Journal of Controlled Release 115 (2006) 298 306 www.elsevier.

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Drugs acting as plasticizers in polymeric systems: A quantitative treatment

F. Siepmann a,b , V. Le Brun a , J. Siepmann a,b,
b

College of Pharmacy, Freie Universitaet Berlin, Kelchstr. 31, 12169 Berlin, Germany College of Pharmacy, JE 2491, University of Lille, 3 Rue du Professeur Laguesse, 59006 Lille, France Received 7 July 2006; accepted 25 August 2006 Available online 1 September 2006

Abstract The objective of the present study was to investigate and quantify the effects of ibuprofen, chlorpheniramine maleate and metoprolol tartrate on the thermal, mechanical and diffusional properties of polyacrylate-based films. Thin drug-containing films were prepared from organic Eudragit RS solutions and physicochemically characterized with respect to their glass transition temperature, mechanical properties and drug release kinetics in phosphate buffer pH 7.4. The apparent diffusion coefficient of the drug within the polymeric systems was determined by fitting an adequate solution of Fick's second law of diffusion to the experimentally determined release profiles. Importantly, the glass transition temperature of the films significantly decreased with increasing initial drug content, whereas the film flexibility and drug release rate increased. This clearly indicates that the three drugs act as efficient plasticizers for Eudragit RS. Interestingly, the mathematical analysis revealed that drug release was primarily controlled by diffusion. An increase in the initial drug content resulted in increased drug diffusivities and, thus, accelerated (absolute and relative) drug release rates. Importantly, quantitative relationships could be established between the drug diffusivity and the initial drug content. Based on this knowledge, the effects of the films' composition and thickness on the resulting drug release kinetics (also from coated solid dosage forms) can be predicted in a quantitative way. 2006 Elsevier B.V. All rights reserved.
Keywords: Plasticizer; Diffusion; Release mechanism; Mathematical modeling; Eudragit RS

1. Introduction Polymers are frequently used to control drug release from pharmaceutical devices. For example, solid dosage forms can be coated with thin polymeric films [1,2]. However, pure polymer coatings are often brittle and poorly permeable for many drugs. To overcome these restrictions, external plasticizers are frequently added to the polymeric networks. They increase the flexibility of the coatings, increase the permeability for the drug and promote film formation (in the case of aqueous polymer dispersions). The extent of plasticization depends largely on the amount of added plasticizer and on the type of plasticizerpolymer interactions [3]. For example, GutierrezRocca and McGinity [4] studied the effects of water-soluble and insoluble plasticizers on the physical and mechanical properties of acrylic resin copolymers. Of the investigated plasticizers,
Corresponding author. College of Pharmacy, JE 2491, University of Lille, 3 Rue du Professeur Laguesse, 59006 Lille, France. Tel.: +33 3 20964708; fax: +33 3 20964942. E-mail address: juergen.siepmann@univ-lille2.fr (J. Siepmann). 0168-3659/$ - see front matter 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2006.08.016

triacetin had the most pronounced effect on the flexibility of the polymeric systems, followed by triethyl citrate. These differences in plasticizing efficiency were attributed to differences in molecular size and ability to interact with the macromolecules. It has to be pointed out that in addition to the classical plasticizers also other film components (e.g., certain preservatives and surfactants) can significantly affect the properties of the polymeric systems. Several studies report the plasticization of polymers by non-classical plasticizers. For instance, Frisbee and McGinity [5] studied the influence of different types of non-ionic surfactants on the physical and chemical properties of a biodegradable pseudolatex based on poly(DL-lactic acid) (PLA). Pluronic F68 was shown to effectively reduce the glass transition temperature (Tg) of PLA. O'Donnell et al. [6] reported plasticization effects of the preservatives methylparaben and propylparaben on the natural polymer zein. Methylparaben was also reported to plasticize other polymers, including acrylic copolymers (Eudragit RS and Eudragit RL) [7]. Importantly, also drugs can act as plasticizers for polymeric systems, resulting in significant changes in the thermo-

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mechanical properties of film coatings and drug release profiles. Aitken-Nichol et al. [8] prepared Eudragit E100-based films loaded with lidocaine HCl and characterized them physicochemically. It was shown that an increase in the drug content led to a significant decrease in the glass transition temperature (Tg) of the polymer and an increase in elongation at break of the films, indicating that this drug acts as an efficient plasticizer for this polymer. Furthermore, Crowley et al. [9] demonstrated the plasticizing ability of ketoprofen for poly(ethylene oxide). The addition of 15% ketoprofen resulted in a more than two-fold increase in % elongation of the films (compared to drug-free systems), and the tensile strength was shown to significantly decrease with increasing ketoprofen content. McGinity and coworkers [1013] showed that chlorpheniramine maleate and ibuprofen are efficient plasticizers for acrylic copolymers. For instance, the addition of chlorpheniramine maleate to Eudragit RS and Eudragit RL-based films resulted in a decrease of the Tg of the polymers [10]. This effect can be very advantageous: For example, it allows to lower the processing temperature during the hot-melt extrusion of tablets [11]. Wu and McGinity [12] investigated the influence of ibuprofen and chlorpheniramine maleate on the thermal and mechanical properties of polymeric films prepared from aqueous dispersions of Eudragit RS30D. In addition, drug release from pellets coated with drug-containing dispersions was studied. Both, ibuprofen and chlorpheniramine maleate were found to decrease the tensile strength of the polymeric films and the Young's modulus of the coated pellets. Importantly, the release rate decreased with increasing drug level in the polymeric film coating, indicating an increasing degree of coalescence between the latex particles (a phenomenon which is also observed with increasing levels of classical plasticizers). Scanning electron microscopy pictures of pellets coated with ibuprofen-containing Eudragit RS30D dispersions confirmed this hypothesis [13]. An increase in the drug content of the film coatings resulted in smoother film surfaces. Fourier Transform Infrared Spectroscopy (FTIR) revealed that ibuprofen interacts via hydrogen bonding with the acrylic copolymer. Different techniques can be used to investigate the plasticizing efficiency of a substance for a particular polymeric system, including the measurement of the tensile strength and % film elongation at break, glass transition temperature (Tg) and intrinsic viscosity of polymer solutions. However, so far only little is known on the effects of a plasticizer on the mobility of a drug in a polymeric system in a quantitative way. This knowledge is of fundamental importance, in particular for controlled drug delivery systems. In general, diffusional mass transport plays a major role for the control of drug release. Thus, a better understanding of the effects of a plasticizer on drug mobility in polymeric systems can be very helpful to facilitate device optimization. This is especially true if the drug itself acts as a plasticizer. Different techniques have been described to experimentally determine diffusion coefficients in polymers. Importantly, once the diffusivity is known, drug release can be predicted in a quantitative way [14,15]. A comprehensive review of adequate mathematical models has been given by Fan and Singh [16]. To adjust desired drug release rates, the diffusion coefficient of the drug in the polymeric system (e.g.,

film coating) can be varied. In general, different types and amounts of classical plasticizers are added. Siepmann et al. [3] presented a quantitative treatment of the effects of acetyltributyl citrate, acetyltriethyl citrate, dibutyl phthalate, dibutyl sebacate, diethyl phthalate, and tributyl citrate on drug mobility in ethylcellulose-based systems. However, yet very little is known on the importance of non-classical plasticizers (in particular drugs) for the resulting release kinetics. The objectives of the present study were: (i) to investigate the effects of chlorpheniramine maleate, ibuprofen and metoprolol tartrate on the properties of polyacrylate-based films; (ii) to use an adequate mathematical theory to determine the apparent diffusion coefficients of the drugs within the polymeric systems; (iii) to establish quantitative relationships between the composition of the device and the resulting release rates; (iv) to better understand the importance of the plasticizing effects of drugs in polymeric controlled drug delivery systems; and (v) to be able to quantitatively predict the effects of different formulation and processing parameters on the resulting drug release profiles. 2. Materials Chlorpheniramine maleate (Sigma Chemical Co., St Louis, MO, USA), ibuprofen (Salutas Pharma GmbH, Barleben, Germany), metoprolol tartrate (BASF, Ludwigshafen, Germany), poly(ethylacrylate methylmethacrylate trimethylammonioethyl methacrylate chloride 1:2:0.1) (Eudragit RS PO; Roehm, Darmstadt, Germany) were used as received. 3. Experimental methods 3.1. Preparation of thin, polymeric films Thin, drug-containing films were prepared by casting ethanolic drug-Eudragit RS solutions onto Teflon plates using a casting knife (Multicator 411; Erichsen, Hemer, Germany). The drug loading was varied from 7.5% to 30% (w/w, based on the polymer mass). The subsequent drying process was standardized as follows: 1 day at room temperature, 1 day at 40 C, and 1 day at room temperature. The thickness of the films (80 120 m) was measured using a thickness gauge (Minitest 600; Erichsen, Hemer, Germany). All films were clear (visual observation), indicating that the drug was molecularly dispersed within the system. Thin, drug-free polymeric films were prepared accordingly. 3.2. Drug release studies Thin, polymeric films were cut into pieces of 5 5 cm, which were placed into plastic containers filled with 150 ml pre-heated phosphate buffer pH 7.4 (USP XXVII), followed by horizontal shaking (37 C, 75 rpm; GFL 3033; Gesellschaft fr Labortechnik, Burgwedel, Germany). At pre-determined time intervals, samples were withdrawn and analyzed UV-spectrophotometrically ( = 262, 275 and 222 nm for chlorpheniramine maleate, ibuprofen and metoprolol tartrate, respectively) (UV-

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2101 PC; Shimadzu Scientific Instruments, Columbia, MD, USA). 3.3. Thermal analysis The glass transition temperature (Tg) of the polymeric systems was determined by differential scanning calorimetry (DSC 821; Mettler Toledo AG, Giessen, Germany). Film samples of approximately 6 mg were accurately weighed into aluminum pans, which were sealed and perforated. The samples were heated (at 5 C/min) under a nitrogen atmosphere from 0 to 100 C, then cooled to 0 C (at 40 C/min), and re-heated to 100 C (at 5 C/min). The glass transition temperature was determined from the second heating cycle. 3.4. Mechanical properties of thin, polymeric films Thin films were characterized using the puncture test and a texture analyzer (TA.XT Plus; Swantech, Gennevilliers, France). Film specimens were mounted on a film holder. The puncture probe (spherical end: 5 mm diameter) was fixed on the load cell (5 kg) and driven downward with a cross-head speed of 0.1 mm/s to the center of the film holder's hole. Load versus displacement curves were recorded until rupture of the films and used to determine the puncture strength and % elongation at break as follows: puncture strength F A 1

The initial condition for this partial differential equation is as follows, expressing the fact that the drug is uniformly distributed throughout the film at the beginning of the experiment: t0 c cini L V x V L 4

Here, cini represents the initial drug concentration in the system and L is the half-thickness of the film. The drug concentration far away from the surface of the film is assumed to be constant and equal to zero because the release medium is well stirred and perfect sink conditions are maintained during the experiments. Near to the surface of the film an unstirred liquid layer is considered (even in well-agitated systems thin unstirred layers exist, leading to an additional mass transfer resistance). As there is no accumulation of the drug on the surface of the film, the rate at which the drug is transported to the surface by diffusion through the film is always equal to the rate at which it leaves the film. This rate, per unit area, is proportional to the difference of the actual concentration on the surface (csur) and the concentration required to maintain equilibrium with the surrounding environment (c). The constant of proportionality is called the mass transfer coefficient in the boundary layer (h). As the thickness of the boundary layer essentially depends on the rate of stirring, h is a function of the stirring rate. This boundary condition is mathematically expressed as: t N0 Dd c jA Ax j hd csur cl 5

xFL

where F is the load required to puncture the film and A is the cross-sectional area of the edge of the film located in the path. p R2 d 2 R elongationat break% d 100% R 2

This initial value problem (Eqs. (3)(5)) can be solved using the method of Laplace transform, leading to [17,18]:  2  l X Mt 2d G2 bn d exp 2 d Dd t 1 6 2 2 2 Ml L n1 bn d bn G G where the n's are the positive roots of: bd tan b G 7

where R denotes the radius of the film exposed in the cylindrical hole of the holder and d is the displacement to puncture. 4. Theoretical methods The apparent diffusion coefficient of the drugs within the polymeric systems were determined by fitting an analytical solution of Fick's second law of diffusion to the experimentally determined drug release kinetics from thin polymeric films, in which the drugs were molecularly dispersed (monolithic solutions). As the surface of the films was very large compared to their thickness (approximately 50 cm2 versus 100 m), edge effects were negligible and the mathematical analysis could be restricted to one dimension. Hence, the release kinetics can be described by Fick's second law of diffusion in a plane sheet [14]: Ac A c Dd 2 At Ax
2

with G Ld h D 8

Here, Mt and M are the cumulative amounts of drug released at time t and t = , respectively; G denotes a dimensionless constant. The diffusion coefficient of the drug (D) and the mass transfer coefficient in the boundary layer (h) were determined by fitting this set of equations (Eqs. (6)(8)) to experimentally measured in vitro drug release kinetics. 5. Results and discussion

5.1. Thermal and mechanical properties of polymeric films The presence of an (external) plasticizer within a polymeric system decreases the attractive forces between the macromolecules,

where c denotes the concentration of the drug within the polymeric system, being a function of the time t and position x.

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Fig. 1. Effects of the drug loading (% w/w) on the glass transition temperature (Tg) of Eudragit RS films. The type of drug is indicated in the figure.

resulting in increased macromolecular mobilities. Consequently, the temperature at which an (amorphous) polymer undergoes the transition from the glassy to the rubbery state (and vice versa) (Tg)

decreases. The extent to which the Tg is lowered is an important measure for the efficiency of the plasticizer [11,12,19]. Fig. 1 illustrates the effects of chlorpheniramine maleate, ibuprofen and metoprolol tartrate on the glass transition temperature of Eudragit RS films. Clearly, the Tg significantly decreased with increasing drug loading, irrespective of the type of drug. This indicates that all three drugs act as plasticizers for the acrylic polymer, with ibuprofen showing the most pronounced effect, followed by chlorpheniramine maleate and metoprolol tartrate. Changes in the mechanical properties of the polymeric films confirmed this observation. The puncture strength and % elongation at break significantly increased with increasing drug loading (Fig. 2). Moreover, the ranking order of the three drugs with respect to their plasticizing ability monitored as increase in % elongation (Fig. 2b) and decrease in Tg (Fig. 1) is the same: ibuprofen N chlorpheniramine maleate N metoprolol tartrate. Interestingly, ibuprofen films showed a decrease in puncture strength above initial loadings of 20% (w/w). This can be explained by the decrease of the glass transition temperature of the polymeric ibuprofen-loaded films below room temperature (at which the experiments were performed) (Fig. 1). Consequently, the polymer undergoes the transition from the glassy to the rubbery state, resulting in a decrease in puncture strength. In contrast, Eudragit RS films containing chlorpheniramine maleate and metoprolol tartrate remained in the glassy state in the investigated range of drug loadings. Thus, their puncture strength monotonically increased with increasing drug content (Fig. 2a). 5.2. Drug release from thin films As an example, Fig. 3 shows the release of metoprolol tartrate from Eudragit RS films in phosphate buffer pH 7.4 (symbols = experimentally measured kinetics). Clearly, the release rate was high at the beginning and then monotonically decreased with time. This is a typical behavior for diffusion controlled drug delivery systems: With increasing time the length of the diffusion pathways increases. Thus, the drug

Fig. 2. Effects of the drug loading (% w/w) on the (a) puncture strength, (b) % elongation at break of Eudragit RS films. The type of drug is indicated in the figure.

Fig. 3. Experiment (symbols) and theory (Eqs. (6)(8), curve): Metoprolol tartrate release from Eudragit RS films in phosphate buffer pH 7.4 (10% w/w drug loading; 83 m film thickness).

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concentration gradients (the driving forces for diffusion) decrease and, consequently, the drug release rate decreases. To better understand the underlying mass transport mechanisms, the presented analytical solution of Fick's second law of diffusion (Eqs. (6)(8)) was fitted to the experimentally measured drug release kinetics (Fig. 3: curve). This mathematical model considers an initial homogeneous drug distribution at t = 0 (before exposure to the release medium), an initial drug concentration lower than drug solubility (monolithic solution), perfect sink conditions and the presence of a thin liquid unstirred layer surrounding the film. This boundary layer causes an additional resistance for drug release, which can be characterized by the so-called mass transfer coefficient, h. Importantly, good agreement between theory and experiment was observed (Fig. 3: curve and symbols) (coefficient of determination R2 = 1.00; only one example is shown, the agreement being similar for the other polymeric films). This clearly indicates that drug release was primarily controlled by pure diffusion. Interestingly, h was found to be very high in all cases, resulting in a high dimensionless number G = Lh/D N 100. This reveals that the mass transfer resistance within the boundary layer on the surface of the films is negligible compared to the mass transfer resistance within the polymeric systems in the present study. Thus, also the following, simplified analytical solution of Fick's second law of diffusion considering drug transport from thin films (with initial drug concentrations lower than drug solubility and initial homogeneous drug distributions) into perfect sink conditions can be used to quantify drug release: ! l X Mt 8 2d n 12 d p2 1 d exp d Dd t 2 2 Ml 4d L 2 n 0 2d n 1 p 9 where Mt and M are the cumulative amounts of drug released at time t and t = ; D denotes the diffusion coefficient of the drug and L is the half-thickness of the polymeric film. Fitting Eq. (9) to the experimentally determined drug release kinetics shown in Fig. 3 resulted in a curve (not shown) which overlaps with the illustrated curve (obtained by fitting Eqs. (6)(8)). The determined diffusion coefficients were equal (in this example: D = 3.8 10 9 cm 2 /s). Thus, both the complex and the simplified mathematical theory (Eqs. (6) (7) (8) and (9), respectively) can be used to determine the apparent drug diffusivities in the investigated polymeric films. In the following, the fittings with more complex mathematical model (Eqs. (6)(8)) are shown, because the negligibility of the mass transfer resistance within the liquid unstirred boundary layer had to be proven. To be able to judge the reproducibility of the experimentally determined drug release kinetics, each film was prepared in triplicate. Fig. 4a shows as an example metoprolol tartrate release from three films of identical composition, but prepared at three different days (experimental results: symbols). As slight variations in the film thickness are difficult to avoid (the films were prepared by casting), the resulting drug release rates slightly differ: With increasing film thickness the relative drug
Fig. 4. Metoprolol tartrate release from Eudragit RS films (10% w/w drug loading): (a) non-normalized data; (b) normalized data (to the film thickness). Results obtained with three different films of identical composition, but different thickness (indicated in the figures) are shown. Experiment (symbols) and theory (Eqs. (6)(8), curves).

release rate decreased. This can be explained by the increase in the length of the diffusion pathways. Fitting (Eqs. (6)(8)) to the drug release kinetics resulted in good agreement between theory and experiment in all cases (Fig. 4a). Based on these calculations, the diffusivity of metoprolol tartrate in Eudragit RS-based films with an initial drug content of 10% (w/w) was determined to be equal to 3.7 ( 0.3) 10 9 cm2/s. Thus, the reproducibility of this technique to determine drug diffusion coefficients in the investigated polymers is good. To be able to directly compare the drug release patterns from polymeric films with slightly different thickness, the results can be normalized: According to Eq. (9), the time can for instance be divided by (2L)2. Fig. 4b shows the normalized drug release kinetics from the three films in phosphate buffer pH 7.4. Clearly, all three curves are overlapping. In the following, generally normalized relative drug release rates are shown to account for the slight, arbitrary variations in film thickness. Importantly, the relative drug release rate from the polymeric films increased with increasing initial drug loading. Fig. 5 shows

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(symbols) was obtained in all cases. Based on these fittings, the apparent diffusion coefficients of the drugs in the investigated polymeric systems could be determined. Fig. 6 shows the significant increase in drug diffusivity in Eudragit RS with increasing initial drug content. This is a further, clear indication for the plasticizing effects of ibuprofen, chlorpheniramine maleate and metoprolol tartrate on Eudragit RS. The presence of the drug in the polymeric systems increases the mobility of the macromolecules and, thus, the free volume available for diffusion. Interestingly, the following quantitative relationships between the diffusion coefficient of the drugs, D, and the initial drug loading (wd, in % w/w) could be established (curves in Fig. 6): D 0:921d exp0:142d wd d 109 cm2 =s; D 0:407d exp0:079d wd d 109 cm2 =s; D 0:008d exp0:073d wd d 109 cm2 =s; R2 0:98 R2 0:97 R2 0:98 10 11 12

for metoprolol tartrate, chlorpheniramine maleate and ibuprofen, respectively. Thus, the mobility of the drug increases exponentially with its initial loading. This is in good agreement with the effects of conventional plasticizers. For example, it was shown that the diffusion coefficient of theophylline in ethyl cellulose increases exponentially with the initial content of acetyltributyl citrate [3]. To be able to compare the release kinetics of the three drugs from the investigated Eudragit RS-based films, the results obtained with systems of identical initial drug content (20% w/w) were compared (Fig. 7). Clearly, metoprolol tartrate release was much faster than that of chlorpheniramine maleate and ibuprofen, the diffusion coefficients being equal to 136, 16 and 0.36 10 10 cm2/s, respectively. As perfect sink conditions were maintained throughout the release experiments and as the drugs were molecularly dispersed within the polymeric

Fig. 5. Effects of the initial drug loading (% w/w, indicated in the figures) on the release patterns from Eudragit RS films in phosphate buffer pH 7.4: (a) metoprolol tartrate, (b) chlorpheniramine maleate, and (c) ibuprofen. Experiments (symbols) and theory (Eqs. (6)(8), curves). Fig. 6. Effects of the initial drug loading on the diffusion coefficient of the drug in Eudragit RS films (the type of drug is indicated in the figure). Symbols: values determined from the fittings shown in Fig. 5, curves: exponential relationships according to Eqs. (10)(12). The blow up is a zoom on the results obtained with ibuprofen.

the results obtained with (a) metoprolol tartrate, (b) chlorpheniramine maleate and (c) ibuprofen. As it can be seen, good agreement between theory (Eqs. (6)(8)) and experiments

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Fig. 7. Effects of the type of drug (indicated in the figure) on the release patterns from Eudragit RS films in phosphate buffer pH 7.4 (20% w/w initial drug loading; normalized data).

networks (monolithic solutions), the drug solubilities in phosphate buffer pH 7.4 (5, 331, and 10 000 mg/ml for ibuprofen, chlorpheniramine maleate and metoprolol tartrate, respectively) cannot explain the observed differences in the release kinetics. But electrostatic interactions between the drugs and the polymer can be expected to play a major role. In contrast to metoprolol and chlorpheniramine, ibuprofen is negatively charged at pH 7.4 and can, thus, interact with the positively charged quaternary ammonium groups of Eudragit RS. Consequently, drug diffusion is significantly hindered. This ionic interaction is in good agreement with the observed marked decrease in the glass transition temperature of ibuprofenEudragit RS systems (Fig. 1). In contrast, electrostatic interactions are unlikely with the two other drugs. Remark: More complex mathematical models, considering desorption as well as diffusion mechanisms (e.g., [20]) can be used to analyze these phenomena in more detail. However, such an analysis

Fig. 9. Theoretical prediction of the effects of (a) the film thickness (indicated in the figure) on chlorpheniramine maleate release from Eudragit RS films (15% w/ w initial drug loading), (b) the initial drug loading (% w/w, indicated in the figure) on chlorpheniramine maleate release (film thickness: 40 m), and (c) the type of drug and film thickness (indicated in the figure) on the release patterns from Eudragit RS films (5% w/w initial drug loading).

Fig. 8. Theoretical prediction (Eqs. (6)(8), curve) and experimental verification (symbols): Ibuprofen release from Eudragit RS films in phosphate buffer pH 7.4 (12.5% w/w initial drug loading; film thickness = 112 m; D = 1.9 10 11 cm2/s).

requires more comprehensive experimental results and was beyond the scope of this study. The determined diffusion coefficients are apparent diffusivities.

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It has to be pointed out that salts of metoprolol and chlorpheniramine were studied and that the respective counterions can be expected to interact with the polymer. Narisawa et al. [21,22] showed that several organic acids (including malic and tartaric acid = the protonated forms of the counterions used in this study) significantly increase the permeability of Eudragit RS films. They showed that these organic acids (in dissociated and undissociated form) affect the film properties. Thus, the observed plasticizing effects can either be attributed to the anions, cations or both (it was beyond the scope of this study to differentiate between the different species). An important practical application of Eqs. (10)(12) is the possibility to predict the diffusion coefficient of the drugs in Eudragit RS for arbitrary initial drug contents in a quantitative way. Knowing these values, Eqs. (6)(8) can be used to calculate the resulting drug release kinetics. Fig. 8 shows as an example the theoretically predicted release patterns from ibuprofen-loaded Eudragit RS films with an initial drug content of 12.5% w/w and a thickness of 112 m (based on a D value of 1.9 10 11 cm2/s) (curve). In order to verify the mathematical analysis, the respective films were prepared in reality and the resulting release patterns measured in phosphate buffer pH 7.4. As it can be seen in Fig. 8, the obtained experimental results (symbols) are in very good agreement with the theoretical predictions, proving the validity of the presented mathematical model. Fig. 9a shows the theoretically predicted effects of the film thickness on chlorpheniramine maleate release from Eudragit RS-based films with an initial drug content of 15% (w/w). Clearly, the variation of the film thickness is a very efficient tool to alter the resulting drug release patterns (an increase in thickness leads to increased diffusion pathway lengths and, thus, decreased relative drug release rates). Importantly, the presented mathematical theory is able to quantitatively predict these effects. In addition, Eqs. (6)(12) can be used to theoretically predict the impact of the initial drug content on the resulting release profiles. In Fig. 9b the simulated release patterns of chlorpheniramine maleate from Eudragit RS films with an initial drug content of 2.512.5% (w/w) are shown as an example. Thus, the required system composition for a desired release rate can be predicted. A further interesting application of the presented mathematical theory is the possibility to predict the required device design (geometry and composition) to achieve the same drug release patterns for different types of drugs. As an example Fig. 9c shows the release profiles of metoprolol tartrate, chlorpheniramine maleate and ibuprofen from Eudragit RSbased films with an initial drug content of 5% (w/w). At film thicknesses of 150, 85 and 12 m, the resulting release rates are virtually overlapping, despite of the tremendous differences in film permeability for these drugs. This type of calculations can be very useful for the optimization of controlled drug delivery systems containing different types of drugs. 6. Conclusions Metoprolol tartrate, chlorpheniramine maleate and ibuprofen are efficient plasticizers for Eudragit RS as shown by the thermal and mechanical properties of drug-loaded polymeric

films. Importantly, mass transport in these systems is primarily controlled by pure diffusion. Interestingly, exponential relationships between the drug diffusivity and the initial drug loading could be established. Based on this knowledge and adequate analytical solutions of Fick's second law of diffusion, the effects of the geometry, dimension and composition of the device on the resulting release patterns can be quantitatively predicted. Importantly, also significant drugpolymer interactions can be taken into account by the presented mathematical analysis, which can be extended to other device geometries, e.g. coated pellets and tablets. Thus, the obtained knowledge can help to facilitate the development and optimization of novel controlled drug delivery systems. Acknowledgements The authors are grateful for the support of this work by French Association for Cancer Research ARC (Association pour la Recherche sur le Cancer: postdoctoral fellowship for Florence Siepmann) and by the CAMPLP (Caisse d'assurance maladie des professions liberales-Provinces). References
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