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Hydrotropic Solubilization by Urea Derivatives: A Molecular Dynamics Simulation Study.

Cui Y - J Pharm (Cairo) (2013)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

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

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.

No MeSH data available.


The overlay of RDFs between hydrotropic agents and water in four hydrotropic solutions at t = 3 ns. EU and BU were represented by C2 (a) and C3 (b) in the calculation. See Figure 1 for carbon atom numbering.
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fig10: The overlay of RDFs between hydrotropic agents and water in four hydrotropic solutions at t = 3 ns. EU and BU were represented by C2 (a) and C3 (b) in the calculation. See Figure 1 for carbon atom numbering.

Mentions: A second note is that the HA-H2O RDFs in Figure 9(d) show that the declines in water concentration near HA molecules are ranked as EU > BU > MU > UR, with the maximum decline claimed by EU instead of BU. The flipping over of the positions of EU and BU was unexpected. It was suspected that as the hydrophobic alkyl chains grow and the molecule elongates, the amide carbon atom sitting at the hydrophilic end of the molecule may become less representative for the whole HA in the RDF calculation. This was proved by the EU-H2O and BU-H2O RDFs recalculated using alternative carbons C2 and C3 (see Figure 1 for the numbering of carbons of BU. EU used the same numbering sequence) of EU and BU, which are illustrated in Figure 10. It is evident that water concentration near the alkyl chain (represented by C2 and C3) of BU is lower than that of EU. Hence, the results in general are consistent with those above and support that the degree of aggregation correlates positively with the growing hydrophobicity of HAs.


Hydrotropic Solubilization by Urea Derivatives: A Molecular Dynamics Simulation Study.

Cui Y - J Pharm (Cairo) (2013)

The overlay of RDFs between hydrotropic agents and water in four hydrotropic solutions at t = 3 ns. EU and BU were represented by C2 (a) and C3 (b) in the calculation. See Figure 1 for carbon atom numbering.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig10: The overlay of RDFs between hydrotropic agents and water in four hydrotropic solutions at t = 3 ns. EU and BU were represented by C2 (a) and C3 (b) in the calculation. See Figure 1 for carbon atom numbering.
Mentions: A second note is that the HA-H2O RDFs in Figure 9(d) show that the declines in water concentration near HA molecules are ranked as EU > BU > MU > UR, with the maximum decline claimed by EU instead of BU. The flipping over of the positions of EU and BU was unexpected. It was suspected that as the hydrophobic alkyl chains grow and the molecule elongates, the amide carbon atom sitting at the hydrophilic end of the molecule may become less representative for the whole HA in the RDF calculation. This was proved by the EU-H2O and BU-H2O RDFs recalculated using alternative carbons C2 and C3 (see Figure 1 for the numbering of carbons of BU. EU used the same numbering sequence) of EU and BU, which are illustrated in Figure 10. It is evident that water concentration near the alkyl chain (represented by C2 and C3) of BU is lower than that of EU. Hence, the results in general are consistent with those above and support that the degree of aggregation correlates positively with the growing hydrophobicity of HAs.

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

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

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.

No MeSH data available.