International Journal of Pharmaceutics 411 (2011) 43–48 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Polymer leaching from film coating: Effects on the coating transport properties Mariagrazia Marucci a,b,∗ , Gert Ragnarsson c , Christian von Corswant b , Anette Welinder b , Annica Jarke b , Frida Iselau b , Anders Axelsson a a Department of Chemical Engineering, Lund University, P.O. Box 124, SE-221 00 Lund, Sweden b AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden c Medical Products Agency, P.O. Box 26, SE-751 03 Uppsala, Sweden article info Article history: Received 25 June 2010 Received in revised form 7 March 2011 Accepted 13 March 2011 Available online 21 March 2011 Keywords: Coating Modelling Pellets Polymer blend Release mechanism abstract The release mechanism of metoprolol succinate pellets coated with a blend of a water-insoluble poly- mer, ethyl cellulose (EC), and a water-soluble polymer, hydroxypropyl cellulose (HPC), is mechanistically explained. The kinetics of drug release and HPC leaching were followed for drug doses. The coating was initially not permeable to the drug, and release started only after a critical amount of the HPC had been leached out. Drug release occurred mainly through pores created in the coating by the HPC dissolution. Single-pellet release experiments were also performed. The coating thickness and size of each pellet were measured. In order to quantitatively characterize the transport properties of the coating of the individual pellets, and to determine the effective diffusion coefficient (D e ) of the drug in the coating, a mechanistic model was used to fit the single-pellet release data. It was found that D e increased with time due to an increase in the amount of HPC leached. It was also found that D e was dependent on the coating thickness, and increased more slowly with a thicker coating. This agreed well with the finding that the HPC leaching rate decreased with increasing film thickness. © 2011 Elsevier B.V. All rights reserved. 1. Introduction The blending of water-insoluble and water-soluble polymers for the controlled release of drugs from coated formulations has been described many times in the literature (Donbrow and Samuelov, 1980; Lindstedt et al., 1989; Umprayn et al., 1999; Tang et al., 2000; Lecomte et al., 2005; Strubing et al., 2007). The existence of a critical concentration of the water-soluble polymer, above which the water permeability and/or the drug permeability of the film increases drastically, has been observed in several cases (Tang et al., 2000; Lecomte et al., 2005; Marucci et al., 2009). For films made of ethyl cellulose (a water-insoluble polymer) and hydroxypropyl cellulose (a water soluble polymer), we have previously shown for water- soluble drugs that below the critical concentration the release mechanism is mainly osmotic pumping (Marucci et al., 2009, 2010), while above it the diffusional contribution becomes increasingly more significant (Marucci et al., 2009). A sigmoid release profile, showing a lag phase with an initially slow release rate followed by a gradual increase in the release rate, has been observed in many cases. During the lag phase the solvent crosses the coating, ∗ Corresponding author at: AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden. Tel.: +46 31 7064532; fax: +46 31 7763729. E-mail addresses: mariagrazia.marucci@astrazeneca.com, mariagrazia.marucci@gmail.com (M. Marucci). mass accumulates inside the formulation (Ensslin et al., 2008) and a hydrostatic pressure builds up (Marucci et al., 2008, 2009). In systems where cracks are not developed in the coating due to the pressure build-up, the length of the lag phase depends on the time required for the water-soluble polymer to leach out, creating a pore system that connects the inside of the formulation with the release medium (Marucci et al., 2009). During drug release, changes take place in the composition and structure of coating films composed of polymer blends due to leaching of the water-soluble polymer. We, recently, qualitatively studied the effects of the leaching of the water-soluble polymer on the properties of free films using a novel release cell. Free films of the water-insoluble ethyl cellulose (EC) and water-soluble hydrox- ypropyl cellulose (HPC) were investigated (Marucci et al., 2009). As HPC is not compatible with EC, phase separation occurs during the film formation process, resulting in regions very rich in HPC (Sakellariou et al., 1986, 1988; Sakellariou and Rowe, 1995). We have shown that the free films are initially not permeable to the drug, but films containing a high amount of HPC become perme- able due to HPC leaching. However, the effects of the leaching of the water-soluble polymer on the transport properties of the EC/HPC films were not quantitatively characterized. Moreover, no coated formulations were used in that study. Coated pellets can be compacted into a multiple-unit tablet or used to fill capsules, and are commonly used in oral modi- fied release formulations. The overall release is determined by the 0378-5173/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2011.03.022