(379g) Molecular Dynamics Study of Drug Diffusion In Hydrogels : Effect of Cross-Linking

Hydrogels, unique class of macromolecular networks that can hold a large fraction of an aqueous solvent within their structures are presently under investigation as a carrier in controlled delivery system for bioactive molecules, because of their similar physical properties as that of living tissues. Anionic hydrogels are used in the design of controlled release devices for site specific drug delivery of therapeutic proteins to large intestine since most of these proteins cannot sustain the acidic environment in stomach.

The functionality of the hydrogel system depends on both its structural and its dynamic properties. Structural aspects of the polymeric gel concern chain conformations, physical and/or chemical junctions, mesh size and the “structuring”/“destructuring” of water molecules due to the interaction of water with the hydrophyllic/hydrophobic polymeric components. Molecular structure of the hydrogel, can thus be characterized by cross-linking density which is a function of several parameters such as type and amount of cross-linking agent, temperature, method of cross-linking etc. The cross-linking density affects gel properties such as swelling, diffusion/release of molecules, stability and density. Experimental estimation of cross-linking density is expensive and time consuming.

In order to design gels for a given application such as drug-release, estimation of cross-linking density is important. Quite often one has to adapt a trial and error methodology to experimentally deduce the optimum cross-linking density for a given polymer – drug system, which is definitely time consuming and expensive. Computer simulations provide an excellent route to study polymer networks. While on one hand, they can reduce trial and error experimentation; on the other hand, they provide insightful information at molecular as well as micro length scales which are often not extracted from experiments. Molecular dynamics (MD) simulations which consider atomic details have been very successful in exploring various phenomena occurring at pico to nanosecond time scales and relating these phenomena to the structure and molecular chemistry. MD simulations also possess an inherent advantage over continuum modeling in addressing nanoscale interactions between water/drug and polymer networks which are crucial for designing gels for certain specialized applications such as control drug release.

In order to develop a robust and scalable MD methodology to study the effects of method of cross-linking and cross-linking density on diffusion of drug molecules in a polymeric network, we have chosen a model hydrogel system consisting of cross-linked Diglycidyl ether of bisphenol A(DGEBA) / Isophorone diamine(IPD). We present the effect of method of cross-linking and system size on cross-linking density. The diffusion of drug and water molecules in cross-linked polymer network have been studied for different cross-linking densities and system sizes. The effect of cross-linking density on gel properties such as swelling, diffusion/release of molecules, stability and density has been compared with experimental results.