Research paper Study of the critical points and the role of the pores and viscosity in carbamazepine hydrophilic matrix tablets Ángela Aguilar-de-Leyva a , Celia Cifuentes a , Ali R. Rajabi-Siahboomi b , Isidoro Caraballo a,⇑ a Department of Pharmacy and Pharmaceutical Technology, University of Seville, Seville, Spain b Colorcon Inc. Global Headquarters, Harleysville, PA, USA article info Article history: Received 19 May 2011 Accepted in revised form 12 September 2011 Available online 17 September 2011 Keywords: Hydroxypropylmethyl cellulose Hydrophilic matrices Carbamazepine Tablet porosity Percolation threshold extended release abstract Percolation theory has been applied to estimate the Hypromellose (HPMC) percolation thresholds and the influence of the polymer viscosity and the initial porosity on these thresholds in carbamazepine multi- component matrix formulations. Different batches containing two viscosity grades of HPMC as hydrophilic matrix forming polymer, MCC and lactose as fillers, and a lubricant mixture have been manufactured varying the compression pressure in order to obtain matrices with three levels of initial porosity. The results suggested the exis- tence of an excipient percolation threshold between 13 and 15% v/v of HPMC for the different batches prepared. It has been found that the percolation threshold for this polymer is independent on the formu- lation factors studied in this paper: polymer viscosity and initial porosity of the matrices. Ó 2011 Elsevier B.V. All rights reserved. 1. Introduction Hydrophilic matrices are one of the most commonly employed extended release systems worldwide. These types of matrices have many favorable properties such as low cost and ease of manufac- ture, their proven record, and relative independent performance on the physico-chemical and physiological conditions of the gas- tro-intestinal tract [1]. These dosage forms are constituted by a dis- persion of a drug in a hydrophilic polymer, which in contact with water, swells and forms a gel or a colloid of high viscosity gelati- nous structure. Other excipients in the matrices are lubricant, gli- dant, water-soluble or water-insoluble fillers and pH modifiers if required [2,3]. Hydroxypropylmethyl cellulose (HPMC) is the most commonly used cellulose ether in the formulation of hydrophilic matrices for extended drug delivery [4]. This could be due to the wide approval as GRAS (Generally Regarded as Safe) by the regulatory bodies. Fur- thermore, it is compatible with numerous drugs, accommodates high levels of drug loading, and can be easily incorporated to form matrix tablets by direct blending or granulation [5]. The hydration of HPMC controls the drug release in swellable matrices, since it forms a barrier gel layer at the surface of the ma- trix, through which the drug is released by diffusion and/or erosion of the matrix [6]. Although the technology is well understood and utilized, there are a large number of research papers reporting about the complex mechanisms of drug release from these matrix systems [7–11]. Our research group has applied the concepts of the percolation theory to the study of extended release matrix systems including both hydrophilic and inert matrices [12–19]. This statistical theory was firstly applied to the field of pharmacy by Leuenberger and co- workers in the University of Basel [20–25]. This theory describes a cluster (called infinite, percolating or coherent), defined as a group of adjacent particles of the same component that extends from one side to the other sides of the system, acting as the outer phase of a disperse system. Otherwise, the cluster is called finite or isolated. The concentration of a component for which there is a maximum probability of appearance of an infinite cluster for the first time is called the percolation threshold of this component. This concen- tration is usually related to a critical point, because close to this point important changes in the properties of the system may be observed [26]. According to percolation theory, controlled release hydrophilic matrices must be formulated above the excipient percolation threshold. This fact assures that a coherent gel layer controlling the drug release rate is formed. The excipient percolation threshold is the limit between a fast release of the drug (below the excipient percolation threshold) and a drug release controlled by the forma- tion of a coherent gel layer (above the excipient percolation thresh- old) [17,27,28]. 0939-6411/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ejpb.2011.09.007 ⇑ Corresponding author. Department of Pharmacy and Pharmaceutical Technol- ogy, University of Seville, Professor García González, 2, 41012 Seville, Spain. Tel.: +34 954556136; fax: +34 954556085. E-mail address: caraballo@us.es (I. Caraballo). European Journal of Pharmaceutics and Biopharmaceutics 80 (2012) 136–142 Contents lists available at SciVerse ScienceDirect European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb