Research paper Quantitative measurements of localized density variations in cylindrical tablets using X-ray microtomography Virginie Busignies a , Bernard Leclerc a , Patrice Porion b , Pierre Evesque c , Guy Couarraze a , Pierre Tchoreloff a, * a Centre d’e ´tudes Pharmaceutiques de l’Universite ´ Paris XI, Innovation Thera ´ peutique: du Fondamental au Me ´dicament, Cha ˆtenay-Malabry, France b Centre de Recherche sur la Matie `re Divise ´e – UMR 6619, CNRS and Universite ´ d’Orle ´ans, Orle ´ ans, France c Laboratoire de Me ´canique: Sols – Structure – Mate ´riaux – UMR 8579, Ecole centrale de Paris, Cha ˆtenay-Malabry, France Received 5 October 2005; accepted in revised form 17 February 2006 Available online 18 April 2006 Abstract Direct compaction is a complex process that results in a density distribution inside the tablets which is often heterogeneous. Therefore, the density variations may affect the compact properties. A quantitative analysis of this phenomenon is still lacking. Recently, X-ray microto- mography has been successfully used in pharmaceutical development to study qualitatively the impact of tablet shape and break-line in the density of pharmaceutical tablets. In this study, we evaluate the density profile in microcrystalline cellulose (Vivapur 12 Ò ) compacts obtained at different mean porosity (ranging from 7.7% to 33.5%) using X-ray tomography technique. First, the validity of the Beer–Lambert law is studied. Then, density calibration is performed and density maps of cylindrical tablets are obtained and visualized using a process with col- our-scale calibration plot which is explained. As expected, important heterogeneity in density is observed and quantified. The higher den- sities in peripheral region were particularly investigated and appraised in regard to the lower densities observed in the middle of the tablet. The results also underlined that in the case of pharmaceutical tablets, it is important to differentiate the mechanical properties representative of the total volume tablet and the mechanical properties that only characterize the tablet surface like the Brinell hardness measurements. Ó 2006 Elsevier B.V. All rights reserved. Keywords: X-ray tomography; Compaction; Tablet; Density distribution; Anisotropy; Quantitative analysis; 3D imaging; Mechanical properties 1. Introduction Direct compaction is commonly used in pharmaceutical industry to produce pharmaceutical tablets. The density distribution inside the tablets is often heterogeneous due to interparticle frictions and die wall frictions [1]. At the beginning of the compaction, interparticle frictions are pre- dominant, but the die wall frictions become more impor- tant when the pressures are increased. More, the shape of tablets used in pharmaceutical industry differs from flat- face cylindrical tablet to more complex geometries with various embossing. The consequence is that the density variations in pharmaceutical tablets may be important and affect the compact mechanical properties. Train [1] performed the first study on the density variation in pow- der compacts. Later, density distribution was investigated using NMR tomography [2] or autoradiography [3]. Sinka et al. [4] also used surface hardness tests on tablets’ cross- section. Recently, X-ray microtomography has been suc- cessfully used in pharmaceutical development. Farber et al. [5] used this method to study the porosity and the morphology of pharmaceutical granules. Sinka et al. [6] have shown the dependence of tablet shape and break-line on the density variations of pharmaceutical tablets. The X-ray tomography which allows 3D characteriza- tion of micro-structure has some advantages compared to other methods [7]. This is a nondestructive investigation 0939-6411/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ejpb.2006.02.007 * Corresponding author. Laboratoire de Physique Pharmaceutique, Centre d’e ´tudes Pharmaceutiques de l’Universite ´ Paris XI, 5 Rue Jean Baptiste Cle ´ment, 92296 Cha ˆtenay-Malabry Cedex, France. Tel.: +33 1 46 83 56 11; fax: +33 1 46 83 58 82. E-mail addresses: pierre.tchoreloff@phypha.u-psud.fr, pierre. tchoreloff@cep.u-psud.fr (P. Tchoreloff). www.elsevier.com/locate/ejpb European Journal of Pharmaceutics and Biopharmaceutics 64 (2006) 38–50