Research paper Ethylene vinyl acetate as matrix for oral sustained release dosage forms produced via hot-melt extrusion A. Almeida a , S. Possemiers b , M.N. Boone c , T. De Beer d , T. Quinten a , L. Van Hoorebeke c , J.P. Remon a , C. Vervaet a,⇑ a Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium b Laboratory of Microbial Ecology and Technology, Ghent University, Ghent, Belgium c Centre for X-ray Tomography (UGCT), Department of Physics and Astronomy, Ghent University, Ghent, Belgium d Laboratory of Pharmaceutical Process Analytical Technology, Ghent University, Ghent, Belgium article info Article history: Received 23 June 2010 Accepted in revised form 6 December 2010 Available online 17 December 2010 Keywords: Hot-melt extrusion Ethylene vinyl acetate Sustained release Multiple-unit dosage form Matrix system Metoprolol tartrate abstract Different ethylene vinyl acetate grades (EVA9, EVA15, EVA28 and EVA40 having a VA content of 9%, 15%, 28% and 40%, respectively) were characterized via differential scanning calorimetry. Glass transition tem- perature (T g ), polymer crystallinity, melting point and polymer flexibility were positively influenced by the vinyl acetate content. The processability of EVA-based formulations produced by means of hot-melt extrusion (2 mm die) was evaluated in function of VA content, extrusion temperature (60–140 °C) and metoprolol tartrate (MPT, used as model drug) concentration (10–60%). Matrices containing 50% MPT resulted in smooth-surfaced extrudates, whereas at 60% drug content severe surface defects (shark skin- ning) were observed. Drug release from EVA/MPT matrices (50/50, w/w) was affected by the EVA grades: 90% after 24 h for EVA15 and 28, while EVA9 and EVA40 formulations released 80% and 60%, respectively. Drug release also depended on drug loading and extrusion temperature. For all systems, the total matrix porosity (measured by X-ray tomography) was decreased after dissolution due to elastic rearrangement of the polymer. However, the largest porosity reduction was observed for EVA40 matrices as partial melt- ing of the structure (melt onset temperature: 34.7 °C) also contributed (thereby reducing the drug release pathway and yielding the lowest release rate from EVA40 formulations). The Simulator of the Human Intestinal Microbial Ecosystem (SHIME) used to evaluate the stability of EVA during gastrointestinal transit showed that EVA was not modified during GI transit, nor did it affect the GI ecosystem following oral administration. Ó 2010 Elsevier B.V. All rights reserved. 1. Introduction Hot-melt extrusion (HME) is a well-known technique in the field of polymer science, and it has proven to be a useful tool for pharmaceutical purposes to develop immediate- or sustained-re- lease formulations. Compared with other techniques, HME has a lower environmental impact (absence of solvents) and reduced costs (few processing steps, continuous operation) [1–3]. As sus- tained release dosage forms have an important role to improve the life quality of chronic and poly-medicated patients by reducing their daily intake of dosage forms, considerable research efforts have been directed towards the use of polymers that provide prac- tical, safe and controlled long-term delivery of drugs. Several poly- mers, suitable for pharmaceutical HME applications have been identified (ethylcellulose, polymethacrylate, hydroxypropylcellu- lose, polyethylene oxide, polyvinylalcohol, etc.) [4–7], but the majority of them require a plasticizer to improve the elasticity and flexibility of the polymers [8–11]. This results in several restrictions related to polymer/plasticizer miscibility, plasticizer concentration, interactions with drug and polymer. In contrast, ethylene vinyl acetate (EVA) does not require a plasticizer to obtain good quality extrudates. EVA is a copolymer of ethylene and vinyl acetate (VA). While polyethylene is a semicrystalline polymer with alternating crystal- line lamellae (with different types of crystals) and amorphous do- mains, the incorporation of VA co-monomer units (typically the VA content varies between 9% and 40%) into a polyethylene backbone chain induces differences in crystallinity and crystalline structure, melting point, solubility, density and glass transition temperature, affecting the flexibility and thermoplastic characteristics of EVA [12,13]. Therefore, the versatility of EVA for hot melt processing re- sulted in a wide spectrum of applications [14]. In the pharmaceu- tical field, it has been specifically used for the development of films 0939-6411/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.ejpb.2010.12.004 ⇑ Corresponding author. Address: Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium. Tel.: +32 (0) 9 264 8069. E-mail address: Chris.Vervaet@UGent.be (C. Vervaet). European Journal of Pharmaceutics and Biopharmaceutics 77 (2011) 297–305 Contents lists available at ScienceDirect European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb