Controlled-release drug delivery systems are being developed as an alternative to conventional medical drug therapy regimens which require frequent administrations due to short pharmaceutical in vivo half-life and poor oral bioavailability. Controlled-release systems have the potential to provide better control of drug concentrations, reduce side effects, and improve compliance as compared to conventional regimens. The model-based design of controlled-release devices, such as biodegradable poly(lactic-co-glycolic acid) (PLGA) polymer microspheres, is challenging because of incomplete understanding of the mechanisms that regulate the release of drug molecules. This research focuses on modeling the autocatalytic polymer degradation and release of dispersed drug molecules from PLGA microspheres to capture size-dependent heterogeneous degradation behavior observed experimentally but not accounted for by existing models. Recently, other researchers have suggested that the autocatalytic polymer degradation is the primary mechanism by which the diffusive drug release is accelerated, and this process should depend strongly on particle size. The hypothesis of the present work is that simultaneously modeling the mathematics of diffusion, autocatalytic chemical reactions, chemical equilibria, and pore formation, the phenomena which are considered to contribute to the degradation of polymer particles, rather than independently modeling any of the phenomena in a purely sequential manner will accurately mimic the actual overall release process. The developed model tracks acid concentration as a function of space and time for determination of intraparticle pH while modeling degradation kinetics, molecular weight distribution variation, and drug transport with varying diffusivity coupled to the concentrations of other reacting species—all of which influence drug release from the polymer microspheres. Acid is considered from two sources—acid found in the external media and the acid produced from dissociation of the carboxylic acid end groups of PLGA. The chemical reaction mechanism including autocatalytic effects is coupled to a simplified diffusion model and pore formation model to incorporate spatial variations in degradation rate for all species within the microspheres. The inclusion of the spatial variation of autocatalytic effects is a unique contribution of this modeling work.

The presentation will also discuss the application of the model for the design and evaluation of different hydrolytically degradable polymeric materials which decompose by the bulk-eroding mechanism in drug delivery systems as PLGA does. Material design variables include the molecular weight distribution, the pore size distribution, and the chemical structure of the polymer. These variables can be optimized simultaneously with the particle size to provide for a desired controlled release profile.