(249a) Physicochemical Modeling of Dissolution and Stability of Poorly Soluble and Unstable Drug Loaded Multilayer Soluble Polymeric Films

Biopharmaceutical Classification System (BCS) Class-II and Class-IV drugs (active pharmaceutical ingredients, APIs) have low aqueous solubility and potentially low bioavailability. To overcome the limitations, soluble polymeric drug dispersion as films by either solvent casting or hot-melt extrusion is emerging as a feasible technique, where lab-scale tablet can be made by 3D printing. Film based solid dispersion of drug formulation can side-step and replace current legacy-based process design through iterative trial-and-error in pharmaceutical industries and facilitate a step-by-step highly scalable and rapidly implementable predictive physicochemical modeling based on drug release, storage stability and mechanical structure of the film. However, product design requirements need to be transformed to mathematical design instructions (dosage, release, stability, aesthetics, multiple APIs) for optimized tuning of the drug release rate, stabilization and dosage flexibility with continuous manufacturing to be predicted in advance. Predictive modeling is greatly simplified for a film-based approach that provide dimensional control by regulating transport and phase behavior to a 1D layer, thus streamlining manufacturing and scaling process. It also provides the opportunity for a multilayer film-based formulation for faster transition from bench to clinical trials to commercial production.

A mathematical modeling framework for the design and parameter optimization during the formulation of hydrophobic API-loaded soluble polymeric film formulations was implemented for the foundation for customer specific drug design in terms of dosage, release rate, storage stability (self-life) and mechanical properties (bending/cutting). Overall optimization initially involves two components: dissolution and stability models, which have to be solved simultaneously for targeted design requirements in terms of thickness, geometry, order, composition and number of layers. Unsteady-state Fickian diffusion describes both dissolution and stability modeling. During dissolution, the relative rate of water intrusion (swelling controlled) and polymer erosion from surface coupled with API diffusion primarily govern the observed release rates, correlated with expected different release mechanisms (immediate/slow). For stability against water/oxygen, barrier polymer layer is modeled by an unsteady-state diffusion of water/oxygen along with mass transfer (partition) in the surface and interface to achieve < 1% impurity formation within 12 months considering impurity formation kinetics. Polymer diffusivity, solubility, active layer and barrier layer thickness, area, mass transfer coefficients and relative rate constants can be estimated and optimized using the model. Physical properties are determined from thermodynamics. Prototype creation and characterization, experiments will provide physical parameters for release, uniformity, stability and dose scaling. Generic algorithm for optimization/parameter fitting is pursued, where inner loops consisting smaller modules (release, stability, structure) are encircled by outer overall optimization loop (onion model) until any of the constraints (total mass < 600 mg, total thickness < 17 mm, area <153 mm², and volume <1071 mm³) are met. The model is adaptive to progressive complexity such as presence of plasticizer/binders, glass-rubbery transition, phase separation, polymer diffusion, aqueous boundary layer, barrier dissolution and multi-dimensional transport, which can be independently adjusted, adapted and improved. Crystal or particle dissolution kinetics can be incorporated in case of crystalline/particulate drugs. Finally, film flexibility testing using 3-points flexural bending to express required mechanical properties (flexural stress, strain and modulus) in terms of force, deflection and dimension can also be incorporated in the overall optimization scheme.