Release kinetics from polymer-based membranes formed by phase inversion

The interplay between the dynamics of phase inversion, membrane formation, and drug release kinetics has been studied for solvent-cast films of a poly (n-butyl cyanoacrylate) (PBCA)-naproxen system. Films cast from solutions containing various amounts of polymer, solvent (acetone) and nonsolvent (water) were analyzed via electron microscopy to determine optimal compositions and casting conditions leading to the formation of desired porous morphologies. In the presence of drug, the formation and locking-in of porous morphologies is found to be controlled by the interplay between the plasticizing effects of the drug and its crystallization kinetics during the phase inversion. Drug release rates from dried films exhibit a non-monotonic pattern with drug loading (DL), depending on whether a collapsed, dense structure or a porous structure forms. The role of glass transition and crystallization for both as-cast and remelted films is separately analyzed by differential scanning calorimetry (DSC). The discussion includes an analysis of the effect of DL on the quaternary (polymer-solvent-nonsolvent-drug) phase diagram, indicating the role of glass composition curves on the locking-in process.;A generalized diffusion-dissolution model for the release kinetics of non-swelling and non-degradable rigid polymer matrices has been proposed by constructing finite dissolution rates for both the dissolved amorphous drug and the dispersed drug particles, respectively. The dissolved amorphous drug in the matrices was visualized as a step-function-type dissolution source releasing drug into the surrounding liquid phase according to the Noyes-Whitney equation. Source layers were applied to describe the dissolution rate for dispersed drug particles, and the focus was played on spherical drug particles with a delta-type dissolution rate based on the Noyes-Whitney equation. Asymptotic cases to the earlier published models have been developed and numerically evaluated to demonstrate the validity and generality of the proposed model. A technique with the Green's function was applied to transform the coupled partial differential equations (PDEs) into implicit integral solutions facilitating the numerical calculations to handle arbitrarily specified model parameters of the PDEs. Further, the integral form solutions provided a better insight into the effects of the meaningful variables on the release behavior than the direct numerical solutions to the PDEs. The effects of the Peclet numbers PeB (the external mass transfer resistance), Peds (the amorphous drug dissolution rate) and Pedp (the dispersed drug particle dissolution rate), have been investigated as well as the effects of the drug solubility in the release medium, the number of source layers, the membrane thickness and/or the particle sizes. It was found that Peds and Pe dp have more profound effects on the release behavior, and the significance of other parameters are determined by the conditions of specified Peclet numbers.;The influence of drug distribution on bursting during release from rigid polymer matrices has been quantified using the generalized diffusion-dissolution model for the release kinetics developed in this thesis study. It has been demonstrated that both the amount and distribution of amorphous drug and drug particles have a profound influence on the release kinetics. Higher amorphous concentrations in the top layer of the membrane lead to higher release rates and stronger initial bursting, and distributing more drug particles close to or at the membrane surface has the same effect. The presence of a boundary layer region in which the amorphous drug concentration drops to zero within very short time increases the contribution of amorphous drug to the burst effects, and also generates overall release profiles in close agreement with experimental data.