International Journal of Pharmaceutics 458 (2013) 218–223 Contents lists available at ScienceDirect International Journal of Pharmaceutics journa l h o me pag e: www.elsevier.com/locate/ijpharm New insights on how to adjust the release profile from coated pellets by varying the molecular weight of ethyl cellulose in the coating film Mariagrazia Marucci a,∗,1 , Helene Andersson b,c,1 , Johan Hjärtstam a , Gary Stevenson a , Julia Baderstedt a , Mats Stading b,c , Anette Larsson d , Christian von Corswant a a AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden b SIK – The Swedish Institute for Food and Biotechnology, Structure and Material Design, P.O. Box 5401, SE-402 29 Gothenburg, Sweden c Chalmers University of Technology, Department of Material and Manufacturing Technology, SE-412 96 Gothenburg, Sweden d Chalmers University of Technology, Department of Chemical and Biological Engineering, SE-412 96 Gothenburg, Sweden a r t i c l e i n f o Article history: Received 25 July 2013 Received in revised form 10 September 2013 Accepted 15 September 2013 Available online 25 September 2013 Keywords: Ethyl cellulose Molecular weight Pellets Diffusion Phase separation Mathematical modeling a b s t r a c t The major aims of this work were to study the effect of the molecular weight (Mw) of ethyl cellulose (EC) on the drug release profile from metoprolol succinate pellets coated with films comprising EC and hydroxypropyl cellulose (HPC) with a weight ratio of 70:30, and to understand the mechanisms behind the different release profiles. A broad range of Mws was used, and the kinetics of drug release and HPC leaching followed. The higher the Mw of EC, the slower the HPC leaching and the drug release processes. Drug release occurred by diffusion through the pores created in the coating by the HPC leaching. A novel method was used to explain the differences in the release profiles: the effective diffusion coefficient (D e ) of the drug in the coating film was determined using a mechanistic model and compared to the amount of HPC leached. A linear dependence was found between D e and the amount of HPC leached and, importantly, the value of the proportionality constant decreased with increasing Mw of EC. This suggests that the Mw of EC affects the drug release profile by affecting the phase separated microstructure of the coating and the hindrance it imparts to drug diffusion. © 2013 Elsevier B.V. All rights reserved. 1. Introduction Insoluble polymer coatings are often used in oral controlled release systems for extended release of drugs. Ethyl cellulose (EC) is a water-insoluble polymer generally regarded as non-toxic and non-allergenic, it has good film forming properties and good sta- bility, and is the cellulosic polymer most commonly used for controlled release formulations. Due to the low permeability of pure EC, blends of EC and water-soluble polymers, such as hydrox- ypropyl cellulose (Donbrow and Samuleov, 1980; Marucci et al., 2010, 2011; Thombre et al., 1994; Umprayn et al., 1999), polyeth- ylene glycols (Donbrow and Samuleov, 1980) and hydroxypropyl methylcellulose (Hjärtstam and Hjertberg, 1998; Lindstedt et al., 1989), are often used in coatings. Although all the aforementioned water-soluble polymers can initially be co-dissolved with EC in a common solvent, phase separation occurs during the film forma- tion process as the solvent evaporates (Sakellariou et al., 1986). This results in a phase separated microstructure presenting domains ∗ Corresponding author. Tel.: +46 31 7064532; fax: +46 31 7763729. E-mail addresses: mariagrazia.marucci@astrazeneca.com, mariagrazia.marucci@gmail.com (M. Marucci). 1 The authors have equally contributed to the work. rich in the water-soluble polymer and domains rich in EC. Dur- ing solvent evaporation, the polymer concentration of the coating mixture increases, resulting in an increase in viscosity that leads to a loss in polymer mobility and at some point will cause the film microstructure to be frozen. The final domain size of the phase sepa- rated microstructure is affected by the extent of time the polymers have sufficient mobility to diffuse. For films made of EC and 30% (w/w) hydroxypropyl cellulose (HPC), it has been shown that the process parameters have a large impact on the final domains size and morphology, as well as on the film permeability (Marucci et al., 2013). Thus, it should be emphasized that any parameter that may affect the phase separated microstructure, for instance the molecu- lar weight (Mw) of the polymers, may also affect the mass transport properties of the final film. EC is available in a wide range of nominal viscosity grades vary- ing from 4 to 300 cP (representing the viscosity at 25 ◦ C of a 5% (w/w) solution in a solvent mixture of 80 parts toluene and 20 parts ethanol by weights), and a linear relationship has been obtained between the nominal viscosity and the Mw of EC (Rowe, 1982). It has been shown that the mechanical properties of free EC films (Rowe, 1986) or of films predominantly composed of EC (Andersson et al., 2013) are strongly dependent on the Mw of EC. The higher the Mw of EC, the better the mechanical properties of the films (Rowe, 1986). 0378-5173/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ijpharm.2013.09.016