Modeling the Drug Release from Hydrogel-Based Matrices Diego Caccavo, † Sara Cascone, † Gaetano Lamberti,* ,† and Anna Angela Barba ‡ † Department of Industrial Engineering and ‡ Department of Pharmacy, University of Salerno, via Giovanni Paolo II, 132, 84084 Fisciano, Salerno, Italy ABSTRACT: In this work the behavior of hydrogel-based matrices, the most widespread systems for oral controlled release of pharmaceuticals, has been mathematically described. In addition, the calculations of the model have been validated against a rich set of experimental data obtained working with tablets made of hydroxypropyl methylcellulose (a hydrogel) and theophylline (a model drug). The model takes into account water uptake, hydrogel swelling, drug release, and polymer erosion. The model was obtained as an improvement of a previous code, describing the diffusion in concentrated systems, and obtaining the erosion front (which is a moving boundary) from the polymer mass balance (in this way, the number of fitting parameters was also reduced by one). The proposed model was found able to describe all the observed phenomena, and then it can be considered a tool with predictive capabilities, useful in design and testing of new dosage systems based on hydrogels. KEYWORDS: hydrogels, swelling, controlled release, transport phenomena, modeling ■ INTRODUCTION Hydrogel-based matrices are the most common controlled release devices among all the solid oral dosage forms. Their success is mainly related to their simplicity of production, their low development costs, and their high adaptability to delivery of different kinds of active molecules. Despite their spread in practical applications, the drug release mechanisms resulting from these systems are rather complex, and, depending on the polymer carrier, several aspects have to be taken into account. One of the main important hydrophilic carrier materials is hydroxypropyl methylcellulose (HPMC), which shows a peculiar release mechanism where diffusion and tablet swelling both play important roles. Indeed when a dry HPMC-based tablet is immersed in a physiological fluid, the solvent starts to penetrate inside the polymer matrix. As soon as the solvent concentration exceed a threshold value, polymeric chains unfold so that a glass-rubbery transition occurs and a gel-like layer is formed. 1 The moving front at which this process takes place is called the “swelling front”, which separates the swollen from nonswollen matrix. 2 In the swollen region the polymeric chains assume an elongated configuration that allows the contained drug molecules to easily diffuse toward the outer dissolution medium, once they are dissolved. Indeed depending on the drug solubility, in the swollen layer there could be a zone in which the drug coexists in the dissolved and dispersed forms. 3 The front that separates the swollen matrix, containing only dissolved drug, from the swollen part, containing both dissolved and dispersed drug, is called the “diffusion front”. Additionally, on the zone at which the swollen matrix is in contact with the outer medium, a third front can be defined: the “erosion front”. On this boundary the polymer network becomes extremely hydrated and a process like chain disentanglement takes place, “eroding” the matrix. 4 Recently, several methods have been developed to study the main phenomena involved in the drug release from a hydrogel- based matrix. These approaches vary from the consideration of thermodynamic parameters of activation to discriminate between diffusion and relaxation control for the solvent penetration and the drug release processes 5 to the measure- ment of the swelling and erosion fronts 6 varying the dissolution time. In fact, the understanding of swelling kinetics and erosion behavior can help in the prediction of drug release mechanism and kinetics. Swelling progression and mobility of water molecules inside polymers have been investigated by several techniques, including magnetic resonance imaging (MRI), atomic force microscopy (AFM), texture analyzer, and ultrasound techniques, all of them summarized in ref 7. Polymer erosion plays an important role in modulating drug release from hydrophilic matrices. 8 To calculate the degree and rate of polymer erosion, the amount of polymer that leaves the matrix and reaches the dissolution medium has to be quantified, taking into account that also different compositions of the same polymer can lead to different results. 9 This can be done using a gravimetric analysis, in which the masses of the matrix components are quantified, weighing the matrix before and after the dissolution, 10 or a phenol-sulfuric acid assay technique, in which the amount of polymer is determined Received: August 18, 2014 Revised: October 25, 2014 Accepted: December 11, 2014 Published: December 11, 2014 Article pubs.acs.org/molecularpharmaceutics © 2014 American Chemical Society 474 DOI: 10.1021/mp500563n Mol. Pharmaceutics 2015, 12, 474-483