Effect of the surface free energy of materials on the lamination tendency of bilayer tablets Kitti Papós a , Péter Kása Jr. a , Ilija Ili9 c b , Sandra Blatnik-Urek c , Géza Regdon Jr. a , Stane Sr9 ci9 c b , Klára Pintye-Hódi a , Tamás Sovány a, * a Department of Pharmaceutical Technology, University of Szeged, Eötvös u. 6, Szeged H-6720, Hungary b Department of Pharmaceutical Technology, University of Ljubljana, Ašker9 ceva cesta 7, Ljubljana 1000, Slovenia c Krka d.d., Šmarješka cesta 6, Novo mesto 8501, Slovenia A R T I C L E I N F O Article history: Received 23 September 2015 Received in revised form 24 October 2015 Accepted 26 October 2015 Available online 4 November 2015 Keywords: Bilayer tablets Lamination tendency Surface free energy Plasto-elastic behaviour A B S T R A C T Dosage forms with fixed dose combinations of drugs is a frequent and advantageous mode of administration, but their production involves a number of technological problems. Numerous interactions in a homogeneous vehicle may be avoided through the use of layered tablets. The mechanical properties of these dosage forms depend on numerous process parameters and material characteristics. The aim of the present study was a detailed investigation of the relationships between the surface characteristics and deformation properties of tableting materials and the tendency of bilayer tablets to undergo lamination. Bilayer tablets were compressed from unlubricated materials with different plastic–elastic properties and surface free energies according to a mixed 2 and 3-level half-replicated factorial design. The results revealed that the surface characteristics play the main role in the lamination of layered tablets and the effect of the plastic–elastic behavior cannot be interpreted without a knowledge of these properties. ã 2015 Elsevier B.V. All rights reserved. 1. Introduction Fixed dose combinations are of increasing interest in pharma- ceutical therapy and among the most commonly used therapeutic systems. In consequence of the synergism of the drugs the doses administered can be reduced considerably. The likelihood of the occurrence of side-effects is therefore lower, which can lead to enhanced patient compliance. The simplest mode of formulation of combined drugs is to disperse them in a homogeneous vehicle, but unexpected chemical and physical incompatibilities can occur because of the extensive intimate contact of the different components (Belda and Mielck, 2006). This problem can be solved by the formulation of bi- or even multilayer tablets. Such dosage forms have a number of advantages, such as a decrease of the incompatibility problems (Jayaprakash et al., 2011), the ensurance of different release kinetics for the different drugs, or biphasic release of the drugs (Ryakala et al., 2015; Dey et al., 2012). The use of various modified- release forms in double-layer tablets can be accompanied by various therapeutic advantages, such as prolongation of the release of a conventional tablet form which normally has a rapid release profile (Krishnaiah et al., 2002), or the provision of an alternative to patent-protected modified-release technology (Choi et al., 2000). However, the development of such layered tablets is rather complex, and certain of the process and materials parameters exert a considerable influence on the critical mechanical properties, and especially the lamination of the tablets. The widely-used method of preparing double-layer tablets is to subject the lower layer to a precompression force and then to apply the second layer with the main compression force. The lamination can be by both the precompression force and the main compression force, and also the compression speed significantly affected. (Vaithiyalingam and Sayeed, 2010; Kottala et al., 2012a). A high precompression force enables a clear identification of the layer borders, but it also decreases the roughness of the interfacial surface (Kottala et al., 2012b), which enhances the possibility of lamination through a diminution of the contact surface between the layers. This phenomenon is more pronounced if plastic materials are compressed in the first layer (Vaithiyalingam and Sayeed, 2010; Kottala et al., 2012a). Besides the plastic/brittle behavior of the tablet materials used, other important material characteristics, such as the size and shape of the particles, can significantly influence the flow properties and rearrangement profile of the materials (Sandler and Wilson, 2010). These parameters also affect * Corresponding author. Fax:+36 62545571. E-mail address: t.sovany@pharm.u-szeged.hu (T. Sovány). http://dx.doi.org/10.1016/j.ijpharm.2015.10.061 0378-5173/ ã 2015 Elsevier B.V. All rights reserved. International Journal of Pharmaceutics 496 (2015) 609–613 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsev ier.com/locate /ijpharm