International Journal of Pharmaceutics 387 (2010) 56–64 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Compaction properties, drug release kinetics and fronts movement studies from matrices combining mixtures of swellable and inert polymers. II. Effect of HPMC with different degrees of methoxy/hydroxypropyl substitution J.J. Escudero, C. Ferrero, M.R. Jiménez-Castellanos ∗ Dpto. Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Sevilla, C/Profesor García González n 2, 41012 Sevilla, Spain article info Article history: Received 15 July 2009 Accepted 1 December 2009 Available online 5 December 2009 Keywords: Hydroxypropyl methylcellulose Hydroxypropylcellulose-methyl methacrylate Substitution degree Release modulation Drug delivery system Theophylline abstract The aim of this paper is the modification of the release behaviour of hydrophilic HPMC-based matrices of different substitution degree (E4M, F4M, K4M) by the introduction of a new inert polymeric excipi- ent hydroxypropylcellulose-methyl methacrylate (HCMMA) at different proportions (75:25, 50:50 and 25:75). The product (HCMMA) was dried either in a vacuum oven – OD copolymers – or freeze-dried—FD copolymers. HPMC E4M formulations showed the worst compaction properties. All mixtures presented a percentage of theophylline release between 47% and 32% at 1440 min. The drying methods employed had only influence over the drug release in E4M and K4M formulations, at higher proportions of HCMMA, showing the highest release the mixtures containing OD-HCMMA. Combinations of diffusion and erosion release mechanisms were found to matrix tablets. All mixtures with F4M did not modify relaxation rate constant values of Peppas and Shalin equation (k r ) respect to F4M 100%. However, all mixtures with K4M showed the highest k r values, which decreased when HCMMA proportion decreased. Only K4M mixtures showed a different diffusion front movement than the other mixtures. The modulation of theophylline monoaxial release was obtained using a high percentage of HCMMA, and HPMCs with a substantial difference of hydroxypropyl groups (F4M and K4M or E4M). © 2009 Elsevier B.V. All rights reserved. 1. Introduction Hydroxypropylmethylcellulose (HPMC) are celluloses ethers which are frequently used to provide a controlled release of drugs from matrix tablets (Melia, 1991). The interaction of these poly- mers with water is a major factor in formulation, processing and sustaining the drug release. Thus, the ability to hydrate rapidly when in contact with liquid water and thus to form a protective gel around the tablet matrix is an essential property for drug release (Carstensen and Li Wan Po, 1992). Application of an impermeable coating that covers different surface portions of the hydrogel matrix (Colombo et al., 1987, 1990, 1992), graft the cellulose with synthetic polymers (Castellano et al., 1997), the use of ion exchange resin in the matrix (Feely and Davis, 1988), the careful control of drug par- ticle size (Ford et al., 1985a,b), drug/cellulose ether ratio (Ford et al., 1985a,b, 1987) or even matrix shape (Ford et al., 1987), and the use of polymeric mixtures (Walker and Wells, 1982; Bonferoni et al., 1994; Traconis et al., 1997) are some examples of the chang- ∗ Corresponding author. Tel.: +34 954556836; fax: +34 954556085. E-mail addresses: mrosa@us.es, gamarusoj@hotmail.com (M.R. Jiménez-Castellanos). ing of drug diffusion or relaxation rates for the modulation of drug release from hydrophilic matrices. Since diffusion plays such a prominent role in controlling drug release, the release kinetics are ever changing because of the chang- ing diffusional path length. Indeed, the release kinetics follows the kinetics of swelling (Colombo et al., 1990). In a previous paper (Escudero et al., 2008), we demonstrate the possibility of modula- tion of theophylline release by mixing HPMC of different viscosity grades (hydrophilic matrices) and a new generation of copoly- mers (Castellano et al., 1997; Ferrero and Jiménez-Castellanos, 2002; Ferrero et al., 2003) introduced as excipient for oral con- trolled released matrices (inert matrices), combining the influence of swelling rate from hydrophilic matrices as well as the porosity, tortuosity and water uptake capacity from inert matrices. Following these principles, and since there is evidence that vary- ing the degree of substitution of HPMC used may also influence drug release characteristics (Alderman, 1984), the aim of this paper is to evaluate the influence of different mixtures on technologi- cal characteristics and drug release from matrix tablets containing HPMC of same viscosity grade but different substitution degree (HPMC K4M; HPMC E4M and HPMC F4M), as hydrophilic poly- mer, hydroxypropylcellulose-methyl methacrylate (HCMMA), as inert polymer and theophylline as model drug. Because in a pre- vious paper (Escudero et al., 2008) we discuss the effect that drying 0378-5173/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2009.12.001