Spontaneous Gelation of a Novel Histamine H4 Receptor Antagonist in Aqueous Solution

Low molecular weight hydrogelators typically require a stimulus such as heat, antisolvent, or pH adjustment to produce a gel. This study examines gelation of a novel histamine H4 receptor antagonist that forms hydrogels spontaneously at room temperature. To elucidate the mechanism and structural moieties responsible for this unusual gelation, hydrogels were characterized by rheology, optical microscopy, and XRD. SEM was performed on xerogels; NMR measurements were conducted in gelator solutions in the presence of a gel-breaker. The influence of temperature, concentration, pH, and ionic strength on elastic and viscous moduli of the hydrogels was evaluated; gel points were established via thorough rheological criteria. The observed are true gels with a fibrillar texture and lamellar microstructure. On a molecular level, the gels are composed of aggregates of partially ionized species stabilized by hydrophobic interactions of aromatic moieties. The gel-to-sol transition occurs at physiologically relevant temperatures and is concentration-, pH-, and ionic strength-dependent. We hypothesize that this spontaneous gelation is due to the so-called spring effect, a high energy salt form that transiently increases aqueous solubility above its equilibrium limit. Upon equilibration, this supersaturated system undergoes aggregation that avoids crystallization and produces a hydrogel.