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

Cui Y - J Pharm (Cairo) (2013)

Bottom Line: A poorly water-soluble compound, nifedipine (NF), was used as the model solute that was solubilized.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.


Related in: MedlinePlus

Nifedipine-urea derivative radial distribution functions in four hydrotropic solutions. (a) NF + UR + Water system; (b) NF + MU + Water system; (c) NF + EU + Water system; (d) NF + BU + Water system.
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fig5: Nifedipine-urea derivative radial distribution functions in four hydrotropic solutions. (a) NF + UR + Water system; (b) NF + MU + Water system; (c) NF + EU + Water system; (d) NF + BU + Water system.

Mentions: We further examined structural evolutions of the simulated solutions by inspecting radial distribution functions (RDFs) within and between each type of molecules. Figure 5 depicts RDFs between NF and four hydrotropic agents as averaged over the periods of 0–100 ps (t = 0) and 2-3 ns (t = 3 ns), respectively. The NF-UR RDFs in Figure 5(a) show that the peak shifted to a shorter distance and was slightly strengthened after the simulation, indicating a weak but positive aggregation of the NF and UR molecules. This effect was too minor to be visually perceived from the snapshots in Figure 2. Additionally, Figures 5(b)–5(d) record clear and significant peak strengthening towards closer distances for the remaining three hydrotropic solutions after 3 ns. Furthermore, the NF-Water RDFs for the four hydrotropic solutions are given in Figure 6. Except for the NF + UR + Water system (Figure 5(a)), which exhibits a fairly minor change, the remaining three (Figures 5(b)–5(d)) all show significant declines in water concentration in the neighborhood of the NF molecule after 3 ns, suggesting that the aggregation reduces the exposure of NF to the solvent. This is consistent with the visual observations presented earlier and confirms that significant aggregations took place in these solutions.


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

Cui Y - J Pharm (Cairo) (2013)

Nifedipine-urea derivative radial distribution functions in four hydrotropic solutions. (a) NF + UR + Water system; (b) NF + MU + Water system; (c) NF + EU + Water system; (d) NF + BU + Water system.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4590820&req=5

fig5: Nifedipine-urea derivative radial distribution functions in four hydrotropic solutions. (a) NF + UR + Water system; (b) NF + MU + Water system; (c) NF + EU + Water system; (d) NF + BU + Water system.
Mentions: We further examined structural evolutions of the simulated solutions by inspecting radial distribution functions (RDFs) within and between each type of molecules. Figure 5 depicts RDFs between NF and four hydrotropic agents as averaged over the periods of 0–100 ps (t = 0) and 2-3 ns (t = 3 ns), respectively. The NF-UR RDFs in Figure 5(a) show that the peak shifted to a shorter distance and was slightly strengthened after the simulation, indicating a weak but positive aggregation of the NF and UR molecules. This effect was too minor to be visually perceived from the snapshots in Figure 2. Additionally, Figures 5(b)–5(d) record clear and significant peak strengthening towards closer distances for the remaining three hydrotropic solutions after 3 ns. Furthermore, the NF-Water RDFs for the four hydrotropic solutions are given in Figure 6. Except for the NF + UR + Water system (Figure 5(a)), which exhibits a fairly minor change, the remaining three (Figures 5(b)–5(d)) all show significant declines in water concentration in the neighborhood of the NF molecule after 3 ns, suggesting that the aggregation reduces the exposure of NF to the solvent. This is consistent with the visual observations presented earlier and confirms that significant aggregations took place in these solutions.

Bottom Line: A poorly water-soluble compound, nifedipine (NF), was used as the model solute that was solubilized.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.


Related in: MedlinePlus