Swelling properties of hyaluronic acid ester membranes

journal of MEMBRANE SCIENCE

ELSEVIER

Journal of Membrane Science 92 ( 1994) 157- 167

Swelling properties of hyaluronic acid ester membranes KC. Sung, E.M. Topp* Department

of Pharmaceutical

Chemistry,

The University of Kansas, Lawrence, KS 66045-2504,

USA

(Received November 15, 1993; accepted in revised form March 4, 1994)

Abstract Swelling equilibrium and kinetics of swelling for hyaluronic acid (HA) benzyl ester membranes were examined in media of different pH and ionic strength, and for varying percent esterification of the polymers. The equilibrium swelling properties for polymers with an intermediate (75-SSW) degree of esterification in different media can be explained by the Donnan equilibrium theory. However, this theory does not apply to the swelling behaviors of membranes with high ( > 85%) and low ( < 75%) degrees of esterification, implying that non-ideal conditions must also be considered. The kinetics of swelling in media of different ionic strength can be described by a secondorder swelling model, with both diffusion and stress relaxation contributing to the process. Ion exchange influences the swelling kinetics of HA ester membranes at lower pH in the medium. Keywords: Water sorption and diffusion; Hydrogels; Hyaluronic acid esters; Donnan equilibrium

1. Introduction

The swelling properties of polyelectrolyte networks, which can be described in terms of the swelling rate and of maximum solution uptake at equilibrium, depend on the physicochemical properties of the polymers and on the composition of the surrounding medium [ 11. Several reports have demonstrated that the swelling equilibrium of a polyelectrolyte network can be altered by varying the backbone hydrophobicity of the polymer and the pH and ionic strength of the medium [2-61. The Donnan equilibrium theory has been used with success to predict the equilibrium swollen state [ 2,4]. Several authors have proposed that, due to the thermodynamic *Corresponding 5612.

author. Tel.: 9 13-864-3644; Fax: 9 13-842-

0376-7388/94/$07.00

SSDZ 0376-7388

non-ideality and polyelectrolyte effect, this theory can only be used to explain the equilibrium swelling phenomenon both qualitatively and quantitatively when the polyelectrolyte network is relatively hydrophilic and has low charge density [ 2,3,7]. The kinetics of swelling have been reported to be controlled by the relative contributions of diffusion and relaxation processes, which are in turn affected by the backbone hydrophobicity, charge density and medium conditions [ 8-101. In most reported studies, polymers with a narrow spectrum of backbone hydrophobicity and charge density have been tested, limiting the range of properties that have been tested against these theories. Therefore, it is desirable to examine the swelling equilibrium and kinetics of a polymer system in which the hydrophobicity and charge density can be varied over a wider range.

0 1994 Elsevier Science B.V. All rights reserved (94)00062-4

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K. C. Sung, EM. Topp /Journal of Membrane Science 92 (1994) 15 7- I6 7

Fig. 1. Structure of hyaluronic acid (HA) esters. The R groups are given in Table 1.

Hyaluronic acid (HA) is a naturally occurring linear mucopolysaccharide consisting of residues of D-glucuronic acid and N-acetylglucosamine. Through the esterification of carboxylate groups of HA with benzyl alcohol, Fidia S.p.A. has been able to produce benzyl esters of HA (Fig. 1). The polymer hydrophobicity increases with increasing benzyl esterification; for example, hyaluronic acid itself is highly water soluble, while the 100% benzyl ester dissolves only in polar aprotic solvents such as dimethyl sulfoxide. In addition, since the pK, of the carboxylate residue on HA is N 3.3, the charge density on the polymer is affected both by esterification, which removes the ionizable group, and by changes in pH. These esters are very promising for use in drug delivery devices, since they are biocompatible and biodegradable [ 111. Devices fabricated from these esters swell and appear gel-like when exposed to aqueous solutions. This suggests that hydrogen bonding interactions and chain entanglements are responsible for the gel network, since no covalent crosslinks are present. Previous work in our laboratories has shown that the release of drugs from HA ester membranes is affected by their swelling properties [ 1 l- 13 ] ; however, the swelling properties of these membranes have not been fully characterized and reported. In the present study, the swelling equilibrium and swelling kinetics of these uncrosslinked HA ester polymer membranes were characterized by varying percent esterification of the polymers (50 to 93%) as well as the pH and ionic strength of the medium. A

semi-empirical approach was used to correlate the effect of medium conditions and percent esterification to the equilibrium swelling of the polyelectrolyte membranes. The equilibrium swelling of HA ester membranes was tested against the Donnan equilibrium theory; swelling kinetics were modeled using kinetic data analysis.

2. Experimental 2. I. Materials Table 1 lists the HA derivatives used in this study. As shown in the table, the polymers differ in the degree of esterification to benzyl alcohol. Each polymer will be referred to by an abbreviation designating the percentage of carboxylate groups that have been esteritied. For example, HA50 designates a polymer in which 50% of the carboxylate groups on the parent polymer have been esterified. The HAlOO, HA75 and HA50 polymers were supplied by Fidia, S.p.A. (Abano Terme, Italy); the other polymers listed in Table 1 were prepared from the HA 100 polymer as described below. All other chemicals were obtained from Sigma Chemical Company (St. Louis, MO ) and used as received. 2.2. Preparation of partial esterified polymers The partially esterified polymers HA6 1, HA85 and HA93 were prepared by hydrolysis of HA1 00. HA100 (200 mg) was suspended in a

K.C. Sung, EM. Topp / Journalofhfembrane

Science 92 (1994) 157-167

159

Table 1 Hyaluronic acid (HA) benzyl esters and solvents used for membrane fabrication Abbreviation

Group ( R )

HA100 HA93 HA85 HA75 HA61 HA50

100%b benzyl ester 93% benzyl ester+7.0% sodium 85% benzyl ester+ 15% sodium 75% benzyl ester+25% sodium 6 1% benzyl ester + 39% sodium 50% benzyl ester + 50% sodium

Solvent compositions”

salt salt salt salt salt

100% HFIP” 98.5% HFIP+ 79.0% HFIP + 79.0% HFIP + 29.0% HFIP + 29.0% HFIP +

(v/v)

1.50% deionized 2 1.O% deionized 2 1.O% deionized 7 1.O% deionized 7 1.O% deionized

water water water water water

a7 ml solvent was used to dissolve 200 mg solute. % refers to the percentage of carboxylate groups derivatized. =HFIP, hexafluoroisopropanol.

USP rotating bottle apparatus with 100 ml of 0.04 M borate buffer (pH 9) and 0.0005 M EDTA as a hydrolysis medium. The temperature and rotating speed were set at 37’ C and 25 rpm. The benzyl alcohol released was monitored by a Shimadzu HPLC system, consisting of a pump (Model LC-6A), a C 18 reverse phase silica column (ODS, Hypersil, 5 mm), a UV detector (Model SPD-6A) and an integrator (Chromatopac CR4A). Phosphate buffer and acetonitrile (70: 30) was used as mobile phase. The flow rate was 1 ml/min and UV wavelength was set at 254 nm. Benzyl alcohol concentrations were determined by measuring peak area and comparing with a calibration curve prepared using known standards. After hydrolysis, the polymer suspensions were filtered, washed with deionized water and resuspended in 1 1 of deionized water for 3 h in order to remove salts. The partially esterified polymers were then recovered by filtration. 2.3. Membrane fabrication The membranes used in the swelling experiments were cast from polymer solutions. Table 1 lists the compositions of the solvents used for the different polymers. The polymer solutions were poured onto glass Petri dishes, and the solvent was allowed to evaporate in a fume hood at room temperature for -36 h. The membranes were peeled from the Petri dishes and cut into 12-mm diameter circular membranes using a cork borer. The membranes were then stored in a vacuum

desiccator with calcium chloride for at least 24 h before the experiment in order to remove residual solvent. The amount of solvent remaining in the membranes at the end of this period was determined to be 1 to 3% (w/w) by incubating the membranes at elevated temperature ( 85 ‘C ) for three days. The thicknesses of the dry membranes were measured using an Ames micrometer (Waltham, MA) and found to be uniform (0.12 0.0 1 mm). Partially esterified HA membranes with all or half of the carboxylate groups protonated were obtained by immersing the polymer membranes in the sodium form into solutions of pH 1, 2 and 3.3 for 9.5 h. The membranes were then blotted dry and stored in a vacuum desiccator prior to measurement of swelling kinetics. 2.4. Kinetic and equilibrium swelling studies Polymer membranes in triplicate were immersed in solution at 25°C. The total ionic strength of each solution was adjusted to a desired level with a calculated amount of NaCl. In studies with varying pH, the total ionic strength was kept constant at 0.15 M. 0.1 and 0.0 1 MHCl were used for the pH 1 and 2 solutions, whereas 0.025 M phosphate buffer was used for other pH values. For studies at varying ionic strength, different concentrations of phosphate buffer were employed in order to keep the solutions at pH 7.4. In all the solutions above, the monovalent ions contribute more than 85% of the total ionic strength. Periodically, the polymer membranes

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KC. Sung, EM. Topp /Journal ofktembranescience

were withdrawn from the solution and weighed on an electronic balance (Mettler Model AE240) after removal of surface water by light blotting with a laboratory tissue. This procedure was repeated until there was no further change in the weight of the membranes. The swelling ratio of the membrane (SW) was defined as: sw= (partially

hydrated membrane weight -dry membrane weight) (dry membrane weight )

The equilibrium swelling ratio of the membrane (EQSW) was defined as: Eosw= (fully

hydrated membrane weight-dry membrane weight) (dry membrane weight)

3. Results 3. I. Swelling equilibrium Effect of ionic strength The values of EQSWwere determined from the plateau region of the swelling kinetics curves. Although the times for the reaching plateau depended on the ionic strength and pH of the media and the types of polymers used, all the SW values began to plateau after 9.5 h. There appeared to be no secondary phase of sorption within this 24-h time period. Swelling did not appear to vary in the axial direction within the disk, suggesting that no gross anisotropies were introduced by the membrane casting method. Due to the slow hydrolysis of benzyl esters, the system is not in its true equilibrium state; in the true equilibrium state, all benzyl ester groups have been hydrolyzed, providing the parent polymer. In these studies, the percent esterification changed by less than 3% within the experimental time frame, as determined by measuring the benzyl alcohol released into the swelling medium. Therefore, the swelling ratios at 24 h were taken as quasi-equilibrium swelling ratios for the membranes. The effect of the ionic strength of the medium

92 (1994) 157-167

on the equilibrium swelling properties of various HA ester membranes at pH 7.4 and 25°C is shown in Fig. 2. The ionic strength of the medium varied from 0.05 to 2 A4. Two effects can be observed in this figure. First, the EQSW increases as ionic strength decreases, with a steeper dependence for membranes with lower percent esterification. Second, the EQSWincreases as the percent esterification decreases at all ionic strength. These effects suggest that the ionic strength of the medium and the percent esterification of the polymers have a profound influence on the equilibrium swelling behaviors of the membranes, as expected. An empirical relationship can be constructed by relating the effects of percent esterification and ionic strength of the medium to the EQSW of these membranes. The EQSW versus natural logarithm of ionic strength were fitted to a linear equation, in which the intercepts and slopes are a function of the percent esterilication: EQSW= (A-BE)

+ (CE-D)lnp

(1) where A, B, C and D are constants obtained from curve fitting (Table 2); (A-BE) and (CE-D) are the intercept and the slope of the empirical equation; E is the percent esterification of the polymer membranes and p is the ionic strength

1.0

Ionic

2.0

1.5 Strength

2.5

(M)

Fig. 2. Swelling isotherms for membranes of HA esters as a function of ionic strength. The pH of the medium and temperature were 7.4 and 25°C. Data for membranes with varying degrees of esterification (see Table 1): HA50 (0 ), HA6 1 (O),HA75 (Cl),HA85(B)andHA93(A).

K.C.Sung,E.M

Topp/JournalofMembraneScience92(1994)157-167

161

Table 2 Constants for equilibrium equations [ Eqs. ( 1) to (3) ] and their standard errors obtained from curve fitting Constant

Value

Standard error

A B C D A’ B’ F G I J

24 0.27 0.23 20 22 0.25 1 0.009 50 0.56

3 0.05 0.03 2 1 0.02 3 0.04 2 0.03

-10

0

10

20

Cnlculsted

of the medium. As percent esterification decreases, the intercept and the absolute value of the slope increase, indicating both a greater EQSWand an increased sensitivity to variations in ionic strength of the medium. Interestingly, the parameter values obtained in the regression show that A is approximate equal to D and B is about equal to C (Table 2). This suggests that both the slope and the intercept of this regression vary in the same way with changing esterification of these polymers. This also implies that the magnitude of the EQSW and the sensitivity of EQSW to changes in ionic strength are similarly influenced by changing esterification. Eq. ( 1) can therefore be replaced by a two-parameter model, since there are no significant differences between the two models according to the F-test: EQSW=(A’-B’E)(l-lnp)

(2)

Here A’ and B’ are constants obtained from curve fitting (Table 2). By using this empirical equation [ Eq. (2 ) 1, a comparison of the calculated EQSW versus experimentally determined EQSW (Fig. 2) can be constructed. The slope and intercept of the regression (Fig. 3a) show a good agreement between the calculated and experimentally determined results. This empirical equation can therefore be used to predict the EQSW for the HA ester membranes in media of different ionic strength at pH 7.4; it can also be used to design a

-5

0

5

10

Cdculated

30

40

EQSW

15

20

25

EQSW

Fig. 3. (a) The experimentally determined equilibrium swelling ratio (EQSW) versus the calculated EQSW according to the empirical equation (2) for different HA benzyl esters in media of different ionic strength. The r* value is 0.9 18. (b) The experimentally determined EQSW versus the calculated EQSW according to the empirical equation (3 ) for the different esters in media of different pH. The r* value is 0.936.

membrane with a desired EQSW in a medium of known ionic strength at pH 7.4. EfSect of pH

The influence of the pH of the medium on the equilibrium swelling properties of various HA ester membranes is shown in Fig. 4. The ionic strength of the medium and temperature were kept at 0.15 A4and 25 “C, while the pH was varied from 1 to 7.4. As shown in Fig. 4, the EQSW

K.C. Sung, E.&f. Topp /JournalofMembraneScience

162

EQSW=F,(F-GE)

T

+F,

(I-JE)

0 0

0

92 (1994) 157-167

7

2

4

6

8

PH

Fig. 4. Swelling isotherms for membranes of HA esters as a function of pH. The ionic strength of the medium and temperature were 0.15 A4 and 25°C. Data for membranes with varying degrees of esterification (see Table 1): HA50 (0 ), HA61 (O), HA75 (El), HA85 (a) andHA (a).

increased with the pH of the medium in a sigmoidal fashion similar to the variation in the ionization ratio of HA monomer ( pK, = 3.3 ) as a function of pH. There was no sharp swelling transition at pH 3.3; however, a steeper increase in EQSW was observed in the pH range 2 to 4.5. For polymer membranes with lower percent esterification ( 50%,6 1%)) the EQSWis more sensitive to changes in pH of the medium. At fixed pH of the medium, membranes with higher percent esterification (93%) also had lower EQSW values. These results demonstrate that, at fixed ionic strength, the EQSW of the membranes is a function of the pH of the medium and the percent esterification of the polymers. A semi-empirical equation can also be constructed to relate the EQSW to the percent esteritication of the polymer membranes and the pH of the medium. Since the increase in EQSW is related to the ionization of HA ester polymers, the total EQSWcan be treated as the sum of contributions from the protonated carboxylate groups and from the ionized form of carboxylate groups within the polymer membranes. As for ionic strength, the relative importance of each term is assumed to be a linear function of the percent esterification:

(3)

in which FH is the fraction of the protonated carboxylate groups, FL is the fraction of the ionized carboxylate groups within the polymer membranes and F, G, I and J are constants obtained from curve fitting (Table 2). The fractions FH and FL can be related to the hydrogen ion concentration ( [H+ ] ) and the dissociation constant of the HA monomer (K,), since FH is equal to [H+]/( [H+] +K,) and F, is equal to K,/( [H+] +K,). (F-GE) and (I-JE) are the equilibrium swelling ratios of the fully protonated and the sodium salt form of the membranes, respectively. As the percent esterification (E) decreases, the values of (F-GE) and (I- JE) both increase; that is, greater EQSW values can be obtained for polymer membranes with lower percent esterification. This empirical equation was tested by plotting the calculated EQSW versus the experimentally determined EQSW. The slope and intercept of the linear regression (Fig. 3b) also showed a good agreement between the calculated and experimentally determined EQSW. Therefore, this empirical approach can also be used to predict the equilibrium swelling ratio of membranes or to design a membrane with desired equilibrium swelling properties when pH is varied at constant ionic strength (0.15 M). The results further imply that the pH dependence of swelling in these membranes is determined by the contributions of ionized and unionized carboxyl groups. 3.2. Test of Don nan equilibrium theory Donnan equilibrium has been used to explain the swelling equilibrium of polyelectrolyte networks; similar swelling phenomena have been reported and tested by the theory elsewhere [ 24,6]. The theory attributes the ion swelling pressure (ni,,), which causes the swelling of a polyelectrolyte network, to the difference between the osmotic pressure of freely mobile ions in the network and in the surrounding solution. It can also be tested against the phenomena observed here.

K.C. Sung, EM. Topp /Journal ofMembraneScience

Donnan equilibrium theory can be described by two equations [ 2 ] : 17,JRT=

AC,,, = C (K”-

1) Ci

(4)

where ni,” is the ion swelling pressure of membranes; Ci and Zi are the concentration and valence of the ith ionic species; and AC,,, is the difference between the total ionic concentration inside and outside the membrane. K is the root ofEq. (5): ~Z~C~K”+dK1O~PH/(K~+K1O~PH)~O

(5)

where pH is the pH of the medium and d is the concentration of ionizable carboxylate groups in the membranes. Some assumptions will be used for simplicity: ( 1) the activity coefficient of ions are equal to unity, (2) the standard state chemical potential of each ion is the same inside and outside the membrane and (3) the dissociation constant of the carboxylate groups in the polymer is the same as that of the HA monomer. Fig. 5 shows the calculated ion swelling pressure values (fli,,/RT) based on the Donnan equilibrium theory [ Eqs. (4) and ( 5 ) ] for a se-

;

0.02

o *

_In

4 6 8 ‘OI

0.00 0

10

20

30

40

50

EQSW

Fig. 5. Calculated ion swelling pressure values (l7io”/RT) based on the Donnan equilibrium theory versus equilibrium swelling ratio (EQSW) for benzyl esters of HA. Data were obtained at 25°C by changing the pH and ionic strength of the medium. Data for membranes with varying degrees of esterifkation (see Table 1): HA50 (0), HA61 (O), HA75 (Cl), HA85 (m) and HA93 (A ). Insert shows data near the origin.

92 (1994) 157-167

163

ries of benzyl esters of HA membranes; the EQ,SW values were obtained from experiments (Figs. 2 and 4 ). For the membranes with intermediate percent esterification (HA75 and HA85 ) , l7JRT was a unique function of EQSW irrespective of the pH or ionic strength of the medium in the experiment, which is in accordance with the Donnan equilibrium theory [ 71. For the membranes with highest percent esteritication (HA93), EQSW was not sensitive to changes in ion swelling pressure, with large changes in l7i,,/RT producing very little change in EQSW. This suggests that the swelling equilibrium of these highly esterified polymer membranes is not controlled by Donnan equilibrium. Conversely, for membranes with low percent esterification (HA50 and HA61 ), changes in EQSW were observed with virtually no change in ion swelling pressure, again suggesting that Donnan equilibrium is not the major factor in controlling swelling equilibrium of those membranes. Several factors may contribute to the deviation from the Donnan equilibrium theory. Polymer membranes with higher percent esterification are relatively hydrophobic and the volume fraction of the polymer in the swollen membrane is appreciable. Hence, the assumptions that the ion activity coefficient equals unity and that the standard state chemical potential of each ion is the same inside and outside the membranes might not be valid, since the swelling of the polymer membranes is not extensive enough to produce the ideal conditions [ 3,7, lo]. For membranes with lower percent esterification, the total charge and EQSW are greater. Katchalsky et al. [ 14-161 showed that the polyelectrolyte effect must be considered to explain the swelling behaviors of highly swollen methacrylic acid gels. In the HA membranes, the deviation from Donnan behavior in these membranes may also be due to the polyelectrolyte effect, which involves the repulsion between charged groups. Moreover, both the degree of swelling and the electrostatic interactions between the charged groups can affect the ionization [ 14- 16 1. The fixed dissociation constant used in the quantitative analysis may also account for the poor performance

K. C. Sung, EM. Topp /Journal of Membrane Science 92 (I 994) 15 7- I6 7

164

of the Donnan equilibrium theory for membranes with the lower and higher percent esterification. 3.3. Swelling kinetics Effect of ionic strength A typical swelling kinetic curve of HA ester membranes is shown in Fig. 6. Initially, the swelling ratio rises steeply, then gradually levels off and approaches the equilibrium value, EQSW. Swelling ratio versus time data have been analyzed using both first- and second-order models [ 171. First-order swelling kinetics is defined as: dSW/dt=P(EQSW-SW)

(6)

with the integrated form: ln[EQSW/(EQSW-SW)]

=Pt

(7)

Second-order swelling kinetics is defined as: dSW/dt=K(EQSW-SW)2

(8)

with the integrated form: sW=KtEQSW2/(

1+KtEQSW)

(9)

where P and K are first- and second-order swelling rate constants, respectively. By fitting the swelling ratio versus time curves to the integrated forms of first- and second-order equations (Eqs. 7 and 9 ), the latter gave better regression coefficients and a smaller total sum of squares. A Wilcoxon rank sum test was also performed, indicating that second-order swelling kinetics is a better model. Therefore, the secondorder model was used to describe the swelling ratio versus time profiles for the HA ester membranes. Advantages to performing such kinetic analysis include the summarizing of the entire kinetic process in the EQSW and swelling rate constant values, and possible insight into the mechanisms involved in the swelling process. Fig. 7 shows the natural logarithm of the second-order swelling rate constant for different HA ester membranes in media of different ionic strength. While there is considerable scatter in these fitted parameters, a rough trend is apparent: greater ionic strength of the medium and greater percent esterification produce larger swelling rate constants. The swelling kinetics of HA ester membranes in media of different ionic strength is therefore affected by the nature of the ”

6

1 I A

4 M

9

=

A

A

A

A

A

n

nP .

0

0.0 0.2 0.4 0.6 0.8 1.0

-l

0.0

0 0

10

20

30

Time (Hours)

Fig. 6. Swelling kinetic curve for HA61 membranes (n = 3 ) at 25 “C. The pH was 7.4 and the ionic strength was adjusted to 2.0 M with NaCl. The plateau value of the swelling ratio was taken as the equilibrium swelling ratio (EQSW) . Insert shows the first hour of the kinetic curve.

0.5

1.0

1.5

2.0

2.5

Ionic Strength (M)

Fig. 7. The natural logarithm of the second-order swelling rate constant (K) versus the ionic strength of the medium for different hyaluronic acid ester membranes. Data for membranes with varying degrees of esteritication (see Table 1): HAS0 (0), HA61 (O), HA75 (Ki), HA85 (m) and HA93 (A).

K.C. Sung, EM. Topp /Journal o$Membrane Science 92 (I 994) 15 7-16 7 pH=l.O

0

2

1

Time

3

4

(Hours)

pa2.0

(b)

2’o

1.5-3

.i 6

lyiiP

f

f

f

f

t

0.5-

0.00 0

1

2

Time

3

4

(Hours) pH=3.3

4

(d

,.fQ

o

0

0 P

g2#@.@

Ip

+

s

165

polymers and the ionic strength of the medium. Two rate processes generally contribute to the swelling of polymer membranes: diffusion and stress relaxation. According to Papini et al. [ 131, the average diffusion coefficient of water molecules in the 100% esterified HA benzyl ester membranes is estimated to be 10-5-10-6 cm2/ s. By applying Einstein’s law of diffusion, a membrane of 0.1 mm initial thickness would then be completely permeated by water within 2 min. In general, complete swelling of HA ester membranes requires at least 25 min. Thus, the longer duration of the swelling process suggests a contribution by stress relaxation, which is influenced by the swelling pressure and the secondary network bonding in polymer. The relaxation process, which involves the rupture of interchain secondary bonds (e.g., hydrogen bonds), permits the expansion of the polymer network and subsequent uptake of more solution [ 171. The contribution of relaxation is also supported by the non-linear relationship between the SW and square root of time at early times (data not shown). The non-linear relationship suggests that the swelling kinetics of these HA ester membranes is not diffusion controlled [ 8 1. Relaxation may be particularly important under two types of experimental conditions: ( 1) in media of low ionic strength and (2) for polymers with low degrees of esterification. High EQ.!W values are observed under both conditions (Figs. 2 and 4 ); this indicates that a significant volume expansion of the membrane occurs, which must be accompanied by extensive polymer relaxation. In addition, the second-order swelling rate constants are smaller under these conditions (Fig. 7). Since stress relaxation is often slower than diffusion, the smaller swelling rate constants are consistent with a greater contribution of stress relaxation. The relative importance of diffusion and stress relaxation in

I-

O.

0

I

2

Time

(Hours)

3

4

Fig. 8. The swelling kinetics for HA75 membranes in either the protonated form ( 0 ) or the sodium salt form ( 0 ) . Data for three experiments conducted at three different pH values: (a) 1.0, (b) 2.0, (c) 3.3. The ionic strength of the medium and temperature were 0.15 M and 25 ‘C.

166

K.C. Sung, EM. Topp /Journal of Membrane Science 92 (1994) 15 7- 16 7

the swelling kinetics may thus depend on the percent esterification of the membranes and the ionic strength of the medium. Eflect of pH The swelling kinetic curves for HA ester membranes at different pH and fixed ionic strength of the medium (PC 0.15 M) have different shapes depending on the pH of the medium. For pH greater than 4.5 and less than 1, the shape is similar to that shown in Fig. 6. A peak phenomenon was observed for media with pH 2 and 3.3. Fig. 8 demonstrates the swelling kinetics of HA75, which is in the sodium salt form, at pH 1, 2, and 3.3. It also shows the swelling kinetics of fully protonated HA75 at pH 1 and 2 and the swelling kinetics of HA75 with half of the carboxylate groups protonated at pH 3.3 for comparison. For the fully protonated or half protonated polymer membranes, no early peak phenomenon in the swelling ratio versus time profiles was observed, but the EQSW were identical to those of the sodium salt form. Furthermore, the peak time of the polymer membrane in the medium of pH 2 was less than that in the medium of pH 3.3. The peak observed for HA ester membranes at pH 2 and 3.3 can be explained in terms of an ion exchange process, in which the sodium ions of the carboxylate groups are replaced by solution hydrogen ions. At low pH, the hydrogen ions protonate the carboxylate groups, which reduces the ionization and creates a more hydrophobic environment; these changes would reduce the swelling pressure. Thus, the peak observed at low pH may be due to rapid initial swelling of an ionizable membrane, followed by protonation and deswelling. This model is consistent with the observed absence of a peak for the membranes in the medium of pH 1 and with the shorter peak time for the membranes at pH 2 relative to pH 3.3. At pH 1, the flux of hydrogen ions into the membranes is greater, providing very rapid protonation of the carboxylate groups and preventing an initial peak. The greater hydrogen ion flux at pH 2 relative to that at pH 3.3 results in more rapid ion exchange and protonation, which explains the shorter peak time observed for the membranes at pH 2.

4. Conclusions In summary, the kinetics and equilibrium state for the swelling of HA benzyl ester membranes have been characterized as a function of the ionic strength and pH of the medium as well as the percent esterification of the polymer. For membranes with intermediate percent esterification (75% and 85%), the swelling equilibrium in media of varying pH and ionic strength can be explained by the Donnan equilibrium theory. However, for membranes with high (HA93 ) and low percent esteritication (HA50 and HA6 1)) the theory does not hold, perhaps due to the thermodynamic non-idealities and the polyelectrolyte effect. Semi-empirical relationships describing the dependence of EQSW on ionic strength at fixed pH and of EQSW on pH at fixed ionic strength have been developed. The kinetics of swelling is described by a second-order model. The duration of the swelling process relative to the estimated rate of diffusion suggests that both diffusion and stress relaxation contribute to the swelling kinetics. Ion exchange processes affect the initial phases of swelling in media at lower PH.

Acknowledgments The authors are thankful to FIDIA, S.p.A., Abano Terme, Italy for financial support and for supplying the HA ester polymers.

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