Development of a new test for the easy characterization of the adhesion at the interface of bilayer tablets: Proof-of-concept study by experimental design Virginie Busignies a, b, *, Vincent Mazel b , Harona Diarra a, b , Pierre Tchoreloff b a Univ Paris-Sud UFR de Pharmacie, 92296 Châtenay-Malabry, France b Institut de Mécanique et d'Ingénierie, I2M, UMR CNRS 5295, Bordeaux, France A R T I C L E I N F O Article history: Received 24 July 2014 Received in revised form 18 October 2014 Accepted 21 October 2014 Available online 1 November 2014 Keywords: Bilayer tablet Interfacial strength Delamination Elasticity Test device A B S T R A C T Although, adhesion at the interface of bilayer tablets is critical for their design it is difficult to characterize this adhesion between layers. In view of this, a new test with an easy implementation was proposed for the characterization of the interface of bilayer tablets. This work is presented as a proof-of-concept study to investigate the reliability of this new test with regard to the effects of some critical process parameters (e.g., compaction pressure applied on each layer) and material attributes (e.g., elasticity of the layered materials) on the interfacial adhesion of bilayer tablets. This was investigated using a design of experiment approach and the results obtained were in good accordance with those obtained with other tests and thus, confirms the potential of such a method for the measurement of the interfacial adhesion of bilayer tablets. ã 2014 Elsevier B.V. All rights reserved. 1. Introduction The benefits of bilayer tablets are now recognized especially for controlled release drug delivery systems (Abebe et al., 2014). Despite the attractiveness of this dosage form, it remains difficult to manufacture. The main problem is the occurrence of fractures at the interface due to insufficient adhesion between layers (Akseli et al., 2013; Busignies et al., 2013; Kottala et al., 2013). The lamination of bilayer tablets may take place immediately after compaction or also at a later stage, during storage (Inman et al., 2007; Klinzing and Zavaliangos, 2013). Some explanations for delamination at the bilayer interface are proposed e.g., the elastic mismatch between layers is one of them (Anuar and Briscoe, 2010; Busignies et al., 2013; Podczeck, 2011; Podczeck et al., 2006; Podczeck and Al-Muti, 2010). Previous studies showed also the importance of the role of compaction pressure applied to the first layer (Akseli et al., 2013; Dietrich et al., 2000; Inman et al., 2009, 2007; Kottala et al., 2013, 2012a; Vaithiyalingam and Sayeed, 2010) It is generally recommended to use low pressure level for the pre- compaction step. Another difficulty is the characterization of the adhesion between layers. Different devices have been proposed in the literature such as the diametral compression test (Belda and Mielck, 2006), the axial strength test (Akseli et al., 2013; Inman et al., 2007), the three-point bending test (Busignies et al., 2013; Wu and Seville, 2009), the shear test (Dietrich et al., 2000), and the friability test (Niwa et al., 2013). The friability test is easy to perform but has the disadvantage not being able to measure a breaking force. In other cases, the tests are not easy to perform and the use of adjuvant (e.g., glue) is necessary. Recently, we proposed a new flexural test adapted to the bilayer tablet (Busignies et al., 2013) and which is easy to perform. Thanks to the test configuration, the maximal tensile stress is located on the lower side of the parallelepipedical tablets at the interface between the two layers, thus, the breaking force is directly correlated with the interfacial layer adhesion. However, the tested samples differ greatly from industrial pharmaceutical tablets. Since, to be in compliance with industrial requirements, industrial tablets should be tested, we developed a new test capable of characterizing bilayer tablets produced with industrial bilayer presses. The specifications were that the novel test device should be able to easily characterize the adhesion at the interface of cylindrical bilayer tablets produced with industrial presses without prior sample preparation. The aim of the present proof-of-concept study is to investigate the reliability of the new test for the characterization of the * Corresponding author at: Univ Paris-Sud, UFR de Pharmacie, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France. Tel.: +33 1 46 83 57 15; fax: +33 1 46 83 59 63. E-mail address: virginie.busignies@u-psud.fr (V. Busignies). http://dx.doi.org/10.1016/j.ijpharm.2014.10.051 0378-5173/ ã 2014 Elsevier B.V. All rights reserved. International Journal of Pharmaceutics 477 (2014) 476–484 Contents lists available at ScienceDirect International Journal of Pharmaceutics journa l home page : www.e lsevier.com/loca te/ijpharm