International Journal of Pharmaceutics 404 (2011) 133–141 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Release behaviour of clozapine matrix pellets based on percolation theory Ángela Aguilar-de-Leyva a,∗ , Tahmer Sharkawi b , Bernard Bataille b , Gilles Baylac b , Isidoro Caraballo a a Department of Pharmacy and Pharmaceutical Technology, University of Seville, Profesor Garcia González, 2, 41012 Seville, Spain b Laboratoire de Pharmacy Galénique et Genie Pharmaceutique, Université Montpellier 1, 15 Avenue Charles Flahault BP 14491, 34093 Montpellier Cedex 5, France article info Article history: Received 5 August 2010 Received in revised form 11 November 2010 Accepted 12 November 2010 Available online 19 November 2010 Keywords: Pellets Clozapine Hydroxypropylmethyl cellulose Percolation threshold abstract The release behaviour of clozapine matrix pellets was studied in order to investigate if it is possible to explain it applying the concepts of percolation theory, previously used in the understanding of the release process of inert and hydrophilic matrix tablets. Thirteen batches of pellets with different proportions of clozapine/microcrystalline cellulose (MCC)/hydroxypropylmethyl cellulose (HPMC) and different cloza- pine particle size fractions were prepared by extrusion–spheronisation and the release profiles were studied. It has been observed that the distance to the excipient (HPMC) percolation threshold is impor- tant to control the release rate. Furthermore, the drug percolation threshold has a big influence in these systems. Batches very close to the drug percolation threshold, show a clear effect of the drug particle size in the release rate. However, this effect is much less evident when there is a bigger distance to the drug percolation threshold, so the release behaviour of clozapine matrix pellets is possible to be explained based on the percolation theory. © 2010 Elsevier B.V. All rights reserved. 1. Introduction The pelletization process involves the agglomeration of active pharmaceutical ingredients and excipients in spherical units of size comprised between 0.5 and 1.5 mm called pellets (Bataille et al., 1993). These multiparticulate systems offer a wide range of therapeu- tic as well as technological advantages compared with monolithic systems: they disperse as individualized units in the gastroin- testinal tract reducing high local drug concentration (minimising side effects like the irritation of the gastric mucosa), maximising drug absorption and reducing peak plasma fluctuation. Another additional therapeutic advantage is that these dosage forms elim- inate the dependence of the drug effect on gastric emptying, thus reducing intra and interindividual variability of the drug plasma concentrations (Bechgaard and Hegermann Nielsen, 1978; Bodmeier, 1997). Examples of technological advantages of the pellets are their spherical shape, their narrow particle size distribution and their low friability which provide them very good flow properties and make it easier to coat them or include them into hard gelatin Abbreviations: MCC, microcrystalline cellulose; HPMC, hydroxypropylmethyl cellulose; cp, centipoise; CI, compresibility index; HR, Haussner ratio; SI, sphericity index. ∗ Corresponding author. Tel.: +34 676212688; fax: +34 954556085. E-mail addresses: aguilardeleyva@us.es, aadeleyva@hotmail.com (Á. Aguilar-de-Leyva). capsules as well as compress them into tablets (Reynolds, 1970). Moreover, these dosage forms allow combining non-compatible drugs or different drug release profiles in the same formulation (Pinto et al., 2001; Quintavalle et al., 2008). Pellets can be manufactured in different ways. Neverthe- less, the most popular method of producing pellets is by an extrusion–spheronisation process which involves four different stages: preparation of the wet mass (granulation), extrusion of the granulated mass to obtain cylindrical extrudates, rounding of the extrudates into spheres (spheronisation) and finally, drying of the spheres (Reynolds, 1970; Vervaet et al., 1995). The excipient most used to produce pellets by this technique is the microcrystalline cellulose due to its favourable plastic properties (Chatlapalli and Rohera, 1998; Delalonde et al., 1997). Clozapine is an atypical antipsychotic whose main indication is the treatment of resistant schizophrenia, although it has also demonstrated efficacy in the treatment of other conditions like schizoaffective disorders, bipolar depression and some neurolog- ical disorders. One important advantage of this drug is its low risk of producing side effects like extrapyramidal side effects, tar- dive diskynesia or elevated prolactine levels compared with other antipsychotics (Elizondo, 2008; Iqbal et al., 2003), which makes it one of the most used drugs in the treatment of schizophrenia. To the best of our knowledge, no pellet formulation of clozapine has been investigated; we therefore undertook formulation stud- ies in order to take advantage of these dosage forms for clozapine treatment. The percolation theory was introduced into the pharmaceutical field by Leuenberger and co-workers (Blattner et al., 1990; Bonny 0378-5173/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2010.11.024