Atypical gelation of Elagolix sodium in aqueous media: Mechanistic insights and Inhibition via coamorphization

Elagolix sodium (ELS), a non-peptide oral gonadotropin-releasing hormone receptor (GnRH) antagonist approved for the treatment of endometriosis-associated pain, displays atypical gelation in aqueous environments along with challenging physical properties such as high hygroscopicity. To address the formulation challenges posed by ELS gelation and high hygroscopicity, this study not only investigates the molecular mechanisms governing ELS gel formation but also evaluates co-amorphization with quercetin as a practical strategy to suppress gelation and enhance stability. Unlike conventional gelation mechanisms of small molecules, ELS was found to self-assemble into a metastable spherulitic gel network in aqueous media, where water molecules acted as critical "binders" for both initiation and stabilization. Comprehensive morphological, thermal, spectroscopic, and rheological analyses were employed to elucidate ELS gelation process. Polarized light microscopy (PLM) revealed that the hydrogel consists of transient spherulite domains, while Fourier Transform Infrared Spectroscopy (FTIR), Raman spectroscopy and Liquid-state ¹H nuclear magnetic resonance spectroscopy (¹H NMR) demonstrated that gel formation is driven by a combination of dipole-dipole electrostatic interactions and π-π stacking between ELS molecules, along with intermolecular hydrogen bonding between ELS and water. Rheological studies further confirmed a temperature-dependent transition from fibrous structure to a densely cross-linked spherulitic network, indicating enhanced gel strength at lower gelation temperatures. Coamorphization of ELS with quercetin (QUE) not only completely inhibits gelation but also significantly reduces the hygroscopicity of ELS. Overall, this study provides fundamental insights into the mechanism of atypical small-molecule gelation while offering a practical strategy to overcome gelation challenges in the formulation and processing of ELS-based pharmaceuticals.