Spontaneous gelation of a novel histamine H4 receptor antagonist in aqueous solution.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Complexities of particulate matter measurement in parenteral formulations of small-molecule amphiphilic drugs.

Reconstituted parenteral solutions of three surface-active anti-infective small-molecule drugs and solutions of sodium dodecyl sulfate (SDS, a model surfactant) were studied to quantify the impact of sample preparation and handling on particle counts. Turbidimetry and light obscuration profiles were recorded as a function of agitation and shearing with and without the introduction of foam into the solutions. SDS solutions at concentrations above the critical micelle concentration (CMC) show significantly greater sensitivity to shear and foam presence than SDS solution below the CMC: Values of >10 µm particles increased 8 fold over control (an unsheared sample) in the micellar solution vs. 4 fold particle count increase over control at a sub-micellar concentration. An even more significant increase in the ratio of particle count in sheared/unsheared solution is seen for >25 µm unit counts, due to the increased interference of foam with the measurement. Two commercial products, injection formulations of teicoplanin and cefotaxime sodium, as well as an investigational compound 1, showed an increase in scattering as a function of foam production. The impact of foaming was significant, resulting in an increase of turbidity and light obscuration measurements in all solutions. The results illustrate some of the challenges that are inherent to optically clear, homogeneous pharmaceutical injections containing compounds which have a tendency toward self-association and surfactant-like behavior.