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

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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.

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Authors and Affiliations

  1. TransForm Pharmaceuticals, Inc., 29 Hartwell Avenue, Lexington, Massachusetts, 02421, USA

    Alexey Popov, Magali B. Hickey, Rupa Hiremath, Matthew Peterson, Poe Ratanabanangkoon, Sara Waggener & Yuri Zimenkov

  2. Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, California, 92121, USA

    Michele Rizzolio

  3. Kala Pharmaceuticals, Inc., 135 Beaver Street, Waltham, Massachusetts, 02452, USA

    Alexey Popov

Authors
  1. Alexey Popov
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  2. Magali B. Hickey
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  3. Rupa Hiremath
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  4. Matthew Peterson
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  5. Poe Ratanabanangkoon
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  6. Michele Rizzolio
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  7. Sara Waggener
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  8. Yuri Zimenkov
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Correspondence to Alexey Popov.

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Popov, A., Hickey, M.B., Hiremath, R. et al. Spontaneous Gelation of a Novel Histamine H4 Receptor Antagonist in Aqueous Solution. Pharm Res 28, 2556–2566 (2011). https://doi.org/10.1007/s11095-011-0483-9

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  • DOI: https://doi.org/10.1007/s11095-011-0483-9

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