Polymer International 43 (1997) 182È186

Non-ionizable Polyacrylic HydrogelsSensitive to for BiomedicalpH

Applications*

Blanca Va� zquez,a¤ Marilo� Gurruchaga,b Isabel Gon8 i,b & Julio San Roma� na

a Instituto de C. y T. de Poli�meros, CSIC, Juan de la Cierva, 3, 28006-Madrid, Spainb Dpto C. y T. de Poli�meros, Facultad de Qui�mica de San Sebastia� n, Apartado 1072, 20080-San Sebastia� n, Spain

(Received 30 September 1996 ; accepted 25 October 1996)

Abstract : Hydrogels based on ethoxytriethyleneglycol monomethacrylate/methylmethacrylate (T/M) copolymers were prepared by free radical polymerization at70¡C in bulk with azobisisobutyronitrile as initiator. The reactivity ratios werecalculated by FinemanÈRoss (FR) and KelenÈTudos (KT) linearization methodsand by the non-linear least square method suggested by Tidwell and Mortimer(TM). The reactivity ratios obtained were (FRrT \ 0É17 ^ 0É03, rM \ 0É70 ^ 0É01method) ; (KT method) andrT \ 0É19 ^ 0É02, rM \ 0É76 ^ 0É03 rT\ 0É18 ; rM \0É75 (TM method). Microstructure was obtained in terms of the distribution ofT- and M-centred triads. The swelling behaviour of the hydrogels was studied byimmersion of the Ðlms in water and in bu†ered solutions at various pH valuesand it was analysed by comparison with that of poly(ethoxytriethyleneglycolmonomethacrylate). It was observed that not only the average copolymer com-position but also the distribution of monomeric sequences play an important rolein the swelling behaviour.

Key words : reactivity ratios, acrylates, pH-sensitivity.

INTRODUCTION

Hydrogels have received signiÐcant attention, especiallyin the last 20 years, because of their exceptional promisein biomedical applications. The preparation, structureand characterization of di†erent hydrogels have beenreported in the literature.1,2 The hydrogels availableleave numerous choices for polymeric formulations. Thebest approach for development of a hydrogel with thedesired characteristics is to combine the macro-molecular structure of the polymers available withswelling and mechanical properties. Because of the pres-ence of certain functional groups, hydrogels are oftensensitive to the conditions of the surrounding environ-

* Presented at “The Cambridge Polymer Conference : Partner-ship in PolymersÏ, Cambridge, UK, 30 SeptemberÈ2 October1996.¤ To whom all correspondence should be addressed.

ment, such as temperature, pH or ionic strength of theswelling agent. This environmentally sensitive behav-iour has led to the extensive use of hydrogels in con-trolled drug delivery systems and in membraneseparations.3h8

In previous work we have developed a pH-sensitivesystem based on a non-ionizable polymer,poly(ethoxytriethyleneglycol monomethacrylate)9 andits further modiÐcation by copolymerization withmethyl methacrylate.10 In this paper we report reactiv-ity ratios for the bulk copolymerization reaction of eth-oxytriethyleneglycol monomethacrylate (T) with methylmethacrylate (M). The reactivity ratios have been calcu-lated using both linearization and non-linear leastsquare methods. We also report comonomer sequencedistribution in terms of T- and M-centred triads for thispair of monomers. We have analysed the inÑuence ofthe incorporation of a hydrophobic component on theswelling behaviour of the copolymers.

182Polymer International 0959-8103/97/$17.50 1997 SCI. Printed in Great Britain(

Non-ionizable hydrogels 183

EXPERIMENTAL

Copolymerization reaction

Ethoxytriethyleneglycol monomethacrylate was synthe-sized as described elsewhere.9 The copolymerizationreaction was carried out in bulk at 70¡C using azobis-isobutyronitrile (AIBN) (0É3 mol% with respect tomonomer) as initiator.10 Copolymers were obtained atconversions below 5 wt%. The reaction medium wasprecipitated in n-hexane. The solid was isolated, washedin methanol, 50/50 water/methanol, Ðltered and dried.

Copolymer characterization

Nuclear magnetic resonance (NMR) spectra wererecorded with a Varian VXR-300 spectrometer oper-ating at 300 MHz for 1H NMR experiments and75É5 MHz for 13C NMR experiments, at room tem-perature, using mixtures of deuterated chloroform anddeuterated triÑuoroacetic acid as solvent and tetra-methylsilane as internal reference.

Dynamic swelling

The dry gels of poly(ethoxytriethyleneglycolmonomethacrylate) or their copolymers with methylmethacrylate (1 ] 1 cm and 0É5 mm thickness) wereimmersed in bu†ered solutions of di†erent pH at roomtemperature (20¡C). The water uptake was obtained byweighing the initial and swollen samples at time inter-vals. The equilibrium water sorption was used tocompute the hydration degree (H), which was deÐned asthe weight of water sorbed to that of the hydrogel. Thebu†ered solutions (titrisol, Merck) ranged from pH 4 to10.

RESULTS AND DISCUSSION

The free radical copolymerization of eth-oxytriethyleneglycol monomethacrylate (T) with methylmethacrylate (M) was studied over a wide interval offeed composition with AIBN as free radical initiator at70¡C, in bulk. The reaction time was regulated to reachconversions below 5 wt% in order to avoid the inÑuenceof conversion on the composition and sequence dis-tribution of the copolymers prepared.11 The copolymerswere characterized by 13C NMR spectroscopy. Com-parison of the resonance signals of the copolymerspectra with those of the corresponding spectra ofpoly(methyl methacrylate)12,13 and poly(ethoxytri-ethyleneglycol monomethacrylate)9 supports a randomdistribution of stereochemical sequences of T/M copoly-mers, with a relative tendency to the formation of syn-diotactic segments. The composition of the copolymerchains was determined from the 1H and 13C NMR

TABLE 1. Average composition, conditional prob-

abilities and copolymer conversion of T/M copoly-

mers prepared in bulk with AIBN

FT

(feed)a fT

(copolymer)b PTM

PMT

Conversion

(wt%)

0·10 0·10 0·98 0·13 4·0

0·20 0·21 0·96 0·25 3·0

0·30 0·28 0·93 0·36 3·6

0·50 0·41 0·85 0·57 3·8

0·60 0·46 0·79 0·67 3·6

0·80 0·60 0·58 0·84 3·2

0·90 0·70 0·38 0·92 4·8

a Molar fraction of monomer T in the feed.

b Molar fraction of monomer T in the copolymer.

spectra.14 The results obtained are summarized in Table1. The conditional probabilities Pij (i, j \ T, M), deÐnedas the probability for the addition of monomer units jto free radical i ends,15 were calculated statistically fromthe best values of the corresponding reactivity ratios.These values are useful to determine the statistical dis-tribution of M- and T-centred sequences along thecopolymer chains.

The reactivity ratios were determined by using theFinemanÈRoss (FR) (Fig. 1a)16 and KelenÈTudos (KT)(Fig. 1b)17 linearization methods as well as by the appli-cation of the non-linear least square analysis suggestedby Tidwell and Mortimer (TM),18 and they are col-lected in Table 2. It is clear from these values that theradicals ending in T units are much more reactivetowards methyl methacrylate molecules than towardstheir own monomer, whereas those radicals ending inan M unit present a rather similar reactivity to bothmonomer molecules.

Non-linear least square analysis allows the desiredparameters to be determined and the precision of themethod to be obtained. Also, the application of themathematical treatment suggested by Behnken19 andTidwell and Mortimer18 provides the so-called 95%conÐdence limit, which gives an idea of the experimentalerror and of the suitability of the experimental condi-tions used to calculate the composition. This limit is

TABLE 2. Reactivity ratios of the free radical

copolymerization of T/M system in bulk at 70ÄCinitiated with AIBN

Method rT

rM

l/rT

l/rM

rT

ÃrM

FR 0·17 À0·03 0·70 À0·01 5·88 1·42 0·12

KT 0·19 À0·02 0·76 À0·03 5·38 1·32 0·14

TM 0·18 0·75 5·53 1·33 0·14

POLYMER INTERNATIONAL VOL. 43, NO. 2, 1997

184 B. V a� zquez et al.

Fig. 1. Diagrams of (a) FinemanÈRoss (FR) and (b) KelenÈTudos (KT) for the radical copolymerization of T with M.

deÐned by the area of the elliptical diagram drawn inFig. 2. This diagram conÐrms the good approximationof the values of the reactivity ratios and asrT rM

Fig. 2. Ninety-Ðve per cent conÐdence diagram for thereactivity ratios of T and M, determined by the non-linearleast square method suggested by Tidwell and Mortimer.Values of reactivity ratios : TidwellÈMortimer ; KelenÈ@, +,

Tudos, FinemanÈRoss.=,

indicated by the reduced dimensions of the ellipse, andthus the values of the reactivity ratios obtained by thenon-linear least square analysis are the most appropri-ate values to be used.

Figure 3 shows the average composition diagram ofthis system. The points correspond to the experimentaldata obtained from the analysis of the copolymersamples prepared at low conversion, whereas the linecorresponds to the theoretical diagram according to theMayoÈLewis equation20 with reactivity ratios values of

and The results obtained indicaterT\ 0É18 rM\ 0É75.that the copolymerization system has a clear azeotropicbehaviour in free radical polymerization, with an azeo-tropic point for a molar fraction of T in the feed,F(T)\ 0É25. This means that for this value the composi-tion of the reaction medium is constant during the poly-merization reaction. Moreover, the average compositionof the copolymer system is the same as that of the feedat the azeotropic point.

Figure 4 shows the statistical diagrams of M- and T-centred sequences in terms of triads determined fromthe reactivity ratios by the TM method as a function ofthe methyl methacrylate molar fraction. The molarfraction of alternating MTM triads and MMM homo-

POLYMER INTERNATIONAL VOL. 43, NO. 2, 1997

Non-ionizable hydrogels 185

Fig. 3. Composition diagram for T/M copolymerizationsystem.

triads increased as the content of the hydrophobicmonomer increased in the copolymer. However, themolar fraction of heterotriads having two T units ortwo M units reached a wide maximum for a molar frac-tion of M in the copolymer, f (M)\ 0É40 and 0É60,respectively. The alternating TMT triads and the TTThomotriads decreased with increase of the hydrophobicmonomer. So, it can be said that as the M monomercontent increases in the hydrogel, the copolymers arenearly formed by MTM and MMM triads, these

Fig. 4. Content of (a) M-centred and (b) T-centred triads as afunction of the methyl methacrylate molar fraction in thecopolymer, f (M) for the copolymerization of methyl meth-

acrylate with ethoxytriethyleneglycol monomethacrylate.

type of sequences being very important in the swellingbehaviour of the hydrogels.

Dynamic swelling behaviour of the copolymers wasstudied by measuring the water sorption of thin Ðlmsimmersed in bu†ered solutions in acidic, neutral andalkaline media at room temperature. Figure 5 shows therelationship between the hydration equilibrium degreeand the copolymer composition at di†erent pH values,together with that obtained for poly(ethoxytriethylene-glycol monomethacrylate). It can be observed that forany pH the copolymer composition inÑuenced theswelling behaviour when the T/M molar fraction ofcopolymers ranged between 10/90 and 30/70, and fromthis composition on, the swelling degree increased at amore gradual rate. That is to say, in a wide range ofmethyl methacrylate content in the copolymer, the pres-ence of a hydrophobic monomer has little e†ect on theswelling behaviour, revealing that the copolymer com-position sequences will play an important role on theability of the copolymers to swell. Figure 6 shows moreclearly the inÑuence of increasing hydrophobicity in the

Fig. 5. Variation of the equilibrium hydration degree with thecomposition of the copolymer systems at di†erent pH values :

4 ; 6 ; 7 ; 9 ; 10.=, …, >, @, +,

Fig. 6. Di†erences between the equilibrium hydration degreesof the homopolymer and the corresponding copolymer as afunction of the pH of the medium. f (T) value : 0É09 ;=,

0É21 ; 0É28 ; 0É41 ; 0É46 ; ], 0É6.…, >, @, +,

POLYMER INTERNATIONAL VOL. 43, NO. 2, 1997

186 B. V a� zquez et al.

hydrogel. This Ðgure shows the di†erences observedbetween the hydration degree of the hydrophilic hydro-gel and the corresponding modiÐed hydrogel for di†er-ent pH values. It is clearly observed that the copolymerswith a molar fraction of methyl methacrylate between0É70 and 0É90 gave the greatest variations of the hydra-tion degree for the whole range of pH values, decreasingthe swelling with respect to that of the homopolymer.However, copolymeric hydrogels with smaller contentof methyl methacrylate did not appreciably change theswelling behaviour of the poly(ethoxytriethyleneglycolmonomethacrylate) at basic pH, although the hydrationdegree decreased slightly at intermediate pH. This factindicates that not only the copolymer composition, butalso the monomer sequence distribution along thecopolymer chains inÑuences the swelling behaviour.Looking at the monomer sequence distribution, whichis plotted in Fig. 4 in terms of triads, it is clear that thecopolymers very rich in methyl methacrylate, i.e.f (M)\ 0É7È0É9, are mainly formed by MMM andMTM triad sequences. For intermediate compositions,i.e. f (T)\ 0É6È0É5, the MMM sequences decrease dras-tically, whereas those of MTM still remain high. Thisindicates that the copolymer must be very rich inMMM sequences in order to change the swellingbehaviour appreciably. Owing to the reactivity param-eters of this pair of monomers, a relatively high MMMmolar triad fraction in the copolymer can only beobtained for a feed composition very rich in the hydro-phobic monomer.

The di†erences of swelling found for any copolymercomposition at di†erent pH values may be due to di†er-ent conformational arrangements through hydrogenbond interactions at di†erent pH values.21h23 In thecopolymers very rich in methyl methacrylate, the pres-ence of MMM sequences might favour a coil confor-mation through hydrophobic interactions at acidicpH by comparison with that of the purepoly(ethoxytriethyleneglycol monomethacrylate), sincelower hydration degrees are obtained for these hydro-gels. However, in the copolymers with a molar fractionof methyl methacrylate lower than 0É7, the presence ofalternating sequences may favour the extended confor-mation of the polymeric chains at basic pH giving riseto no signiÐcant di†erences in the swelling ratio.

CONCLUSIONS

(1) The copolymerization reaction of ethoxytri-ethyleneglycol monomethacrylate and methyl

methacrylate gives random copolymers with reacti-vity ratios of 0É18 and 0É75, respectively.

(2) These copolymer systems provide an e†ective routefor the design and application of polyacrylic hydro-gels with swelling extent controlled by averagecomposition, as well as by the distribution of Tand M sequences along the copolymer chains.

(3) In addition, these systems present an interestingglobular transition in a relatively narrow intervalof pH, just in the range of physiological conditions,which o†ers enormous possibilities in the Ðeld ofdrug delivery systems, or even for the design of bio-membranes for dermal applications.

ACKNOWLEDGEMENT

We thank the CICYT (Mat96-0981) for the facilitiesgranted to have this work performed.

REFERENCES

1 Andrade J. D., Hydrogels for Medical and Related Applications.ACS Symposium Series, Vol 31, ACS, Washington, DC.

2 Peppas, N. A., Hydrogels in Medicine and Pharmacy. CRC. Press,Boca Rato� n, FL.

3 Dusek, K. & Janacek, J., J. Appl. Polym. Sci., 19 (1987) 3061.4 Cartidge, S. A., Duncan, R., Lloyd, J. B., Kopeckova-Rejmanova� ,

P. & Kopecek, J., J. Controlled Release, 4 (1987) 265.5 Hu, D. S-G. & Chou, K. J-N, Polymer, 37 (1995) 1019.6 Siegel, R. A. & Firestone, B. A., in Advances in Drug Delivery

Systems, 4th edn, eds J. M. Anderson, S. W. Kim, K. Knutson.Elsevier, New York, 1990, p. 181.

7 Brondsted, H. & Kopecek, J., Biomaterials, 12 (1991) 584.8 Chang, S. F. & Chien, Y. W., in T reatise on Controlled Drug

Delivery. Fundamentals. Optimization. Applications, ed. A. Kydon-ieus. Marcel Dekker, New York, 1991.

9 Vazquez, B., Gurruchaga, M., Gon8 i, I., Narvarte, E. & SanRoma� n, J., Polymer, 36 (1995) 3327.

10 Vazquez, B., Gurruchaga, M., Gon8 i, I. & San Roma� n, J., Bio-materials, (in press).

11 Odian, G., Principles of Polymerization, 3rd edn. Wiley Inter-science, New York, 1991.

12 Pham, Q. T., Petiaud, R. & Waton, H., Proton and Carbon NMRSpectra of Polymers. Penton Press, London, 1991.

13 Bovey, F. A., Makromol. Chem. Macromol. Symp. 20/21 (1988) 105.14 Gon8 i, I., Gurruchaga, M., Vazquez, B., Valero, M., Guzman, G.

M. & San Roma� n, J., Polymer, 35 (1994) 1535.15 Koenig, J. L., Chemical Microstructure of Polymer Chains. Wiley

Interscience, New York, 1980.16 Fineman, M. & Ross, S. D., J. Polym. Sci., 5 (1950) 259.17 Kelen, T. & Tudos, F., J. Macromol. Sci., A9 (1975) 1.18 Tidwell, P. W. & Mortimer, G. G. A., J. Polym. Sci., A3 (1965) 369.19 Behnken, D. W., J. Polym. Sci., Part A, 2 (1964) 645.20 Mayo, F. R. & Lewis, F. M., J. Am. Chem. Soc., 66 (1944) 1594.21 Bekturov, E. A. & Bimendina, L. A., Adv. Polym. Sci., 41 (1981) 99.22 Bell, C. L. & Peppas, N. H., Biomaterials, 17 (1996) 1203.23 Bell, C. L. & Peppas, N. A., J. Biomater. Sci., Polym. Edn., 7 (1996)

671.

POLYMER INTERNATIONAL VOL. 43, NO. 2, 1997