Graft copolymers of ethyl methacrylate on waxy maize starch derivatives as novel excipients for matrix tablets: Drug release and fronts movement kinetics

Abstract

A previous paper [1] deals with the physicochemical and technological characterization of novel graft copolymers of ethyl methacrylate (EMA) on waxy maize starch (MS) and hydroxypropylstarch (MHS). The results obtained suggested the potential application of these copolymers as excipients for compressed non-disintegrating matrix tablets. Therefore, the purpose of the present study was to investigate the mechanism governing drug release from matrix systems prepared with the new copolymers and anhydrous theophylline or diltiazem HCl as model drugs with different solubility. The influence of the carbohydrate nature, drying procedure and initial pore network on drug release kinetics was also evaluated. Drug release experiments were performed from free tablets. Radial drug release and fronts movement kinetics were also analysed, and several mathematical models were employed to ascertain the drug release mechanisms. The drug release markedly depends on the drug solubility and the carbohydrate nature but is practically not affected by the drying process and the initial matrix porosity. A faster drug release is observed for matrices containing diltiazem HCl compared with those containing anhydrous theophylline, in accordance with the higher drug solubility and the higher friability of diltiazem matrices. In fact, although diffusion is the prevailing drug release mechanism for all matrices, the erosion mechanism seems to have some contribution in several formulations containing diltiazem. A reduction in the surface exposed to the dissolution medium (radial release studies) leads to a decrease in the drug release rate, but the release mechanism is not essentially modified. The nearly constant erosion front movement confirms the behaviour of these systems as inert matrices where the drugs are released mainly by diffusion through the porous structure.

Introduction

Among the different approaches experimented for obtaining sustained-release delivery systems, matrix tablets, particularly if obtained by direct compression, still appear as one of the most efficient and interesting from both the economic and the process development points of view [2].

A variety of polymers is employed as matrix-forming excipients whose nature and characteristics may play an important role and significantly influence the behaviour of these devices. The controlling effect of a polymer material on drug release depends on its physicochemical properties and the way it is mixed during the manufacture of the system. To be more specific, the effect is due to the polymer molecular properties, such as the nature of the monomer, type and degree of substitution and whether the polymer is mixed dry or dissolved [3], [4].

Three main types of polymers may be used as drug delivery modulators: natural, synthetic and semi-synthetic. Among semi-synthetic polymers, modified starches have been proposed as direct compression excipients for controlled release matrices [5], [6], [7], [8], [9]. For instance, substituted amylose leads to hydrophilic matrix systems resistant to biodegradation [10] whereas starch acetate and graft copolymers with vinyl monomers yield hydrophobic matrices [8], [11]. Therefore, native starch properties are substantially modified, and the mechanism involved on drug release differs depending on the type of polymer used.

In a previous work [1], a novel generation of copolymers combining waxy maize starch (amylose content < 1%) derivatives (MS, MHS) and ethyl methacrylate (EMA) were synthesised by free-radical polymerization and alternatively dried by vacuum oven (OD) or freeze-drying (FD) techniques. The physicochemical and technological properties of these materials were thoroughly evaluated and their performance compared with the raw starches. The grafting of EMA on the carbohydrates backbone introduced hydrophobicity and leaded to amorphization and changes in particle size and morphology that affected the densification behaviour of the original carbohydrates. Graft copolymerization also improved the compactibility and mechanical resistance of native starches, suggesting the potential value of these copolymers as excipients for compressed non-disintegrating matrix tablets.

In addition to the polymer nature, drug properties such as polymorphism, degree of crystallinity, particle size, solubility and amount in the pharmaceutical dosage form can influence the release kinetic [12]. From all these variables, the solubility characteristics of the active are particularly important when designing extended-release dosage forms, as they can strongly influence the overall release profile. In fact, an excessively high or an extremely low solubility may give rise to formulation problems. Indeed, it is widely accepted that for both inert and swellable systems, diffusion, preceded by dissolution, may represent the key parameter for controlling drug release [13]. Thus, in the present study, two model drugs were selected, anhydrous theophylline and diltiazem HCl, because both are suitable candidates for controlled release formulations [2], [14] and have different solubility.

For the above reasons, the aim of this work was to identify the mechanism governing drug release from matrix systems prepared with the novel copolymers of ethyl methacrylate and waxy maize starch derivatives, using as model drugs anhydrous theophylline (a slightly water soluble drug) and diltiazem hydrochloride (a freely water soluble drug). Attention has also been focused on the influence of the carbohydrate nature, drying process and matrix porosity on the mechanistic aspects of drug release from the tested matrices.