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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

Snapshots of MD simulations of methylurea aqueous solutions with and without nifedipine. Water molecules are deleted for the sake of clarity. The nifedipine molecule is in colored ball and stick, and methylurea molecules are in black line. (a–d) NF + MU + Water system. (a) t = 3 ns, OA direction; (b) t = 3 ns, OC direction; (c) t = 4 ns, OA direction; (d) t = 4 ns, OC direction. (e and f) MU + Water system, OA direction. (e) t = 3 ns; (f) t = 4 ns. OA, OB, and OC are the three dimensions of the cubic simulation boxes; O is the original point.
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fig3: Snapshots of MD simulations of methylurea aqueous solutions with and without nifedipine. Water molecules are deleted for the sake of clarity. The nifedipine molecule is in colored ball and stick, and methylurea molecules are in black line. (a–d) NF + MU + Water system. (a) t = 3 ns, OA direction; (b) t = 3 ns, OC direction; (c) t = 4 ns, OA direction; (d) t = 4 ns, OC direction. (e and f) MU + Water system, OA direction. (e) t = 3 ns; (f) t = 4 ns. OA, OB, and OC are the three dimensions of the cubic simulation boxes; O is the original point.

Mentions: The snapshots of simulated systems are provided in Figures 2–4. The representativeness of these snapshots was checked by examining the last 0.5 ns of each running trajectory. Both NF + UR + Water and UR + Water systems in Figure 2 appeared to be homogeneous solutions after the 3 ns simulation, with little structural changes perceived visually. Clearly, these two systems were still one-phase systems after the NPT runs. The NF + MU + Water and MU + Water systems, on the other hand, demonstrated significant aggregation of solute molecules after 3 ns as shown in Figures 3(a)-3(b) and Figure 3(e), respectively. Furthermore, in comparing frames captured at 3 (Figures 3(a), 3(b), and 3(e)) and 4 ns (Figures 3(c), 3(d), and 3(f)) from the same perspectives, drastic changes in the shape of aggregates were observed for both NF + MU + Water and MU + Water systems over the period of 1 ns, indicating that the aggregates were rather fluidic. While clearly in the aggregation mode, the translational movement of MU molecules swept across the whole simulation box in 1 ns, showing clearly a single-phase liquid system. Similar to the MU systems, significant aggregation of solutes was also observed in the NF + EU + Water (Figures 4(a)-4(b)) and the NF + BU + Water (Figures 4(c)-4(d)). The snapshots of the EU + Water and BU + Water systems were omitted due to their resemblance to Figure 4. When comparing frames of the EU and BU systems at 3 (Figures 4(a) and 4(c)) and 4 ns (Figures 4(b) and 4(d)), morphological changes of aggregates were also evident, albeit that solutes in these systems appeared to be in a more clearly defined “aggregation” mode constantly in 1 ns, in contrast to the UR and MU systems. Consequently, for the BU and EU systems, it is difficult to tell by visual inspection in 1 ns period whether the aggregates are still in a single phase with aqueous medium or phase-separated. Finally, in all models simulated, the aggregation was found nonstoichiometric, and little parallel stacking was perceived among the solute molecules.


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

Cui Y - J Pharm (Cairo) (2013)

Snapshots of MD simulations of methylurea aqueous solutions with and without nifedipine. Water molecules are deleted for the sake of clarity. The nifedipine molecule is in colored ball and stick, and methylurea molecules are in black line. (a–d) NF + MU + Water system. (a) t = 3 ns, OA direction; (b) t = 3 ns, OC direction; (c) t = 4 ns, OA direction; (d) t = 4 ns, OC direction. (e and f) MU + Water system, OA direction. (e) t = 3 ns; (f) t = 4 ns. OA, OB, and OC are the three dimensions of the cubic simulation boxes; O is the original point.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Snapshots of MD simulations of methylurea aqueous solutions with and without nifedipine. Water molecules are deleted for the sake of clarity. The nifedipine molecule is in colored ball and stick, and methylurea molecules are in black line. (a–d) NF + MU + Water system. (a) t = 3 ns, OA direction; (b) t = 3 ns, OC direction; (c) t = 4 ns, OA direction; (d) t = 4 ns, OC direction. (e and f) MU + Water system, OA direction. (e) t = 3 ns; (f) t = 4 ns. OA, OB, and OC are the three dimensions of the cubic simulation boxes; O is the original point.
Mentions: The snapshots of simulated systems are provided in Figures 2–4. The representativeness of these snapshots was checked by examining the last 0.5 ns of each running trajectory. Both NF + UR + Water and UR + Water systems in Figure 2 appeared to be homogeneous solutions after the 3 ns simulation, with little structural changes perceived visually. Clearly, these two systems were still one-phase systems after the NPT runs. The NF + MU + Water and MU + Water systems, on the other hand, demonstrated significant aggregation of solute molecules after 3 ns as shown in Figures 3(a)-3(b) and Figure 3(e), respectively. Furthermore, in comparing frames captured at 3 (Figures 3(a), 3(b), and 3(e)) and 4 ns (Figures 3(c), 3(d), and 3(f)) from the same perspectives, drastic changes in the shape of aggregates were observed for both NF + MU + Water and MU + Water systems over the period of 1 ns, indicating that the aggregates were rather fluidic. While clearly in the aggregation mode, the translational movement of MU molecules swept across the whole simulation box in 1 ns, showing clearly a single-phase liquid system. Similar to the MU systems, significant aggregation of solutes was also observed in the NF + EU + Water (Figures 4(a)-4(b)) and the NF + BU + Water (Figures 4(c)-4(d)). The snapshots of the EU + Water and BU + Water systems were omitted due to their resemblance to Figure 4. When comparing frames of the EU and BU systems at 3 (Figures 4(a) and 4(c)) and 4 ns (Figures 4(b) and 4(d)), morphological changes of aggregates were also evident, albeit that solutes in these systems appeared to be in a more clearly defined “aggregation” mode constantly in 1 ns, in contrast to the UR and MU systems. Consequently, for the BU and EU systems, it is difficult to tell by visual inspection in 1 ns period whether the aggregates are still in a single phase with aqueous medium or phase-separated. Finally, in all models simulated, the aggregation was found nonstoichiometric, and little parallel stacking was perceived among the solute molecules.

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