ABSTRACT
CONTEXT: Using chemical penetration enhancers to improve the penetration effect is one kind of important strategies in transdermal drug delivery system. Azone is a widely used transdermal absorption enhancer for transdermal drug delivery. To shed light on the permeation-promoting mechanism of azone, we selected ternary systems formed by azacyclopentane-2-one and N-methylolacetamide (1: 2) and explored the synergetic effect of hydrogen-bonding interactions among them and their thermodynamic properties. The findings indicate that the synergetic effects can enhance the ability of azone to change the original conformation of ceramides and even break the original hydrogen bonds, which is more beneficial for azone to destroy the 3D network structure of ceramides. When azone interacts with ceramide, the order of action tends to interact with one molecule of ceramide first and then with another molecule of ceramide. METHODS: The synergetic effects of hydrogen-bonding interactions in ternary systems were computed at the B3LYP/6-311 + + G** and MP2(full)/6-311 + + G** levels. Thermodynamic parameters for two ternary-complex routes were worked out at the B3LYP/aug-cc-pVDZ level. The shift of the electron density occurring simultaneously with trimer formation was analyzed at the MP2(full)/6-311 + + G** level. The above calculations were carried out using the Gaussian 03 program packages. Atoms in molecules (AIM) method and the AIMPAC program showed the topological charge density at the MP2(full)/6-311 + + G** level. The synergetic effects of hydrogen-bonding interactions and thermodynamic property in the 1: 2 (azacyclopentane-2-one: N-methylolacetamide) ternary systems were investigated using the B3LYP and MP2(full) methods.
ABSTRACT
The structures of the N-(hydroxymethyl)acetamide (model molecule of ceramide) dimers have been fully optimized at B3LYP/6-311++G** level. The intermolecular hydrogen bonding interaction energies have been calculated using the B3LYP/6-311++G**, B3LYP/6-311++G(2df,2p), MP2(full)/6-311++G** and MP2(full)/6-311++G(2df,2p) methods, respectively. The results show that the O-H···O, N-H···O, O-H···N, and C-H···O hydrogen bonding interactions could exist in N-(hydroxymethyl)acetamide dimers, and the O-H···O, N-H···O, and O-H···N hydrogen bonding interactions could be stronger than C-H···O. The three-dimensional network structure formed by ceramide molecules through intermolecular hydrogen bonding interactions may be the main reason why the stratum corneum of skin could prevent foreign substances from entering our body, as is in accordance with the experimental results. The stability of hydrogen-bonding interactions follow the order of (a) > (b) ≈ (c) > (d) > (e) ≈ (f) > (g) > (h). The analyses of the energy decomposition, frequency, atoms in molecules (AIM), natural bond orbital (NBO), and electron density shift are used to further reveal the nature of the complex formation. In the range of 263.0-328.0 K, the complex is formed via an exothermic reaction, and the solvent with lower temperature and dielectric constant is favorable to this process. Graphical abstract The structures and the O-H···O=C, N-H···O=C and C-H···O=C H-bonding interactions in the N-(hydroxymethyl)acetamide (model molecule of ceramide) dimers were investigated using the B3LYP and MP2(full) methods.
