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

• Published in: Pharmaceutical research 2011-10, Vol.28 (10), p.2556-2566
• Main Authors: Popov, Alexey, Hickey, Magali B., Hiremath, Rupa, Peterson, Matthew, Ratanabanangkoon, Poe, Rizzolio, Michele, Waggener, Sara, Zimenkov, Yuri
• Format: Article
• Language: English
• Subjects: Antagonist drugs; Aqueous solutions; Attention; Biochemistry; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; General pharmacology; Histamine Antagonists - chemistry; Hydrogels; Hydrogels - chemistry; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Medical Law; Medical sciences; Osmolar Concentration; Pharmaceutical sciences; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacy; Phase Transition; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, Histamine; Receptors, Histamine H4; Research Paper; Rheology; Rheology - methods; Salts - chemistry; Solutions - chemistry; Temperature; Water - chemistry
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-011-0483-9

ABSTRACT 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.