Drugs acting as plasticizers in polymeric systems a quantitative treatment.pdf

7/30/2019 Drugs acting as plasticizers in polymeric systems a quantitative treatment.pdf

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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,

a College of Pharmacy, Freie Universitaet Berlin, Kelchstr. 31, 12169 Berlin, Germanyb 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 aqueouspolymer dispersions). The extent of plasticization depends

largely on the amount of added plasticizer and on the type of

plasticizerpolymer interactions [3]. For example, Gutierrez-

Rocca 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,

triacetin had the most pronounced effect on the flexibility of the

polymeric systems, followed by triethyl citrate. These differ-

ences 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 ofdifferent 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-

Journal of Controlled Release 115 (2006) 298306

www.elsevier.com/locate/jconrel

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: [email protected](J. Siepmann).

0168-3659/$ - see front matter 2006 Elsevier B.V. All rights reserved.doi:10.1016/j.jconrel.2006.08.016
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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 physico-

chemically. 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 forthis 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 co-

workers [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 Tgof the polymers [10]. This effect can be very advantageous: For

example, it allows to lower the processing temperature duringthe 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 phenom-

enon which is also observed with increasing levels of classical

plasticizers). Scanning electron microscopy pictures of pelletscoated 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 ibupro-

fen 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. Thisknowledge 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 particulardrugs) 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 drugrelease profiles.

2. Materials

Chlorpheniramine maleate (Sigma Chemical Co., St Louis,

MO, USA), ibuprofen (Salutas Pharma GmbH, Barleben,

Germany), metoprolol tartrate (BASF, Ludwigshafen, Ger-

many), poly(ethylacrylate methylmethacrylate trimethylammo-

nioethyl 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 etha-

nolic 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 standard-

ized 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 dispersedwithin the system. Thin, drug-free polymeric films were

prepared accordingly.

3.2. Drug release studies

Thin, polymeric films were cut into pieces of 55 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-spectro-

photometrically (=262, 275 and 222 nm for chlorpheniramine

maleate, ibuprofen and metoprolol tartrate, respectively) (UV-

299F. Siepmann et al. / Journal of Controlled Release 115 (2 006) 298306


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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 (at40 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 FA

1

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.

elongationat break % ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi

R2 d2p RR

d100% 2

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, inwhich 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

At DdA

2c

Ax23

where c denotes the concentration of the drug within the

polymeric system, being a function of the time tand position x.

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:

t 0 c cini LV xVL 4Here, 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 thesurface (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:

tN0 DdjAcAxj

xFL hd csurcl 5

This initial value problem (Eqs. (3)(5)) can be solved using

the method of Laplace transform, leading to [17,18]:

Mt

Ml

1Xln1

2dG2

b2nd b2n G2 Gdexp

b2nL2

dDd t

6

where the n's are the positive roots of:

bd tan b G 7with

G LdhD

8

Here, Mt and M are the cumulative amounts of drugreleased 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,

300 F. Siepmann et al. / Journal of Controlled Release 115 (2006) 298306


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resulting in increased macromolecular mobilities. Consequently,the temperature at which an (amorphous) polymer undergoes the

transition from the glassyto 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, withibuprofen 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:

ibuprofenNchlorpheniramine maleateNmetoprolol tartrate. In-

terestingly, 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 ofthe polymeric ibuprofen-loaded films below room temperature

(at which the experiments were performed) (Fig. 1). Conse-

quently, 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 metoprololtartrate 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 thefigure.

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.

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 mechan-

isms, 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 mathemat-

ical model considers an initial homogeneous drug distribution att=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 allcases, resulting in a high dimensionless numberG=Lh/DN100.

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 homoge-

neous drug distributions) into perfect sink conditions can be

used to quantify drug release:

Mt

Ml

1Xl

n0

8

2dn 12p2 dexp 2dn

1

2dp2

4dL2 dDd t !

9where 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 =3.8109 cm2/s). Thus, both the complex and the

simplified mathematical theory (Eqs. (6) (7) (8) and (9),

respectively) can be used to determine the apparent drugdiffusivities 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

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) wasdetermined to be equal to 3.7 (0.3)109 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

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).



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the results obtained with (a) metoprolol tartrate, (b) chlorphenir-

amine maleate and (c) ibuprofen. As it can be seen, good

agreement between theory (Eqs. (6)(8)) and experiments

(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, chlorphenir-

amine maleate and metoprolol tartrate on Eudragit RS. Thepresence 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 exp0:142dwdd109cm2=s; R2 0:98 10

D 0:407d exp0:079dwdd109cm2=s; R2 0:97 11

D 0:008d exp0:073dwdd109cm2=s; R2 0:98 12for metoprolol tartrate, chlorpheniramine maleate and ibuprofen,

respectively. Thus, the mobility of the drug increases exponen-

tially 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 ob-

tained 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 andibuprofen, the diffusion coefficients being equal to 136, 16

and 0.361010 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. Experi-

ments (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 indicatedin 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 withibuprofen.



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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 ibuprofen-Eudragit 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

requires more comprehensive experimental results and was

beyond the scope of this study. The determined diffusion

coefficients are apparent diffusivities.

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).

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=112m;D =1.91011 cm2/s).

Fig. 9. Theoretical prediction of the effects of (a) the film thickness (indicated in

the figure) on chlorpheniramine maleate release fromEudragit 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).



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It has to be pointed out that salts of metoprolol and chlor-

pheniramine 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 andundissociated form) affect the film properties. Thus, the ob-

served plasticizing effects can either be attributed to the anions,

cations or both (it was beyond the scope of this study to dif-

ferentiate 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 1.91011

cm

2

/s)(curve). In order to verify the mathematical analysis, the res-

pective 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 thick-

ness leads to increased diffusion pathway lengths and, thus,

decreased relative drug release rates). Importantly, the presentedmathematical 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 RS-

based 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 relation-

ships 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 forFlorence Siepmann) and by the CAMPLP (Caisse d'assur-

ance maladie des professions liberales-Provinces).

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