title: A unified multicomponent stress-diffusion model of drug release from non-biodegradable polymeric matrix tablets.
abstract: We propose a new transport model of drug release from hydrophilic polymeric matrices, based on Stefan-Maxwell flux laws for multicomponent transport. Polymer stress is incorporated in the total mixing free energy, which contributes directly to the diffusion driving force while leading to time-dependent boundary conditions at the tablet interface. Given that hydrated matrix tablets are dense multicomponent systems, extended Stefan-Maxwell (ESM) flux laws are adopted to ensure consistency with the Onsager reciprocity principle and the Gibbs-Duhem thermodynamic constraint. The ESM flux law for any given component takes into account the friction exerted by all other species and is invariant with respect to reference velocity, thus satisfying Galilean translational invariance. Our model demonstrates that penetrant-induced plasticization of polymer chains partially or even entirely offsets the steady decline of chemical potential gradients at the tablet-medium interface that drive drug release. Utilizing a Flory-Huggins thermodynamic model, a modified form of the upper convected Maxwell constitutive equation for polymer stress and a Fujita-type dependence of mutual diffusivities on composition, depending on parameters, Fickian, anomalous or case II drug transport arises naturally from the model, which are characterized by quasi-power-law release profiles with exponents ranging from 0.5 to 1, respectively. A necessary requirement for non-Fickian release in our model is that the matrix stress relaxation time is comparable to the time scale for water diffusion. Mutual diffusivities and their composition dependence are the most decisive factors in controlling drug release characteristics in our model. Regression of the experimental polymer dissolution and drug release profiles in a system of Theophylline/cellulose (K15M) demonstrate that API-water mutual diffusivity in the presence of excipient cannot generally be taken as a constant.
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Salehi
authors.affiliation: Dow Pharma and Food Solutions, The Dow Chemical Company, Midland, MI 48674, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Dow Pharma and Food Solutions, The Dow Chemical Company, Midland, MI 48674, USA.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Cabelka
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: rlarson@umich.edu.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Larson
mesh_terms: D000465:Algorithms; D002626:Chemistry, Pharmaceutical; D003198:Computer Simulation; D004058:Diffusion; D016503:Drug Delivery Systems; D005079:Excipients; D008962:Models, Theoretical; D010968:Plasticizers; D011108:Polymers / Q000737:chemistry*; D013607:Tablets / Q000737:chemistry*; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D005079:Excipients; D010968:Plasticizers; D011108:Polymers; D013607:Tablets; D014867:Water
keywords: Drug Release; Excipient; Modeling; Multicomponent diffusion