(486c) Physicochemical Modeling of Drug Stability in Multilayer Polymeric Films Containing an Aqueous Moisture Barrier Layer

Designing a drug dosage form requires the inclusion of excipients that provide enhanced drug solubilization, drug stabilization, controlled release, flavor masking, dilution, among many other properties. The inclusion of these additives can often result in complex interactions requiring significant formulation development to identify the correct combination of additives for a specific active pharmaceutical ingredient. An alternative to this approach is to prepare excipients into discrete layers that provide their relative benefits without needing to identify all blend compatibilization and concerns. Multilayer films provide advantage of incorporating separate additives in separate layers in order to provide different functions such as enhancing aqueous solubility and bioavailability of Biopharmaceutical Classification System (BCS) Class-II and Class-IV drugs in the form of soluble polymeric drug dispersions, and including a beneficial layer of moisture barrier to maintain drug stability in storage. This separation also provides ease of developing mathematical modeling considering only one-dimensional transport for predictive impact during industrial formulation ensuring specific drug release profiles and stability requirements. Here, we model and develop a barrier layer to prevent/minimize water vapor permeation to the active layer so that water sensitive APIs can be protected to a stipulated level during the long-term storage.

Multilayer drug loaded films consisting polyvinyl alcohol (PVA) active layer and tannic acid modified chitosan barrier layer (both layers were prepared by solvent casting) are fabricated using a uniaxial heat press. Active and barrier layers are laminated by putting edible starch-based hot-melt adhesive made from powdered corn-syrup and fructose. Water vapor transmission through the barrier layer was determined by ASTM E96M moisture transmission test at a relative humidity of 70%. Water vapor transmission through the barrier layers is modeled by unsteady-state Fickian diffusion equation coupled with mass transfer at the surface and interface between two layers, and drug impurity formation kinetics. The partial differential equation (PDE) is solved by the method of lines, where ordinary differential equations (ODEs) obtained after spatial discretization are coupled with the ODEs from drug impurity formation kinetics. The water vapor concentration profiles in the barrier layer are used to find mass flux, mass flow rate and cumulative water transmission to the active layer. Data from the experimental water uptake by the active layer and impurity formation were fitted to the model profiles to optimize the transport (diffusivity), mass transfer (surface mass transfer coefficient, partition coefficient) and reaction kinetic constants based on <1% impurity formation in a year. Finally, relationship between film properties (types, thickness, moisture absorption, delamination upon solvation) and user provided requirements were established in order to develop a generalized procedure for drug formulations.