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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.


Radial distribution functions between urea derivatives. (a) UR-UR RDFs. Red open triangle: NF + UR + Water system, t = 3 ns; black cross: UR + Water system, t = 3 ns; blue line: NF + UR + Water system, t = 0 ns; purple line: UR + Water system, t = 0 ns; (b) MU-MU RDFs. Red open triangle: NF + MU + Water system, t = 3 ns; black cross: MU + Water system, t = 3 ns; blue line: NF + MU + Water system, t = 0 ns; purple line: MU + Water system, t = 0 ns; (c) EU-EU RDFs. Red open triangle: NF + EU + Water system, t = 3 ns; black cross: EU + Water system, t = 3 ns; blue line: NF + EU + Water system, t = 0 ns; purple line: EU + Water system, t = 0 ns; (d) BU-BU RDFs. Red open triangle: NF + BU + Water system, t = 3 ns; black cross: BU + Water system, t = 3 ns; blue line: NF + BU + Water system, t = 0 ns; purple line: BU + Water system, t = 0 ns.
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fig7: Radial distribution functions between urea derivatives. (a) UR-UR RDFs. Red open triangle: NF + UR + Water system, t = 3 ns; black cross: UR + Water system, t = 3 ns; blue line: NF + UR + Water system, t = 0 ns; purple line: UR + Water system, t = 0 ns; (b) MU-MU RDFs. Red open triangle: NF + MU + Water system, t = 3 ns; black cross: MU + Water system, t = 3 ns; blue line: NF + MU + Water system, t = 0 ns; purple line: MU + Water system, t = 0 ns; (c) EU-EU RDFs. Red open triangle: NF + EU + Water system, t = 3 ns; black cross: EU + Water system, t = 3 ns; blue line: NF + EU + Water system, t = 0 ns; purple line: EU + Water system, t = 0 ns; (d) BU-BU RDFs. Red open triangle: NF + BU + Water system, t = 3 ns; black cross: BU + Water system, t = 3 ns; blue line: NF + BU + Water system, t = 0 ns; purple line: BU + Water system, t = 0 ns.

Mentions: The comparison between the structures of the hydrotropic solutions with and without NF was conducted via the HA-HA and HA-H2O RDFs as shown in Figures 7 and 8, respectively. Again, the UR-UR (Figure 7(a)) and UR-H2O (Figure 8(a)) RDFs in both NF + UR + Water and UR + Water systems exhibited little changes after the simulations, while substantial increases in HA concentrations and decreases in water concentration near the HA molecules were revealed for the remaining six systems (Figures 7(b)–7(d) and 8(b)–8(d)). This confirms significant aggregations taking place in these systems. More importantly, the HA-HA and the HA-H2O RDFs of the four hydrotropic solutions (with NF) resemble closely their respective counterparts of the four HA solutions (without NF), suggesting that structurally the systems in the presence of NF correlate closely with their counterparts in the absence of NF. This advocates that the self-aggregation of HAs may be a prerequisite in enabling the incorporation of the drug into the HA aggregates. Interestingly, earlier reports [23–25] indicated that hydrotropic agents often tend to self-aggregate in aqueous solutions, which is consistent with the results above.


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

Cui Y - J Pharm (Cairo) (2013)

Radial distribution functions between urea derivatives. (a) UR-UR RDFs. Red open triangle: NF + UR + Water system, t = 3 ns; black cross: UR + Water system, t = 3 ns; blue line: NF + UR + Water system, t = 0 ns; purple line: UR + Water system, t = 0 ns; (b) MU-MU RDFs. Red open triangle: NF + MU + Water system, t = 3 ns; black cross: MU + Water system, t = 3 ns; blue line: NF + MU + Water system, t = 0 ns; purple line: MU + Water system, t = 0 ns; (c) EU-EU RDFs. Red open triangle: NF + EU + Water system, t = 3 ns; black cross: EU + Water system, t = 3 ns; blue line: NF + EU + Water system, t = 0 ns; purple line: EU + Water system, t = 0 ns; (d) BU-BU RDFs. Red open triangle: NF + BU + Water system, t = 3 ns; black cross: BU + Water system, t = 3 ns; blue line: NF + BU + Water system, t = 0 ns; purple line: BU + Water system, t = 0 ns.
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Related In: Results  -  Collection

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fig7: Radial distribution functions between urea derivatives. (a) UR-UR RDFs. Red open triangle: NF + UR + Water system, t = 3 ns; black cross: UR + Water system, t = 3 ns; blue line: NF + UR + Water system, t = 0 ns; purple line: UR + Water system, t = 0 ns; (b) MU-MU RDFs. Red open triangle: NF + MU + Water system, t = 3 ns; black cross: MU + Water system, t = 3 ns; blue line: NF + MU + Water system, t = 0 ns; purple line: MU + Water system, t = 0 ns; (c) EU-EU RDFs. Red open triangle: NF + EU + Water system, t = 3 ns; black cross: EU + Water system, t = 3 ns; blue line: NF + EU + Water system, t = 0 ns; purple line: EU + Water system, t = 0 ns; (d) BU-BU RDFs. Red open triangle: NF + BU + Water system, t = 3 ns; black cross: BU + Water system, t = 3 ns; blue line: NF + BU + Water system, t = 0 ns; purple line: BU + Water system, t = 0 ns.
Mentions: The comparison between the structures of the hydrotropic solutions with and without NF was conducted via the HA-HA and HA-H2O RDFs as shown in Figures 7 and 8, respectively. Again, the UR-UR (Figure 7(a)) and UR-H2O (Figure 8(a)) RDFs in both NF + UR + Water and UR + Water systems exhibited little changes after the simulations, while substantial increases in HA concentrations and decreases in water concentration near the HA molecules were revealed for the remaining six systems (Figures 7(b)–7(d) and 8(b)–8(d)). This confirms significant aggregations taking place in these systems. More importantly, the HA-HA and the HA-H2O RDFs of the four hydrotropic solutions (with NF) resemble closely their respective counterparts of the four HA solutions (without NF), suggesting that structurally the systems in the presence of NF correlate closely with their counterparts in the absence of NF. This advocates that the self-aggregation of HAs may be a prerequisite in enabling the incorporation of the drug into the HA aggregates. Interestingly, earlier reports [23–25] indicated that hydrotropic agents often tend to self-aggregate in aqueous solutions, which is consistent with the results above.

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.