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Journal of Pharmaceutics
Volume 2013 (2013), Article ID 791370, 15 pages
http://dx.doi.org/10.1155/2013/791370
Research Article

Hydrotropic Solubilization by Urea Derivatives: A Molecular Dynamics Simulation Study

Small Molecule Pharmaceutical Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA

Received 7 November 2012; Accepted 4 January 2013

Academic Editor: David S. Jones

Copyright © 2013 Yong Cui. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Hydrotropy is a phenomenon where the presence of a large quantity of one solute enhances the solubility of another solute. The mechanism of this phenomenon remains a topic of debate. This study employed molecular dynamics simulation to investigate the hydrotropic mechanism of a series of urea derivatives, that is, urea (UR), methylurea (MU), ethylurea (EU), and butylurea (BU). A poorly water-soluble compound, nifedipine (NF), was used as the model solute that was solubilized. Structural, dynamic, and energetic changes upon equilibration were analyzed to supply insights to the solubilization mechanism. The study demonstrated that NF and urea derivatives underwent significant nonstoichiometric molecular aggregation in the aqueous solution, a result consistent with the self-aggregation of urea derivatives under the same conditions. The analysis of hydrogen bonding and energy changes revealed that the aggregation was driven by the partial restoration of normal water structure. The energetic data also suggested that the promoted solubilization of NF is favored in the presence of urea derivatives. While the solutes aggregated to a varying degree, the systems were still in single-phase liquid state as attested by their active dynamics.