding and ensuring product quality during small-molecule pharmaceutical development. Historically, the development of an analytical method has been an iterative process, wherein an analytical scientist optimizes chromatographic conditions to accommodate critical impurities identified during process development over the lifetime of the asset, usually 6-10 years. Method conditions are locked by the time of process performance qualification and the development culminates with commercial method validation.

In contrast, disruptive, late-breaking changes to a synthetic route that improve process robustness, cost, or sustainability do not afford the luxury of time and experience typical for the development of a robust and reliable analytical method, particularly if the asset is approaching commercialization. Fortunately, the advent of various method screening platforms and in silico chromatographic modeling software have served as useful tools to greatly accelerate chromatographic method development, thereby keeping pace with the rapidly changing needs of chemical process development.

Herein, the authors describe the utilization of two key tools, an ultra-high performance liquid chromatography (UHPLC) screening platform and in silico modeling, to develop a fit-for-purpose UHPLC separation for a sulfone intermediate utilized in the synthesis of Adagrasib. This work will also describe investigations into method scaling from UHPLC to traditional high-performance liquid chromatography to ensure widespread transferability that is agnostic to the instrument capabilities of commercial quality control laboratories. The investigation into method scaling will also illustrate the potential pitfall of frictional heating during method scaling and demonstrate a rapid manner to combat this pitfall.

Robert Menger

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