Abstract

Elagolix, a GnRH antagonist for endometriosis-associated pain, exhibits two atropisomers due to hindered rotation about its C5–C16 bond. Separating these atropisomers is crucial for drug development and quality control. Although rotational energy barriers are the key parameters governing the interconversion kinetics of atropisomers, studies that correlate these calculated values to chromatographic behavior are relatively limited. This study integrates green supercritical fluid chromatography (SFC) with quantum chemical calculations to explore this relationship. An SFC method was optimized, achieving good separation of the two atropisomers of elagolix (Rs > 2.0) within 15 min. Quantum chemical calculations revealed rotational energy barriers of 23~26 kcal/mol, with half-lives ranging from minutes to days, placing elagolix into Class II of the LaPlante classification. Experimentally, the changes in the interconversion plateau under different temperature conditions showed good consistency with the calculated kinetic trends. By integrating chromatographic experiments with rotational energy barrier calculations, this study provides mechanistic insights into the separation behavior of elagolix atropisomers and may provide information for understanding the potential separability of other atropisomeric drugs.