Journal of Controlled Release 90 (2003) 97107 www.elsevier.

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A general approach to describe the antimicrobial agent release from highly swellable lms intended for food packaging applications
G.G. Buonocore b , M.A. Del Nobile a , *, A. Panizza b , M.R. Corbo a , L. Nicolais b
b

Istituto di Produzioni e Preparazioni Alimentari, University of Foggia, Via Napoli, 25 -71100 Foggia, Italy Department of Materials and Production Engineering, University of Naples Federico II, P. le Tecchio, 80 -0125 Naples, Italy Received 17 December 2002; accepted 11 March 2003

Abstract A mathematical model able to describe the release kinetics of antimicrobial agents from crosslinked polyvinylalcohol (PVOH) into water is presented. The model was developed by taking into account the diffusion of water molecules into the polymeric lm, the counter-diffusion of the incorporated antimicrobial agent from the lm into water, and the polymeric matrix swelling kinetic. To validate the model the water sorption kinetics as well as the release kinetics of three antimicrobial agents (i.e., lysozyme, nisin and sodium benzoate, all approved to be used in contact with food) were determined at ambient temperature (25 8C). The three investigated active agents were entrapped in four lms of PVOH with a different degree of crosslink. The model was successfully used to t all the above sets of data, corroborating the validity of the hypothesis made to derive it. 2003 Elsevier Science B.V. All rights reserved.
Keywords: Modeling; Swelling; Controlled release of antimicrobial agent; Moving boundary; Packaging

1. Introduction In the last years antimicrobic release systems have been used mainly in pharmaceutical applications [1 4], while their use in food packaging is still restricted [5], although it is expected to grow due to the increase of the concept of active packaging. The aim of controlled release systems intended for food packaging applications is to transfer the antimicro* Corresponding author. Tel.: 1 39-881-589-233; fax: 1 39-881740-211. E-mail addresses: ma.delnobile@unifg.it (M.A. Del Nobile), delnobil@unina.it (M.A. Del Nobile).

bial agent from the polymeric carrier to the liquidlike food in order to maintain a predetermined concentration of the active compound in the packed food for a determined period of time. Drug release has been often studied in the past because of its importance in the pharmaceutical eld. In fact, several studies are reported in the literature focused on the studying and modelling of drug delivery devices for pharmaceutical applications [6 12]. As reported by Siepman and Peppas [13], the quantitative description of the phenomena controlling the drug release kinetics is highly desirable to properly design a new controlled drug delivery device. The practical benet of a mathematical

0168-3659 / 03 / $ see front matter 2003 Elsevier Science B.V. All rights reserved. doi:10.1016 / S0168-3659(03)00154-8

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model consists in the possibility to simulate the effects of the design parameters on the performance of the release system. In the review proposed by Siepmann and Peppas [13], different mathematical models are presented to describe the drug release kinetics. The simplest are the empirical and semiempirical models. Among them, the most used are that proposed by Higuchi [14], and the power law equation. The simplicity of the above two models is counterbalanced by the fact that their applicability is restricted to very few cases, as also pointed out by Peppas and co-worker [15,16]. Besides the above approach, mechanistics theories were proposed, with the attempt to give a real insight into the underlying mechanisms controlling the drug release. Most of the mechanistics models take into account the diffusion of the penetrant into the slab, the swelling and dissolution of the polymer and the release of the drug into the external liquid solution. In the specic case of antimicrobial lms intended for food packaging applications several studies can be found in the literature dealing with this subject [1720]. However, the results obtained are quite limited because the study has been restricted to the case of release of the antimicrobial agents from hydrophobic or moderately hydrophilic polymeric matrices. Therefore, the developed models cannot be applied to the case of highly swellable polymeric matrices. The aim of this work is to develop a mathematical model able to describe the release kinetics of active compounds from a highly swellable lms intended for food packaging applications. The proposed model consists of two parts: the rst describing the water uptake kinetic, the second describing the release of the antimicrobial agent from the polymeric matrix. The mass balance for the penetrant and the active substance were numerically solved by means of the nite volume method.

of a 4% water solution at 20 8C: 1114 cps). The crosslinking agent was glyoxal (40% aqueous solution, SigmaAldrich) and the catalyser was HCl (37%, SigmaAldrich). The active compounds used were: lysozyme from chicken egg white (purchased from SigmaAldrich), nisin (donated by Danisco Innovation, 15 NorthStreet, Beaminster, Dorset DT8 3DZ, UK) and sodium benzoate (purchased from SigmaAldrich). Lysozyme consists of 129 amino acids and has a molecular weight of 14 000 Da. Nisin consists of 34 amino acids and has a molecular weight of 3400 Da. Sodium benzoate has a molecular weight of 121 g / mol.

2.2. Methods 2.2.1. Film preparation PVOH (6.5 g) was dissolved into 50 ml of distilled water by keeping the solution 30 min into an autoclave at 120 8C. The obtained solution was slowly cooled and crosslinked by adding rst a known amount of glyoxal and, immediately after, 0.2 ml of a 37% aqueous solution of HCl. The obtained solution was cast onto a plate and dried at ambient conditions for 48 h. The obtained lms had an average thickness of 120 mm. The thickness of the obtained lms was measured by means of a Digimatic Micrometer (Mitutoyo, accuracy equal to 0.5 mm). The value of the lm thickness was obtained by averaging 100 measurements. The active lms were obtained by using the following procedure: PVOH (3.25 g) was dissolved in 25 ml of distilled water by keeping the solution for 30 min in an autoclave at 120 8C. The obtained solution was slowly cooled at room temperature. Later, 100 mg of active agent were added, the obtained solution was stirred at ambient temperature until the preservative was completely dissolved. The obtained solution was crosslinked adding rst a known amount of glyoxal and, immediately after, 0.2 ml of a 37% aqueous solution of HCl. For the sake of simplicity the investigated lms will be referred to as: 2.2.1.1. Film without active compound. Film A: pure glyoxal: 7.7% (w / w) of PVOH; Film B: pure glyoxal: 2.0% (w / w) of PVOH; Film C: pure

2. Materials and methods

2.1. Materials
The lms studied in this work were obtained crosslinking PVOH (Sigma catalog code P1763. MW570 000100 000. Hot water soluble. Viscosity

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glyoxal: 0.77% (w / w) of PVOH; Film D: pure glyoxal: 0.077% (w / w) of PVOH.

2.2.1.2. Film with the active compounds (100 mg). Film A L (lysozyme), Film A N (nisin), and A SB (sodium benzoate): pure glyoxal: 7.7% (w / w) of PVOH. Film B L (lysozyme), B N (nisin), and B SB (sodium benzoate): pure glyoxal: 2.0% (w / w) of PVOH. Film C L (lysozyme), C N (nisin), and C SB (sodium benzoate): pure glyoxal: 0.77% (w / w) of PVOH. Film D L (lysozyme), D N (nisin), and D SB (sodium benzoate): pure glyoxal: 0.077% (w / w) of PVOH. 2.2.2. Water sorption kinetics The produced lms were cut in small pieces (131 cm) and desiccated under vacuum at least 48 h. They were weighed and left at ambient temperature in 30 ml of distilled water. The swelling kinetics were evaluated by periodically measuring the weight of the lms by means of a micro-balance (Scaltec model SPB32, with an accuracy of 0.0001 g), after gently blotting the surface with a tissue, until the equilibrium condition was reached. The swelling ratio was evaluated as:
g Film 2 g Dry Film S.r. 5 ]]]]]]. g Dry Film All data shown are the average value of three replicates.

Liao et al. [21]. In particular, lysozyme was determined by means of an HPLC (Agilent Mod. 1100). A C18 Reverse phase column was used (250 3 4 mm, 5 mm) and a gradient elution with wateracetonitrile gradients (1 ml / min) containing 0.1% TFA was used. Typical gradient was 060% acetonitrile over 20 min, with lysozyme eluting at 10 min. The detection was made at a wavelength of 254 and 225 nm. The calibration curve was constructed for peak area against lysozyme concentration of standard solutions from 6 to 300 ppm, with ve replicate samples for each lysozyme concentration.

2.2.3.2. Nisin determination. Quantitative determination of nisin into the water solution was made by slightly modifying the method proposed by Liu and Hansen [22]. In particular, nisin was determined by means of an HPLC (Agilent Mod. 1100). A C18 reversed-phase column was used (250 3 4 mm, 5 mm) and a gradient elution with wateracetonitrile gradients (1 ml / min) containing 0,1% TFA was used. Typical gradient was 2060% acetonitrile over 20 min, with nisin eluting at 10 min. The detection was made at a wavelength of 254 and 225 nm. The calibration curve was constructed for peak area against nisin concentration of standard solutions from 2.5 to 100 ppm, with ve replicate samples for each nisin concentration. 2.2.3.3. Sodium benzoate determination. Quantitative determination of sodium benzoate into the water solution was made following the method proposed by Pylypiw and Grether [23]. In particular, sodium benzoate was determined by means of an HPLC (Agilent Mod. 1100) using a C18 Reverse phase column (250 3 4 mm, 5 mm). Isocratic conditions of mobile phase with a ow of 0.8 ml / min were used, with sodium benzoate eluting at 15 min. The detection was made at a wavelength of 225 nm. The calibration curve was constructed for peak area against sodium benzoate concentration of standard solutions from 2.5 to 100 ppm, with ve replicate samples for each sodium benzoate concentration. 2.2.3.4. Modeling. In the following a model to describe the release kinetics of an active compound from a swelling polymeric network is presented. The antimicrobial agent is initially entrapped into a

2.2.2. Active compounds release kinetics The prepared active lms (0.012 cm 3 200 cm 2 ) were put into a container and brought in contact with 250 ml of distilled water at ambient temperature, under moderate stirring. The active compounds release kinetics were evaluated by monitoring, by means of an HPLC, the antimicrobial concentration in the surrounding solution until an equilibrium value was reached. All data shown are the average value of three replicates. 2.2.3. HPLC active compounds assay 2.2.3.1. Lysozyme determination. Quantitative determination of lysozyme into the water solution was made by slightly modifying the method proposed by

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highly hydrophilic dry polymer (PVOH). The release kinetics of an active compound from a highly hydrophilic polymer placed in contact with water depends on the following phenomena: (1) water diffusion; (2) macromolecular matrix relaxation kinetic; (3) diffusion of the active compound through the swollen polymeric network. For the sake of simplicity the description of the above phenomena will be presented separately in the following.

2.2.3.5. Water diffusion and macromolecular matrix relaxation. The sorption kinetics of low molecular weight compounds in polymers are generally governed by two simultaneously occurring phenomena. A substantially stochastic phenomenon (related to Brownian motion), where the penetrant ows exclusively driven by a concentration gradient and a relaxation phenomenon driven by the distance of the local system from the equilibrium [24]. When the mass transfer takes place in a substantially unperturbed polymeric matrix, as in the case of gas diffusion in rubbery polymers (or wherever the solvent-induced polymer swelling is negligible), the diffusion process is substantially controlled by a stochastic phenomenon. The other limiting behaviour is encountered when a very thin slab of polymer is put in contact with a swelling compound. In this case the characteristic diffusion time is much lower than the polymer relaxation time; hence, polymer relaxation becomes the limiting phenomenon controlling the solvent uptake kinetic [24]. In the case of water diffusion in hydrophilic polymers, such as in the case under investigation, the experimental observations range between these two limiting phenomena. To better illustrate these two distinct aspects of the water sorption kinetics, stochastic diffusion and polymer matrix relaxation will be presented separately in the following. Water diffusion related to Brownian motions is generally described by means of the Ficks First Law. In the specic case of diffusion through a plane sheet, the Ficks model reduces to the following expression:
W C W J 5 2 D F ? ]] ? x x

Among them, one of the simplest is that proposed by Long and Richman [25]. They assumed that when the external water activity is suddenly increased (i.e., the lm is placed in contact with water), the solvent concentration at the polymer surface does not reach instantaneously its equilibrium value (as it would be if polymer matrix relaxation was negligible). On the contrary, it rst suddenly increases to a value lower than the equilibrium one. At a later stage, it gradually increases until the system reaches the equilibrium. The rate at which the water concentration at the boundaries gradually increases is directly related to the relaxation of the macromolecular matrix. In this investigation the following empirical expression [26] is proposed to describe the boundary condition relaxation rate: dastd ]] 5 ha1 ?] astd j ? h1 2 exp f 2s1 2 astdd g j dt (2)

a (t ) is the normalised water volume fraction at the boundaries of the lm at time t. It spans from zero to one, and represents the driving force of the macromolecular matrix relaxation phenomenon. As reported in Eq. (2), dastd / dt is expressed as the product of two terms. The rst one, which prevails at the early stage of the hydration process, is the kinetic constant of the polymer relaxation phenomenon; therefore, it is an increasing function of polymer macromolecular mobility. The second term, which prevails at the later stage of the hydration process, accounts for the fact that dastd / dt has to decrease as the concentration at the boundary of the lm approaches its equilibrium value (i.e., as a (t ) levels off to one); therefore it is a decreasing function of a (t ). 2.2.3.6. Determination of the water sorption kinetics. The evolution of the water concentration prole inside the polymeric matrix was calculated by solving a set of differential equations obtained by writing the integral water mass balance equation for each of the n elements in which the lm was divided. For each of the n elements it is possible to write the following equation:
d ] dt

(1)

E srC d dV 5 E FD
W
Sstd

W F

]s r CWd ? x n x

G dS

(3)

Several approaches are reported in the literature to describe solvent-induced polymer relaxation [24].

Vstd

It is worth noting that by considering elements with a

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volume that changes during hydration (the volume of each element changes in such a way that it contains always the same amount of the polymeric matrix, Lagrangian approach) instead of considering elements with a xed volume (Eulerian approach), it is possible to neglect the convective mass ux. The set of n equations, obtained by writing Eq. (3) for the n elements, were solved numerically using the following initial and boundary conditions:

CW 5 0 t 5 0; 0 , x , L
B CW 5 C W std ; t ; x 5 L(t ) s r CWd ]]] 5 0 ; t ; x 5 0 x

(4)

2.2.3.7. Determination of the active compound release kinetics. The amount of antimicrobial agent released into water was calculated by solving simultaneously a set of differential equations obtained by writing the integral mass balance equation for both water (Eq. (3)) and the active substance for each of the n elements in which the lm was divided:
d ] dt

E srC

AC

d dV 5

E FD

AC F

] s r CACd x n x

G dS

(5)

Vstd

Sstd

Eqs. (3) and (5) were solved numerically using Eq. (4) for water and the following initial and boundary conditions for the active compound:

In. CAC 5 C AC t 5 0; 0 , x , L

(5) were tted to the antimicrobial agent release kinetics data to test the entire model and to determine the values of the diffusion coefcient and the partition coefcient of the active agent. The second tting was conducted by xing the values of D W F , CB (0) and a to that found in the rst tting. It is W 1 worth noting that the approach proposed to validate the model is more severe than the classical approach, which consists in tting Eqs. (3) and (5) to active compound release kinetics data to determine all the B AC models parameters (i.e., D W and F , C W (0), a1 , D F KAC ). Figs. 1 and 2 show the amount of water sorbed into the polymer plotted as function of hydration time. As shown in the above gures, the amount of water sorbed at equilibrium increases as the degree of crosslink decreases. In the same gures the curves obtained by tting Eq. (3) to the experimental data are also shown. The values of the models parameters obtained are listed in Table 1. As expected, the value of the water diffusion coefcient increases as the degree of crosslink decreases. The accuracy of t was evaluated by means of the relative percent difference [28]. In the case under investigation the % for the four sets of data are calculated values of E listed in Table 2. From the curves shown in Figs. 1 % reported above, it can and 2, and from the values E be inferred that the rst part of the model satisfactorily ts the data, corroborating the hypothesis made to derive it.

CAC 5 C AC (t ) ; t ; x 5 L(t ) s r CACd ]]] 5 0 ; t; x 5 0 x

B

(6)

The value of C B AC (t ) was determined assuming that the outer solution can be treated as a well stirred solution [27]. The expression used was:
W rC B AC (t ) 5 KAC r W C AC (t )

(7)

3. Results and discussions The model validation was conducted in two subsequent steps. First Eq. (3) was used to t to the water sorption kinetics data. In this way the rst part of the model was tested, and the values of D W F , CB (0) and a , were determined. Later, Eqs. (3) and W 1

Fig. 1. Swelling ratio plotted as a function of time. ( j ) Film A, ( s ) Film B, () best t of the proposed model to the experimental data.

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Fig. 2. Swelling ratio plotted as a function of time. ( j ) Film C, ( s ) Film D, () best t of the proposed model to the experimental data.

Fig. 3. Amount of lysozyme released plotted as a function of time. ( j ) Film A, ( s ) Film B, () best t of the proposed model to the experimental data.

Table 1 B Values of D W F , C W (0) and a1 obtained by tting Eq. (3) to the water sorption kinetics data Sample
2 DW F (cm / s) B CW (0) (g H 2 O / g dry polymer)

a1 (1 / s)

Film Film Film Film

A B C D

5.41 3 10 2 8 1.124 3 10 2 7 1.804 3 10 2 7 3.863 3 10 2 7

0.336 0.722 1.363 1.473

1.997 3 10 2 4 1.419 3 10 2 4 1.637 3 10 2 4 2.359 3 10 2 4

Figs. 38 show the antimicrobial agent release kinetics for the four investigated lms. As shown in the above gures, the amount of the active compound released at equilibrium always decreases as the degree of crosslink of the polymeric matrix increases. Considering that the degree of crosslink slightly inuence the partition coefcient of the

Fig. 4. Amount of lysozyme released plotted as a function of time. ( j ) Film C, ( s ) Film D, () best t of the proposed model to the experimental data.

Table 2 % for both the water sorption kinetics and Calculated values of E the active compound release kinetics Sample % E Water Film Film Film Film A B C D 3.5 5.9 3.3 5.3 Lysozyme 12 9.1 8.7 8.9 Nisin 16 7.8 6.4 9.5 Sodium benzoate 5.6 7.0 6.5 6.6

Fig. 5. Amount of nisin released plotted as a function of time. ( j ) Film A, ( s ) Film B, () best t of the proposed model to the experimental data.

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Fig. 6. Amount of nisin released plotted as a function of time. ( j ) Film C, ( s ) Film D, () best t of the proposed model to the experimental data.

Fig. 8. Amount of sodium benzoate released plotted as a function of time. ( j ) Film C, ( s ) Film D, () best t of the proposed model to the experimental data.

active agent, it is reasonable to hypothesize that part of the preservative loaded into the lm is chemically bonded to the polymer backbone via the crosslinking reaction. In fact, one of the active site of the crosslinking agent could react with one of the sites on the polymer backbone, attaching the crosslinking agent to the matrix, while the other site could react with the active compound, bonding the preservative to the matrix. Therefore, as the quantity of the crosslinking agent increases, also the number of the above unreacted sites increases, leading to an increase of the active compound molecules bonded to the PVOH backbone. Figs. 38 also point out that

Fig. 7. Amount of sodium benzoate released plotted as a function of time. ( j ) Film A, ( s ) Film B, () best t of the proposed model to the experimental data.

the shape of the active compound release kinetics curve strongly depends on the molecular weight of the antimicrobial agent. In fact, as the molecular weight of the active compound decreases and / or the degree of crosslink decreases the release kinetics curve shows an overshoot. As in the case of nisin entrapped in samples C and D, and in the case of sodium benzoate entrapped in lm A, B, C and D. In fact, the concurrence of the following can lead to an inversion in the sign of the active compound concentration gradient during the release process: (a) the preservative concentration at the boundary increases as the amount of active compound released increases; (b) there is a superposition between water penetration into the polymeric matrix and diffusion of the active agent in the outer water solution. The curves shown in Figs. 38 were obtained by tting Eqs. (3) and (5) to the experimental data, the values of the diffusion coefcient and partition coefcient of the active compound obtained are listed in Table 3. As one would expect, the value of the active compound diffusion coefcient always increases as the degree of crosslink decreases. Also in this case the accuracy of t was evaluated by %; the values obtained are listed in Table means of E 2. As it can be inferred from the data shown in Figs. %, the 38 and from the calculated values of E proposed model satisfactorily ts the experimental data corroborating the hypothesis used to derive it. It is worth noting that regardless the presence of an

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Table 3 Values of the diffusion coefcient and partition coefcient of the active agent obtained by tting Eqs. (5) and (6) to the antimicrobial agent release kinetics data Sample Lysozyme D (cm / s) Film Film Film Film A B C D 3.83 3 10 2.45 3 10 2 10 2.10 3 10 2 9 9.98 3 10 2 9
2 11 L F 2

Nisin KL 431.37 45.62 15.06 6.33 D

N F

Sodium benzoate
2

(cm / s)
2 10

KN 152.80 67.58 34.57 26.73

D SB (cm 2 / s) F 1.25 3 10 4.20 3 10 2 8 2.55 3 10 2 8 2.54 3 10 2 8

28

KSB 55.82 60.01 25.96 21.39

3.01 3 10 3.16 3 10 2 9 6.24 3 10 2 9 8.61 3 10 2 9

overshoot the proposed model satisfactorily ts the antimicrobial agent release kinetics.

C iW C iAC

4. Conclusion In this work a model able to describe the release kinetics of active compounds from crosslinked PVOH was presented. The model was developed by taking into account the phenomena involved during the release of the active compound from a polymeric swelling matrix; i.e., water diffusion, macromolecular matrix relaxation and antimicrobial agent diffusion through the polymeric matrix. Model validation was conducted by rst tting Eq. (3) to the water sorption kinetic data. Subsequently, Eqs. (3) and (5), developed to describe the antimicrobial agent release kinetics, were tted to the active compound release data. From the obtained results, it can be inferred that the proposed models satisfactorily t the experimental data, corroborating the hypothesis made to derive it. The adopted approach has a potential relevance on practical aspects of packaging because the modeling of the antimicrobial release from food packaging material can be considered as a useful tool needed to simulate and therefore to predict the behavior of the release device in the real working condition.

CB W (t ) CB AC (t ) CW AC (t ) C In. AC CB W (0)

DW F DW F D AC F DW F DL F DN F SB DF % E

i 11

5. List of symbols CW CAC the local water concentration expressed as g water / g dry polymer the active compound concentration expressed as g active compound / g dry polymer

J KAC KL KN

the water concentration at the center of the element i the active compound concentration at the center of the element i the water concentration at the lm boundary at time t the active compound concentration at the lm boundary at time t the active compound concentration into the outer water at time t the initial active compound concentration into the lm the water concentration at the lm boundary at time zero, it represents the instantaneous response of the system to the increase of the external water activity the water diffusion coefcient at the interface between the element i and the element i 2 1 the water diffusion coefcient at the interface between the element i 1 1 and the element i the active compound diffusion coefcient the water diffusion coefcient the lysozyme diffusion coefcient the nisin diffusion coefcient the sodium benzoate diffusion coefcient the mean relative deviation modulus dened by the following equation: N exp u M i 2 M p u 100 %5] ]] E N exp ? o i 5 1 Mi the diffusive mass ux the active compound partition coefcient the lysozyme partition coefcient the nisin partition coefcient

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KSB L(t ) m ip ML (t )

MN (t )

MSB (t )

N n S S(t ) Vi V V(t )

x r a (t )

a1 nB W (t ) n eq. W di din dy dz ri

rP rW rAC Dt

the sodium benzoate partition coefcient the half-thickness of the lm at time t the initial mass of the element i amount of lysozyme released into water at time t expressed as g lysozyme / g dry polymer amount of nisin released into water at time t expressed as g nisin / g dry polymer amount of sodium benzoate released into water at time t expressed as g sodium benzoate / g dry polymer the number of time integration steps the versor normal to the surface the surface of the volume V the surface of the volume V(t ) the volume of the element i an arbitrary volume xed in space the volume that contains an amount of macromolecular matrix equal to the initial one the axial coordinate the axial versor is dened by the following equation: eq. a (t ) 5 n B W (t ) / n W constant to be evaluated by tting the model to the experimental data the water volume fraction at the lm boundary at time t the equilibrium water volume fraction sorbed in the lm the side length of the element i the initial side length of the sample the length of the y -side of the sample the length of the z -side of the sample the average macromolecular matrix density, it was evaluated by means of the following expression: m ip / V i the density of the polymeric matrix dened as the ratio between the weight of the matrix and the volume of the mixture (i.e., water plus matrix) ex3 pressed as g matrix / cm hydrated matrix the initial density of the polymer the water density the active compound density the time step used to integrate Eqs. (3) and (4)

Dx i

the difference between the inner and outer axial coordinate of the element i

Acknowledgements The work was funded under the MURST Piani di Potenziamento della Ricerca Scientica e Tecnologica.

Appendix A The polymeric lm was discretized as shown in the following gure:

Eq. (3) was approximated by means of the following expression [2931]: m ip ?sC iWssN 1 1d Dtd 2 C iWsN Dtdd 5 DtSsN Dtd

DF

W i 11

sN Dtd
i 11 i i

r sN Dtd ? C W sN Dtd 2 r sN Dtd ? C WsN Dtd ? ]]]]]]]]]]]]] 1 0.5sDx i 1 1sN Dtd 1 Dx isN Dtdd
i 2 DW F sN Dtd

i 11

r sN Dtd ? C WsN Dtd 2 r sN Dtd ? C W sN Dtd ? ]]]]]]]]]]]]] 0.5sDx isN Dtd 1 Dx i 2 1sN Dtdd

i 21

i 21

G
(A1)

Eq. (5), related to active substance mass balance, was approximated exactly in the same way of Eq. AC (3), substituting D W F with D F and C W with CAC . i To evaluate D , it was assumed that the water concentration changes linearly between two adjacent elements [32]. The following expression was used to evaluate r i ((N 1 1) Dt ):

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G.G. Buonocore et al. / Journal of Controlled Release 90 (2003) 97107 [3] A.J. Kuijpers, G.H.M. Engbers, P.B. van Wachem, J. Krijgsveld, S.A.J. Zaat, J. Dankert, J. Feijen, Controlled delivery of antibacterial proteins from biodegradable matrices, J. Control. Release 53 (1998) 235247. [4] J.M. Bezemer, R. Radersma, D.W. Grijpma, P.J. Dijkstra, J. Feijen, C.A. van Blitterswijk, Zero-order release of lysozyme from poly(ethylene glycol)-poly(butylene terephthalate) matrices, J. Control. Release 64 (2000) 179192. [5] J. Floros, P. Nielsen, J. Farkas, Advances in modied atmosphere and active packaging with applications in the dairy industries, Bull. Int. Dairy Fed. 346 (2000) 2228. [6] M. Grassi, R. Lapasin, S. Pricl, Modeling of drug release from a swellable matrix, Chem. Eng. Commun. 169 (1998) 79109. [7] P.I. Lee, N.A. Peppas, Prediction of polymer dissolution in swellable controlled release systems, J. Control. Release 6 (1987) 207215. [8] R.S. Harland, A. Gazzaniga, M.E. Sangalli, P. Colombo, N.A. Peppas, Drug / polymer matrix swelling and dissolution, Pharm. Res. 5 (1988) 488494. [9] S.K. Mallapragada, N.A. Peppas, Crystal unfolding and chain disentanglement during semicrystalline polymer dissolution, AIChE J. 43 (1997) 870876. [10] S.K. Mallapragada, N.A. Peppas, Crystal dissolution-controlled released systems: I. Physical characteristics and modeling analysis, J. Control. Release 45 (1997) 8794. [11] M. Grassi, I. Colombo, R. Lapasin, Drug release from an ensemble of swellable crosslinked polymer particles, J. Control. Release 68 (2000) 97113. [12] A.J. Kuijpers, P.B. van Wachem, M.J.A. van Luyn, G.H.M. Engbers, J. Krijgsbveld, S.A.J. Zaat, J. Dankert, J. Feijen, In vivo and in vitro release of lysozyme from cross-linked gelatin hydrogels: a model system for the delivery of antibacterial proteins from prosthetic heart valves, J. Control. Release 67 (2000) 323336. [13] J. Siepman, N.A. Peppas, Modeling the drug delivery systems based on hydroxypropyl methylcellulose, Adv. Drug Deliv. Rev. 48 (2001) 139157. [14] T. Higuchi, Rate of release of medicaments from ointment bases containing drugs in suspensions, J. Pharm. Sci. 50 (1961) 874875. [15] N.A. Peppas, Analysis of Fickian and non-Fickian drug release from polymers, Pharm. Acta Helv. 60 (1985) 110 111. [16] N.A. Peppas, R.W. Lorsmeyer, Dynamically swelling hydrogels in controlled release applications, in: N.A. Peppas (Ed.), Hydrogels in Medicine and Pharmacy, Vol. 3, CRC Press, Boca Raton, FL, 1986, pp. 109136. [17] J.H. Han, J.D. Floros, Simulating diffusion model and determining diffusivity of potassium sorbate through plastic to develop antimicrobial packaging lms, J. Food Preservation 22 (1998) 107122. [18] D. Chung, S.P. Papadakis, K.L. Yam, Release of propyl paraben from a polymer coating into water and food simulating solvents for antimicrobial packaging applications, J. Food Processing Preservation 25 (2001) 7187. [19] D. Chung, M.L. Chikindas, K.L. Yam, Inhibition of Saccharomyces cerevisiae by slow release of propyl paraben

r issN 1 1d Dtd
1 5 ]]]]]]]]]]] i C WssN 1 1d Dtd C iACssN 1 1d Dtd 1 ] 1 ]]]]] 1 ]]]]] rp rW rAC (A2)

The following expression was used to evaluate V i ((N 1 1) Dt ):

i m ip C iWssN 1 1d Dtd ? m p V issN 1 1d Dtd 5 ] 1 ]]]]]] rp rW i C iACssN 1 1d Dtd ? m p 1 ]]]]]] rAC

(A3)

The following expression was used to evaluate Dx i 1 1 ((N 1 1) Dt ): V i 1 1ssN 1 1d Dtd Dx i 1 1ssN 1 1d Dtd 5 ]]]]] SssN 1 1d Dtd

(A4)

The evolution of the polymer surface was evaluated by considering an isotropic swelling of the wet polymer. The above approximation is reasonable, since experiments show that the elastic modulus of the polymer does not vary signicantly after water sorption. Since S((N 1 1) Dt ) 5 dy ((N 1 1) Dt ) ? dz ((N 1 1) Dt ), we need an equation for dy ((N 1 1) Dt ) and another for dz ((N 1 1) Dt. The two equations have the same form, so we can write a single equation in terms of the generic symbol d ((N 1 1) Dt ). Assuming the additivity upon mixing of the water and macromolecular matrix volumes, we get: ]]]] i i 3 V ssN 1 1d Dtd d ssN 1 1d Dtd 5 ]]]] V is0d ? d iin.ssN 1 1d Dtd (A5)

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