Diffusion of Drug Molecules in Polymeric Membranes- Molecular Dynamics Simulations and Free Volume Theory Analysis

• Main Authors: Ching Ya Wang, 王靜亞
• Other Authors: Da Ming Wang
• Format: Others
• Language: en_US
• Published: 2002
• Online Access: http://ndltd.ncl.edu.tw/handle/48228843603275240336

博士 === 國立臺灣大學 === 化學工程學研究所 === 90 === In the first part of the present study, the effect of swelling on the diffusion of drug molecules is examined by diffusion theories. On the basis of the Flory-Huggins and Yasuda theories, an equation which expresses the diffusion coefficient of drug molecules in powers of the activity of swelling agent is deduced. In the second part of the present study, molecular dynamics (MD) simulations were performed to investigate the diffusion of drugs in polymer membranes. The microscopic information concerning the intermolecular forces and the dynamics of polymers, which is not readily available by experiments, can be obtained by MD. In addition, the free volume theory, which is commonly used to explain the penetrant diffusion within polymer systems, would be invoked to analyze the simulation results. Initially, the validations of the simulated packing models are examined by comparing the simulated and experimental x-ray diffraction spectra. Afterwards, the diffusion coefficients of drug molecules are calculated and compared with available experimental data. In order to clarify the effect of swelling agents, the diffusion mechanisms of drugs under various swelling conditions are demonstrated such that the complex interplay among drugs, swelling agents and polymer membranes can be revealed. In pure polymer system, it seems that the ignorance of the energy term may lead to unexpected deviations from what the free volume theory estimates. The importance of the intermolecular forces between drugs and polymers are also manifested: the aspirin molecule is dragged by the stronger attraction forces from the host PVA matrices so that it performs reptile diffusive motions instead of the “hopping mechanism”; on the other hand, the hydrophobic benzocaine molecule would confine the local polymer chain dynamics and lead to a lower accessible free volume, which results in lower diffusion rates in compared with hydrophilic theophyllin molecules. As the swelling agents (water molecule) increases, the interaction between the drugs and polymers becomes modified. In pure water systems, the drug molecule shows a fluid-like diffusion mechanism, which differs from that in pure polymer membranes. Under such circumstances, the steric effect becomes more decisive than others on the diffusion of drugs. Consequently, a bulky penetrant, like theophylline, would diffuse slower than linear ones. However, in swollen membranes, a dual mode diffusion mechanism of the drug molecule is observed. Besides, it is found that some of the water molecules disperse individually into the polymer matrices, while others may get clustered. The higher the swelling condition is, the more and larger the water clusters become. From this point of view, the whole system is no longer microscopically homogeneous and two distinct domains, the water-decorated polymer domain and the water cluster domain, can be seen within swollen membranes. Therefore, it is clearly that the swollen membrane provides two paths for drugs to diffuse, which clearly explains why both the hopping and fluid-like diffusion mechanisms are performed alternatively.