Hydrogels of poly(ethylene glycol): mechanical characterization and release of a model drug

Journal of Controlled Release 52 (1998) 41–51

Hydrogels of poly(ethylene glycol): mechanical characterization and release of a model drug M. Iza*, G. Stoianovici, L. Viora, J.L. Grossiord, G. Couarraze ´ Laboratoire de Physique Pharmaceutique, URA CNRS 1218, Faculte´ de Pharmacie, Universite´ Paris-Sud, 5, rue J.B.Clement , ´ , France 92296 Chatenay-Malabry Cedex Received 9 October 1996; received in revised form 29 May 1997; accepted 18 September 1997

Abstract Thermosensitive polymer networks were synthesized from poly(ethylene glycol), hexamethylene diisocyanate and 1,2,6-hexanetriol in stoichiometric proportions. By varying the amount of 1,2,6-hexanetriol and the molar mass of the poly(ethylene glycol), a wide range of networks with different crosslinking densities was prepared. The networks obtained were characterized by the temperature dependence of their degree of equilibrium swelling in water and by their Young’s moduli. For each network, the molecular weight between crosslinks was estimated. The structure of the hydrogels was analysed with respect to scaling laws, and it was found that the results obtained with PEG 1500 and PEG 6000 hydrogels are in agreement with theoretical predictions, whereas those obtained with PEG 400 hydrogels are in disagreement. The release properties of PEG hydrogels were studied by the determination of the diffusion coefficient for acebutolol chlorhydrate and by an analysis of the effect of temperature on these coefficients. Finally, these release properties were correlated with the swelling and structural properties of the hydrogels.  1998 Elsevier Science B.V. Keywords: Poly(ethylene glycol); Thermosensitive hydrogels; Scaling laws; Acebutolol chlorhydrate; Diffusion

1. Introduction Thermosensitive hydrogels are a class of hydrogels of great interest in the pharmaceutical and biomedical fields, as evidenced by the large amount of published literature [1–6]. They include various polymers, such as N-substituted acrylamide, methylacrylamide, poly(ethylene oxide), etc. In addition to their fundamental scientific interest, thermosensitive hydrogels have been used in a large number of applications such as sensors, switchs, separation membranes, adsorbents, mechano-trans*Corresponding author. Tel.: 133 1 46835610; fax: 133 1 46835882; e-mail: mustapha. [email protected]

ducers, dehydrants and materials for drug delivery system [7]. Several authors [8,9] have reported that the kinetics, duration, and rate of drug release from hydrogels are influenced by the structural properties of polymer and, more particularly, the degree of crystallinity, size of crystallites, degree of swelling and molecular weight between crosslinks. Recently, hydrogels based on poly(ethylene glycol) (PEG) have attracted considerable attention in controlled release technology because of their good biocompatibility and excellent physicochemical properties. Graham and McNeill [10,11] reported the prolonged delivery of a variety of bioactive materials, such as prostaglandin E 2 , caffeine and melatonin, from these hydrogels. Merril et al. [12]

0168-3659 / 98 / $19.00  1998 Elsevier Science B.V. All rights reserved. PII S0168-3659( 97 )00191-0

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M. Iza et al. / Journal of Controlled Release 52 (1998) 41 – 51

studied the diffusion of tricyclic antidepressants, cyanocobalamin and proteins through poly(ethylene oxide) hydrogels prepared by electron beam irradiation of aqueous solutions, and have related the diffusion coefficients to the molecular weight between crosslinks. In this paper we describe the preparation of networks based on poly(ethylene glycol). A wide range of PEG networks of various crosslinking densities was obtained by varying the amount of crosslinking agent and the molar mass of the polymer (400# M #10 000). These systems have been characterized by their degree of swelling as a function of temperature (T ,LCST (lower critical solution temperature)), by their Young’s modulus and by their molecular weight between crosslinks determined from the classical theory of gelation. The relationship between Young’s modulus and polymer concentration was established, and compared with theoretical predictions proposed by de Gennes in order to discuss the structure of the networks. The release properties of these hydrogels were studied by the determination of the diffusion coefficient for acebutolol and by correlation of these values with network characteristics. The effect of temperature on the release properties of hydrogels was also determined and analysed in terms of competition between swelling and diffusion processes.

2. Materials and methods

2.1. Hydrogel synthesis The hydrogels were obtained by chemical crosslinking of the poly(ethylene glycol) through urethane groups by incorporating diisocyanate and triol according to the procedure described by Graham et al. [13].

2.1.1. Reactants Poly(ethylene glycol) (PEG): the poly(ethylene glycol) samples were supplied by Hoechst Co., under designations which indicate their approximate molar mass. The molar mass distributions were determined by size exclusion chromatography (using H 2 O as the

eluent) by comparison with a PEO calibration curve. The values of the number average molecular weight, ¯ n , and polydispersity indices, I p , are shown in M Table 1. When incorporating the crosslinking agent and diisocyanate into the gel, these values were used to calculate the molar equivalents of diisocyanate and 1,2,6-hexanetriol. Each PEG sample was dried under vacuum at 110–1208C, for 6 h before use. 1,2,6-Hexanetriol (HT), the crosslinking agent, supplied by AldrichChimie, was dried by a similar procedure to PEG. Hexamethylene diisocyanate (HMDI), used as chain extender, was supplied by Aldrich-Chimie, and used as received, without further purification.

2.1.2. Preparation of the PEG network The synthesis of the PEG network was performed according to the following general procedure: The PEG and hexanetriol were mixed together and heated at 75–808C, under magnetic stirring (250 rpm). One drop of benzoyl chloride was added to the mixture in order to delay a possible gelation reaction. HMDI was added drop by drop. All components were rapidly mixed with a magnetic stirrer (250 rpm) and the resultant liquid poured `  ). into a preheated polypropylene mould (Nalgene The mould was tightly covered and the network cured at 90–1008C for 15 h. Various percentages of 1,2,6-hexanetriol were used to obtain different degrees of crosslinking in the PEG network at a stoichiometric ratio ([NCO]5[OH]). The hydrogel composition was defined by the following reactions: PEG 1 a HT 1 b HMDI→ Xerogel, Xerogel1H 2 O→Hydrogel a is the mole number of hexanetriol, b 5111.5 a. The following naming system was used to identify

Table 1 ¯ n and I p determined by SEC Values of M Sample code

¯n M

Ip

PEG PEG PEG PEG PEG

400 1330 3467 5460 10 280

1.10 1.06 1.07 1.09 1.19

400 1500 4000 6000 10 000

M. Iza et al. / Journal of Controlled Release 52 (1998) 41 – 51

43

PEG hydrogel samples. The two numbers separated by a slash in parentheses indicate the mole percentages of PEG and triol in the composition, respectively. PEG 400, PEG 1500, PEG 4000, PEG 6000 and PEG 10 000 represent the commercial codes for the particular poly(ethylene glycol). Thus, for example, the hydrogel denoted PEG 1500 (1 / 0.25) is the hydrogel based on 1 mole of poly(ethylene glycol) 1500, HMDI, and 0.25 mole (a 50.25) of the crosslinking agent (hexanetriol). The proportion of HMDI can be deduced from the stoichiometric ratio (1.375 moles in the example).

2.1.3. Structure of PEG networks PEG hydrogels synthesized in this study were composed of hydrophilic PEG chains and hydrophobic domains constituted by clusters of crosslinkers. A schematic representation of the structure of these materials is given in Fig. 1. The figure indicates the presence of crosslinking sites, polymer joining the crosslinking sites (the number of chains between crosslinking sites depends on the percentages of hexanetriol and diisocyanate). 2.2. Swelling isotherms Equilibrium swelling properties of the hydrogel were studied in the 10–1008C temperature range in deionized water. After equilibration at one temperature, samples were reequilibrated at another temperature to constant weight (|48 h). The equilibrium weight swelling ratio G was calculated using the following relationship: M 2 M0 G(%) 5 ]]] M0

(1)

where M is the hydrogel weight at equilibrium swelling and M0 the xerogel (dry hydrogel) weight.

Fig. 1. Schematic representation of PEG hydrogel structure.

cal probe of diameter 20 mm, and ran at 0.1 mm / s. The hydrogel samples of diameter 20 mm, with thickness520–30 mm were submitted to an unidirectional strain. The applied strain was small enough (,10%) in order to remain in linear region of the stress-strain response. The plots of force against strain were recorded and Young’s modulus was derived as the slope divided by corresponding cross-sectional area of the hydrogel. The indentation test was also performed in order to confirm the E values determined by uniaxial compression. Theoretical considerations of the procedure are based on the method developed by Waters [14]. The texture analyser TA-XT2 was used to determine the compressive force (F ) necessary to maintain a constant indentation (d) (displacement). The E values were given by the equation Eq. (2) below: 2 ]

2.3. Modulus measurements

K?F 3 E 5 ]] 1 ] R3 ?d

The values of the Young’s modulus E in the swollen state were obtained from uniaxial compression measurements using a texture analyser TA-XT2 (SMS). The apparatus was equipped with a cylindri-

where R is the indentor radius (3.125 mm) and K a constant. The molecular weight between crosslinks (Mc ), was deduced from the modulus measurements.

2 ] 3

(2)

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M. Iza et al. / Journal of Controlled Release 52 (1998) 41 – 51

In the case of affine deformation of network [15], then:

gel composition was calculated from the following equation [16]:

r RT ]1 Mc 5 3]] ? w 3 E

]] Q Q D?t ]t 5 4 ]]2 for ]t , 0.6 Q` Q ph `

(3)

where R is the gas constant, T the absolute temperature, r the polymer density, and w the equilibrium volume fraction of polymer in the swollen state.w was approximated by M0 /M.r 51.126 g / cm 3 (PEG 400), r 51.20 g / cm 3 for other polymers.Mechanical tests were carried out at 20618C

2.4. Acebutolol chlorhydrate diffusion To study the release of a dissolved solute from the ˆ hydrogel, acebutolol chlorhydrate (Rhone-Poulenc) was chosen as a model drug. Acebutolol is a drug of medium molecular weight (M5372.9). In the hydrochloride form, its solubility in water is very high (about 1 g / g). Drug loading: the slabs (their dimensions were so as to lead to a one-dimensional release, i.e. length / thickness .10) of dried PEG hydrogels were swollen to equilibrium for 5 days in 5 mg / ml aqueous solution of acebutolol (aqueous sink), usually at 108C. The temperature effect on the diffusion coefficient was studied on PEG 6000 gels by varying the loading temperature.

Drug release: after removal from the acebutolol solution 1 the swollen slabs were transfered to flasks containing deionized water. The flasks were maintained at 378C in a thermostatically controlled bath. Release of the drug was monitored continuously by recording absorbance with respect to time at the appropriate wavelength. In the UV analysis (DU-70 spectrophotometer Beckman), the samples showed a characteristic UV absorption band at 316 nm. The diffusion coefficient, D, of acebutolol in each 1 The polymer samples were removed from the acebutolol solution and blotted with filter paper to remove excess drug solution on the sample surface

œ

(4)

where h denotes the slab thickness, Q t denotes acebutolol desorption at time t, and Q ` denotes the amount of solute, which is released at infinite time.

3. Results and discussion

3.1. Hydrogel synthesis The xerogels obtained were opaque and off-white, except for the xerogels based on PEG 400 and PEG 1500 (1 / 2) which were transparent. In the hydrated state, opaque hydrogels became transparent. To obtain reproducible hydrogels, special precautions were taken: changes in mixing efficiency, the mixing temperature and the drying conditions were the major sources of variability. `  ), or a By using a polypropylene mould (Nalgene glass mould lubricated with silicon wax (Rhodorsil  ), homogeneous networks were obtained. The duration of reaction was about 15 h for all polymers. Nevertheless, an exception was noted for hydrogels based on PEG 400, where the reaction was complete after 5 h. The sol fraction (extractable polymer), determined gravimetrically, in fully cured polymers, was lower than 5 wt.%, and was not taken into account in the swelling calculations. The preparation of these hydrogels was reproducible, as shown by the low values of the coefficients of variation (always ,7%) of the values of swelling ratio, given in the swelling section.

3.1.1. Choice of polymers This study only concerns the polymers whose properties were varied enough to provide different behaviour. For these reasons, criteria of choice were retained. They were based on: a) The manufacture of the hydrogels. b) The structural properties of the polymers. 3.1.1.1. The manufacture. The hydrogel formula-

M. Iza et al. / Journal of Controlled Release 52 (1998) 41 – 51

tions were excellent when the polymer molecular weight was below 10 000, but were inhomogeneous and unsatisfactory with PEG 10 000: the viscosity of this polymer was too high to allow good mixing. For this reason, hydrogels based on PEG 10 000 were not studied further.

3.1.1.2. The structural properties of polymers. We have considered the polymers, which differ by the presence or absence of crystalline domains and entangled chains. Hence, the networks based on the following polymer models were retained to synthesize the hydrogels: PEG 400: amorphous polymer without entanglements. PEG 1500: crystalline polymer without entanglements. PEG 6000: entangled chains with crystalline structure. These properties (crystallinity, entanglement) could influence the structure of hydrogels, but they not the only factor; the variety of reactions during the preparation of gels (e.g. crosslinker-to-crosslinker reaction) could also affect the ultimate hydrogel properties. In general, it is not possible to isolate each factor for study independently. 3.1.2. Molar composition of hydrogels The topology of networks was modified by varying the amount of crosslinking agent in stoichiometric proportions. The networks with a small quantity of triol were non-homogeneous and presented poor mechanical characteristics, and in addition were difficult to handle. On the other hand, xerogels with a high degree of crosslinking were not very swellable in water, and thus uninteresting for diffusion studies. Systems with molar proportions of triol ranging from: 0.1 mole to 1 mole for PEG 400, 0.1 mole to 2 mole for PEG 1500, 0.75 mole to 5 mole for PEG 6000 were prepared. The molar proportions of the systems selected for further study are listed in Table 2. These compositions were chosen so as to have systems, which presented: a) Different topologies, by varying either the amount of triol or the molar mass of the polymer.

45

Table 2 Molar composition of PEG networks (PEG mole / hexanetriol mole) PEG 400

PEG 1500

PEG 6000

(1 / 0.13) (1 / 0.25) (1 / 0.5) (1 / 1)

(1 / 0.25) (1 / 0.5) (1 / 1) (1 / 2)

(1 / 1) (1 / 2) (1 / 3) (1 / 4)

b) Similar theoretical densities of crosslinking (if we suppose that crosslinker-to-crosslinker reactions, and other defects were not preponderant), with different molar mass of PEG and different amounts of crosslinking agent: the PEG 400 (1 / 0.13), PEG 1500 (1 / 0.5) networks, were manufactured in order to obtain a density of crosslinking which should be identical to that of the system PEG 6000 (1 / 2).

3.2. Swelling properties of hydrogels 3.2.1. Rate of swelling At room temperature, it was observed that the time taken to achieve swelling equilibrium of the hydrogels decreased with increasing molar proportion of crosslinking agent (Fig. 2), and this time was at least 10 h. 3.2.2. Thermal variation of swelling ratio PEG is a water-soluble polymer with a lower critical solution temperature (LCST) of 958C, as reported by Gnanou et al. [17]. Table 3, Figs. 3 and 4 show the effect of tempera-

Fig. 2. Swelling equilibrium of PEG 6000 hydrogels in water at 258C.

M. Iza et al. / Journal of Controlled Release 52 (1998) 41 – 51

46

Table 3 Temperature dependence of swelling degree (G %) of PEG networks: numbers in square brackets are the coefficients of variation as a percentage T (8C)

10 25 37 60

PEG 400

PEG 1500

PEG 6000

(1 / 0.13)

(1 / 1)

(1 / 0.25)

(1 / 2)

(1 / 1)

(1 / 4)

141[1] 95 [2] 69 [2] 43 [5]

37 [2] 30 [2] 25 [2] 18 [7]

439 334 242 133

96 [6] 79 [1] 65 [2] 48 [1]

645 [3] 554 [2] 465 [2] 406 [1]

216 [3] 191 [3] 167 [3] 134 [4]

Fig. 3. Swelling ratio as a function of temperature and molar mass of PEG.

ture on the equilibrium swelling ratio of hydrogels. It can be seen from these results that increasing the temperature decreased the swelling ratio of hydrogels. At temperature close to the LCST, the G values

Fig. 4. Swelling equilibrium of PEG 400 hydrogels as a function of temperature and molar proportion of crosslinking agent.

[6] [1] [5] [1]

became constant and seemed independent of the proportion of hexanetriol (Fig. 4). It was noted that the G values of low-density crosslinked hydrogels (PEG 6000 (1 / 1) network for example) at temperatures higher than 708C were not accessible experimentally because of polymer oxidation. It seems that the oxidation products were watersoluble. For example, the decrease of the G value was about 70% for PEG 400 (1 / 0.13) hydrogel and 40% in the case of PEG 6000 (1 / 4) hydrogel when the temperature was varied up to 608C. These results are in agreement with those reported by several authors [17,18]. It has been reported [19–21] that the PEG gel swells with water and also forms specific hydrates through hydrogen bonding. Hydrogen bond formation between the oxygen atom of PEG and the hydrogen atom of water would clearly be very temperature-dependent and when the temperature is increased this bond is liable to break, while hydrophobic interactions are enhanced. The nature of the hydrates formed was polymer precursor-dependent as demonstrated by the literature [19] and our unpublished data. Thus, decreasing the temperature can induce swelling. This property will be exploited further to modify the release kinetics of a drug.

3.2.3. Effect of the structure of polymer on the swelling ratio The swellability of the polymer at a given temperature was increased either by increasing the molecular weight of PEG (Fig. 3), or by decreasing the molar amount of crosslinking agent (Fig. 4). For example, the amount of water in an equilibrated PEG 6000 hydrogel at 258C decreased 3-fold as the crosslinking agent was varied from 1 to 4 moles. In

M. Iza et al. / Journal of Controlled Release 52 (1998) 41 – 51 Table 4 Swelling ratio (6 S.D.) of networks of similar theoretical density of crosslinking at 258C and 608C: G 10 is the swelling ratio determined at 108C and G 60 the ratio at 608C Hydrogels

G 10 (%)

G 60 (%)

PEG 400 (1 / 0.13) PEG 1500 (1 / 0.5) PEG 6000 (1 / 2)

14162 24162 411616

4362 8165 22965

47

to-crosslinker reaction) are likely to play a significant role in network formation.

3.3. Mechanical measurements 3.3.1. Comparison of E values determined by the indentation test and by uniaxial compression The indentation test was performed on some networks, which differed in their average molecular weight between crosslinks; a relatively good agreement between the E values determined by the two methods was found, as shown in Table 5. The two tests are appropriate for elastic products.

the same way, the amount of water increased 18-fold as the molecular weight of PEG was varied from 400 to 6000 (systems with a proportion of triol of 1 mole). These results show that a higher swelling ratio is associated with longer chain length of PEG between crosslinks, achieved either by increasing PEG mass or by decreasing the amount of crosslinking agent. Since the equilibrium swelling is a property which is characteristic of the network, we could predict that the networks would have the same swelling ratio, for the same theoretical density of crosslinking. Table 4, which gave the values of swelling ratio for (assumedly) identical network topology, i.e., PEG 400 (1 / 0.13), PEG 1500 (1 / 0.5) and PEG 6000 (1 / 2), shows that this is not true. These results suggested that the process controlling crosslinking was PEG precursor-dependent: the structure of polymer and the reaction conditions during hydrogel preparation (particularly crosslinker-

3.3.2. Molecular weight between crosslinks The values of Young’s modulus and molecular weight between crosslinks, for the hydrogels studied are listed in Table 6. For any hydrogel series, increasing the molar amount of crosslinking agent reduces the molecular weight between crosslinks and increases the Young’s modulus. It is noteworthy that some Mc values of the systems based on PEG 6000 are below the PEG molar mass, which is theoretically impossible; however the values predicted from affine theory are only indicative, because it is probable that the networks formed in this way contain many structural imperfections (entanglements, hydrogen bonding, crosslinking density heterogeneity,...) which affect the validity of

Table 5 Values of Young’s modulus determined by uniaxial compression and indentation test Sample

Hydrogel 6000 (1 / 4)

Hydrogel 6000 (1 / 2)

Hydrogel 1500 (1 / 2)

Xerogel 400 (1 / 1)

Xerogel 400 (1 / 0.13)

E comp E ind

2.4 2.3

1.2 1.3

4.6 5.9

5.6 5.6

2.9 3.0

E comp: modulus value determined by uniaxial compression (MPa). E ind: modulus value determined by indentation test (MPa).

Table 6 Young’s modulus and molar mass between crosslinks of the PEG hydrogels PEG 400

E MPa

Mc

PEG 1500

E MPa

Mc

PEG 6000

EMPa

Mc

(1 / 0.13) (1 / 0.25) (1 / 0.5) (1 / 1)

0.49 2.1 2.9 4.8

13 200 3300 2300 1300

(1 / 0.25) (1 / 0.5) (1 / 1) (1 / 2)

1.9 2.5 3.8 4.6

2900 2500 1700 1500

(1 / 1) (1 / 2) (1 / 3) (1 / 4)

0.39 1.2 1.6 2.4

17 200 5900 4500 3100

Mc (g / mole): molecular weight between crosslinks.

48

M. Iza et al. / Journal of Controlled Release 52 (1998) 41 – 51

Eq. (3). However, the order of magnitude of these values seems satisfactory. The swelling results and modulus values for hydrogels studied suggest a classification in two categories: 1. Hydrogels of PEG 6000 and PEG 1500. 2. Hydrogels of PEG 400. In the case of category 1, the high swelling degree was associated with a small modulus and therefore a larger mesh size. However, the crosslinking reaction, and the variety of reactions during network formation were specific to each polymer, since the swelling ratio of networks having a similar topologies were different. PEG 400 hydrogels exhibit lower swelling values with relatively low moduli. This behaviour probably originates from crosslinker-crosslinker reactions, which are preponderant in this case. It is possible that the mobility of crosslinker was constrained by the longer chains.

3.3.3. Scaling laws Scaling laws established by de Gennes [22] predict that the Young’s modulus of gels at swelling equilibrium varies with polymer volume fraction w as w n , where the exponent n depends upon the nature of the polymer-solvent interaction. Fig. 5 shows the variation of the log (E) with log (w ), for the networks studied. For the PEG 1500 and PEG 6000 networks, the curves are continuous, as would be expected if we

Fig. 5. Relationship between log(E) and log(w ) for hydrogels prepared with PEG 400, PEG 1500 and PEG 6000.

consider that the structure would be unchanged by varying the chain length. The slope of the straight line is 2.32 (correlation factor r50.99), which is close to the theoretical values (2.25 in good solvent conditions and 3 in theta conditions). Hild et al. [23] have reported a value of 2.51 for the same PEG crosslinked in organic solution. It therefore seems that the hydrogels of PEG 6000 and PEG 1500 had homologous structures. For the PEG 400 hydrogels, the curve log (E)-log (w ) was not superimposable on the other hydrogel curves, and was found to have a slope of 3.2, which differs from the theoretical value. The structure of hydrogels based on PEG 400 is probably very different from other hydrogels and cannot be considered as homologous. These results confirm the previous observations.

3.4. Acebutolol chlorhydrate diffusion coefficients 3.4.1. Diffusional properties of hydrogels Fig. 6 shows a typical release profile of acebutolol chlorhydrate from a hydrogel based on PEG 6000 (1 / 2) loaded at 258C. It can be seen clearly that the diffusion was Fickian since a straight line was obtained up to 60%

Fig. 6. Fickian interpretation of acebutolol chlorhydrate release from hydrogel 6000 (1 / 2) loaded at 258C.

M. Iza et al. / Journal of Controlled Release 52 (1998) 41 – 51

49

Table 7 Diffusion coefficient (D?10 26 cm 2 / s) of chlorhydrate acebutolol in PEG 400, PEG 1500 and PEG 6000 hydrogels PEG 400

PEG 1500

PEG 6000

System

D

System

D

System

D

(1 / 0.13) (1 / 0.5) (1 / 1)

0.85 0.41 0.14

(1 / 0.25) (1 / 1) (1 / 2)

7.8 3.3 0.40

(1 / 1) (1 / 2) (1 / 4)

11 5.9 3.8

of the total release in the plot of fractional released amount versus t 0.5 for each composition. The diffusion coefficients, calculated from Eq. (4) are given in Table 7. The calculated values of D varied in a range of approximately two decades and increased when the molar proportion of crosslinking agent was reduced. These results indicate that drug diffusion through swollen hydrogels depends on the porous structure of hydrogel: the higher the swelling ratio, the higher the molecular weight between crosslinks and the greater the diffusion coefficient. Smaller D values were obtained for hydrogels based on PEG 400 and hence these systems could be used as delayed-release systems.

3.4.2. The effect of temperature on release properties of matrix As predicted by the swelling properties of PEG hydrogels, the apparent diffusion of acebutolol in PEG networks was faster when the temperature of the drug loading was decreased, as indicated by Table 8 which gives the values of diffusion coefficients for hydrogels based on PEG 6000 loaded at 108C and 258C. The increase of D value reached about 20%, so the variation was significant, since the D values determined had a coefficient of variation smaller than 12%. Table 8 Diffusion coefficient (D) of acebutolol chlorhydrate in hydrogels based on PEG 6000 as a function of the loading temperature System

6000 (1 / 1) 6000 (1 / 2) 6000 (1 / 4)

D(10 26 cm 2 / s) 108C

258C

11 5.9 3.8

9.1 4.9 3.1

Fig. 7. Timecourse of acebutolol chlorhydrate release from PEG 6000 (1 / 2) loaded at 258C.

It should be noted that acebutolol was released at 378C from systems whose the initial structure was determined by the loading conditions and was unaltered by temperature during the release. In fact, as demonstrated by the kinetics of swelling equilibrium and drug release, the time to reach equilibrium of swelling is at least 10 h (Fig. 2), whereas the release time was at most 3 h (Fig. 7). Thus the net difference between the characteristic times of the two processes (swelling and release) allowed the release kinetics of the drug to be modified in this way.

4. Conclusion A thermosensitive series of hydrogels from poly(ethylene glycol) has been synthesized. A wide range of hydrogels was obtained by varying of PEG molar mass (from 400 to about 6000) and the amount of crosslinking agent. The results of swelling characterization have shown that: The process of crosslinking was dependent on polymer-precursor and preparation conditions. The swelling ability was very temperature depen-

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M. Iza et al. / Journal of Controlled Release 52 (1998) 41 – 51

dent and varied considerably (up to approximately 5 times their dry weight). Analysis of these hydrogels on the basis of scaling laws has shown different behaviour for PEG 400 networks and the other hydrogels. Although PEG 1500 and PEG 6000 hydrogels fulfil theoretical expectations, the hydrogels based on PEG 400 deviate from them. The discrepancy between theoretical predictions and experimental results could originate from the hydrophobic character of the aliphatic urethane linkages, the proportion of which would be higher in networks containing shorter PEG chains. The hydrogels prepared from PEG 1500 and PEG 6000 form a family, whose structure is probably homologous, where structural defects play a minimal role in determining elastic characteristics. The structure of PEG 400 hydrogels is different from the other hydrogels, and the heterogeneity of crosslinking density certainly has a preponderant effect. It was also shown that these mechanical properties affect and control the diffusion process, as demonstrated by diffusion experiments, where the release of acebutolol was quite fast for moderately crosslinked samples, while for highly crosslinked systems, the diffusion of the drug was much delayed. The studies of swelling and release kinetics have shown that the equilibrium swelling process is slow in comparison with the release process. So the structure of hydrogel during the release experiments remained unchanged with respect to its original structure (structure at the temperature of loading). This leads to increased diffusion when the release temperature was higher than the loading one. So it seems possible to envisage two main ways of controlling and modulating the drug release kinetics: by varying the crosslinking density, or by changing the loading temperature.

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