Unified chromatography in drug development: Exploiting chaotropic/kosmotropic salts for an accelerated method...

Recent trends in supercritical fluid chromatography (SFC) introduced an innovative gradient profile called Unified Chromatography (UC), which pushes the amount of liquid modifier up to 80-100 % of the total mobile phase composition. These new conditions allow the full transition from a supercritical to a liquid state, unifying the benefits of both SFC and liquid chromatography. However, to facilitate the use of UC for industrial drug development, a stronger effort is needed to streamline and simplify its method development and optimization. In this work, a quick and novel method development procedure for UC is introduced, enabled by the first-time use of novel additives in SFC/UC that exploit chaotropic/kosmotropic properties. A comprehensive view on some fundamental properties, such as the amount of liquid modifier blended with supercritical CO₂ (scCO₂) and the percentage of water added in the mobile phase is given, to clarify the benefits of using either a chaotropic salt (NaClO₄), kosmotropic (HCOONa) or salt with mixed properties (NaOMs - sodium methanesulfonate). With this expanded knowledge, challenging separations of nucleosides, nucleotide, indoles, triazoles and related derivates have been accomplished with UC. Finally, we provide an example of UC delivering a faster and better method for an AbbVie pipeline compound under accelerated stability study. The combined use of scCO₂-based chromatography and the novel additive NaClO₄ ensures the retention and elution of all degradation species generated at different conditions, where RP-HPLC failed to provide satisfactory performance.