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Polymer International 43 (1997) 182È186
Non-ionizable Polyacrylic Hydrogels
Sensitive to pH for Biomedical
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, Spain
b 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/methyl
methacrylate (T/M) copolymers were prepared by free radical polymerization at
70¡C in bulk with azobisisobutyronitrile as initiator. The reactivity ratios were
calculated by FinemanÈRoss (FR) and KelenÈTudos (KT) linearization methods
and by the non-linear least square method suggested by Tidwell and Mortimer
(TM). The reactivity ratios obtained were r \ 0É17 ^ 0É03, r \ 0É70 ^ 0É01 (FR
T (KT method) and
M r \ 0É18 ; r \
method) ; r \ 0É19 ^ 0É02, r \ 0É76 ^ 0É03
T
M
M of
0É75 (TM method). Microstructure was obtained in terms of the Tdistribution
T- and M-centred triads. The swelling behaviour of the hydrogels was studied by
immersion of the Ðlms in water and in bu†ered solutions at various pH values
and it was analysed by comparison with that of poly(ethoxytriethyleneglycol
monomethacrylate). It was observed that not only the average copolymer composition but also the distribution of monomeric sequences play an important role
in the swelling behaviour.
Key words : reactivity ratios, acrylates, pH-sensitivity.
ment, such as temperature, pH or ionic strength of the
swelling agent. This environmentally sensitive behaviour has led to the extensive use of hydrogels in controlled drug delivery systems and in membrane
separations.3h8
In previous work we have developed a pH-sensitive
system
based
on
a
non-ionizable
polymer,
poly(ethoxytriethyleneglycol monomethacrylate)9 and
its further modiÐcation by copolymerization with
methyl methacrylate.10 In this paper we report reactivity ratios for the bulk copolymerization reaction of ethoxytriethyleneglycol monomethacrylate (T) with methyl
methacrylate (M). The reactivity ratios have been calculated using both linearization and non-linear least
square methods. We also report comonomer sequence
distribution in terms of T- and M-centred triads for this
pair of monomers. We have analysed the inÑuence of
the incorporation of a hydrophobic component on the
swelling behaviour of the copolymers.
INTRODUCTION
Hydrogels have received signiÐcant attention, especially
in the last 20 years, because of their exceptional promise
in biomedical applications. The preparation, structure
and characterization of di†erent hydrogels have been
reported in the literature.1,2 The hydrogels available
leave numerous choices for polymeric formulations. The
best approach for development of a hydrogel with the
desired characteristics is to combine the macromolecular structure of the polymers available with
swelling and mechanical properties. Because of the presence of certain functional groups, hydrogels are often
sensitive to the conditions of the surrounding environ* Presented at “The Cambridge Polymer Conference : Partnership in PolymersÏ, Cambridge, UK, 30 SeptemberÈ2 October
1996.
¤ To whom all correspondence should be addressed.
182
Polymer International 0959-8103/97/$17.50 ( 1997 SCI. Printed in Great Britain
Non-ionizable hydrogels
EXPERIMENTAL
Copolymerization reaction
Ethoxytriethyleneglycol monomethacrylate was synthesized as described elsewhere.9 The copolymerization
reaction was carried out in bulk at 70¡C using azobisisobutyronitrile (AIBN) (0É3 mol% with respect to
monomer) as initiator.10 Copolymers were obtained at
conversions below 5 wt%. The reaction medium was
precipitated in n-hexane. The solid was isolated, washed
in methanol, 50/50 water/methanol, Ðltered and dried.
Copolymer characterization
Nuclear magnetic resonance (NMR) spectra were
recorded with a Varian VXR-300 spectrometer operating at 300 MHz for 1H NMR experiments and
75É5 MHz for 13C NMR experiments, at room temperature, using mixtures of deuterated chloroform and
deuterated triÑuoroacetic acid as solvent and tetramethylsilane as internal reference.
Dynamic swelling
The
dry
gels
of
poly(ethoxytriethyleneglycol
monomethacrylate) or their copolymers with methyl
methacrylate (1 ] 1 cm and 0É5 mm thickness) were
immersed in bu†ered solutions of di†erent pH at room
temperature (20¡C). The water uptake was obtained by
weighing the initial and swollen samples at time intervals. The equilibrium water sorption was used to
compute the hydration degree (H), which was deÐned as
the weight of water sorbed to that of the hydrogel. The
bu†ered solutions (titrisol, Merck) ranged from pH 4 to
10.
RESULTS AND DISCUSSION
The
free
radical
copolymerization
of
ethoxytriethyleneglycol monomethacrylate (T) with methyl
methacrylate (M) was studied over a wide interval of
feed composition with AIBN as free radical initiator at
70¡C, in bulk. The reaction time was regulated to reach
conversions below 5 wt% in order to avoid the inÑuence
of conversion on the composition and sequence distribution of the copolymers prepared.11 The copolymers
were characterized by 13C NMR spectroscopy. Comparison of the resonance signals of the copolymer
spectra with those of the corresponding spectra of
poly(methyl methacrylate)12,13 and poly(ethoxytriethyleneglycol monomethacrylate)9 supports a random
distribution of stereochemical sequences of T/M copolymers, with a relative tendency to the formation of syndiotactic segments. The composition of the copolymer
chains was determined from the 1H and 13C NMR
POLYMER INTERNATIONAL VOL. 43, NO. 2, 1997
183
TABLE 1. Average composition, conditional probabilities and copolymer conversion of T/M copolymers prepared in bulk with AIBN
F (feed)a
T
f (copolymer)b
T
0·10
0·20
0·30
0·50
0·60
0·80
0·90
0·10
0·21
0·28
0·41
0·46
0·60
0·70
P
TM
0·98
0·96
0·93
0·85
0·79
0·58
0·38
P
MT
Conversion
(wt%)
0·13
0·25
0·36
0·57
0·67
0·84
0·92
4·0
3·0
3·6
3·8
3·6
3·2
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 Table
1. The conditional probabilities Pij (i, j \ T, M), deÐned
as the probability for the addition of monomer units j
to free radical i ends,15 were calculated statistically from
the best values of the corresponding reactivity ratios.
These values are useful to determine the statistical distribution of M- and T-centred sequences along the
copolymer chains.
The reactivity ratios were determined by using the
FinemanÈRoss (FR) (Fig. 1a)16 and KelenÈTudos (KT)
(Fig. 1b)17 linearization methods as well as by the application of the non-linear least square analysis suggested
by Tidwell and Mortimer (TM),18 and they are collected in Table 2. It is clear from these values that the
radicals ending in T units are much more reactive
towards methyl methacrylate molecules than towards
their own monomer, whereas those radicals ending in
an M unit present a rather similar reactivity to both
monomer molecules.
Non-linear least square analysis allows the desired
parameters to be determined and the precision of the
method to be obtained. Also, the application of the
mathematical treatment suggested by Behnken19 and
Tidwell and Mortimer18 provides the so-called 95%
conÐdence limit, which gives an idea of the experimental
error and of the suitability of the experimental conditions used to calculate the composition. This limit is
TABLE 2. Reactivity ratios of the free radical
copolymerization of T/M system in bulk at 70ÄC
initiated with AIBN
Method
FR
KT
TM
r
T
0·17 À 0·03
0·19 À 0·02
0·18
r
M
0·70 À 0·01
0·76 À 0·03
0·75
l/r
T
5·88
5·38
5·53
l/r
M
1·42
1·32
1·33
r Ãr
T
M
0·12
0·14
0·14
B. V a zquez et al.
184
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 in
Fig. 2. This diagram conÐrms the good approximation
of the values of the reactivity ratios r and r as
T
M
Fig. 2. Ninety-Ðve per cent conÐdence diagram for the
reactivity ratios of T and M, determined by the non-linear
least square method suggested by Tidwell and Mortimer.
Values of reactivity ratios : @, TidwellÈMortimer ; +, KelenÈ
Tudos, =, FinemanÈRoss.
indicated by the reduced dimensions of the ellipse, and
thus the values of the reactivity ratios obtained by the
non-linear least square analysis are the most appropriate values to be used.
Figure 3 shows the average composition diagram of
this system. The points correspond to the experimental
data obtained from the analysis of the copolymer
samples prepared at low conversion, whereas the line
corresponds to the theoretical diagram according to the
MayoÈLewis equation20 with reactivity ratios values of
r \ 0É18 and r \ 0É75. The results obtained indicate
T
M
that the copolymerization system has a clear azeotropic
behaviour in free radical polymerization, with an azeotropic point for a molar fraction of T in the feed,
F(T) \ 0É25. This means that for this value the composition of the reaction medium is constant during the polymerization reaction. Moreover, the average composition
of the copolymer system is the same as that of the feed
at the azeotropic point.
Figure 4 shows the statistical diagrams of M- and Tcentred sequences in terms of triads determined from
the reactivity ratios by the TM method as a function of
the methyl methacrylate molar fraction. The molar
fraction of alternating MTM triads and MMM homoPOLYMER INTERNATIONAL VOL. 43, NO. 2, 1997
Non-ionizable hydrogels
Fig. 3. Composition diagram for T/M copolymerization
system.
triads increased as the content of the hydrophobic
monomer increased in the copolymer. However, the
molar fraction of heterotriads having two T units or
two M units reached a wide maximum for a molar fraction of M in the copolymer, f (M) \ 0É40 and 0É60,
respectively. The alternating TMT triads and the TTT
homotriads decreased with increase of the hydrophobic
monomer. So, it can be said that as the M monomer
content increases in the hydrogel, the copolymers are
nearly formed by MTM and MMM triads, these
185
type of sequences being very important in the swelling
behaviour of the hydrogels.
Dynamic swelling behaviour of the copolymers was
studied by measuring the water sorption of thin Ðlms
immersed in bu†ered solutions in acidic, neutral and
alkaline media at room temperature. Figure 5 shows the
relationship between the hydration equilibrium degree
and the copolymer composition at di†erent pH values,
together with that obtained for poly(ethoxytriethyleneglycol monomethacrylate). It can be observed that for
any pH the copolymer composition inÑuenced the
swelling behaviour when the T/M molar fraction of
copolymers ranged between 10/90 and 30/70, and from
this composition on, the swelling degree increased at a
more gradual rate. That is to say, in a wide range of
methyl methacrylate content in the copolymer, the presence of a hydrophobic monomer has little e†ect on the
swelling behaviour, revealing that the copolymer composition sequences will play an important role on the
ability of the copolymers to swell. Figure 6 shows more
clearly the inÑuence of increasing hydrophobicity in the
Fig. 5. Variation of the equilibrium hydration degree with the
composition of the copolymer systems at di†erent pH values :
=, 4 ; …, 6 ; >, 7 ; @, 9 ; +, 10.
Fig. 4. Content of (a) M-centred and (b) T-centred triads as a
function of the methyl methacrylate molar fraction in the
copolymer, f (M) for the copolymerization of methyl methacrylate with ethoxytriethyleneglycol monomethacrylate.
POLYMER INTERNATIONAL VOL. 43, NO. 2, 1997
Fig. 6. Di†erences between the equilibrium hydration degrees
of the homopolymer and the corresponding copolymer as a
function of the pH of the medium. f (T) value : =, 0É09 ;
…, 0É21 ; >, 0É28 ; @, 0É41 ; +, 0É46 ; ], 0É6.
B. V a zquez et al.
186
hydrogel. This Ðgure shows the di†erences observed
between the hydration degree of the hydrophilic hydrogel and the corresponding modiÐed hydrogel for di†erent pH values. It is clearly observed that the copolymers
with a molar fraction of methyl methacrylate between
0É70 and 0É90 gave the greatest variations of the hydration degree for the whole range of pH values, decreasing
the swelling with respect to that of the homopolymer.
However, copolymeric hydrogels with smaller content
of methyl methacrylate did not appreciably change the
swelling behaviour of the poly(ethoxytriethyleneglycol
monomethacrylate) at basic pH, although the hydration
degree decreased slightly at intermediate pH. This fact
indicates that not only the copolymer composition, but
also the monomer sequence distribution along the
copolymer chains inÑuences the swelling behaviour.
Looking at the monomer sequence distribution, which
is plotted in Fig. 4 in terms of triads, it is clear that the
copolymers very rich in methyl methacrylate, i.e.
f (M) \ 0É7È0É9, are mainly formed by MMM and
MTM triad sequences. For intermediate compositions,
i.e. f (T) \ 0É6È0É5, the MMM sequences decrease drastically, whereas those of MTM still remain high. This
indicates that the copolymer must be very rich in
MMM sequences in order to change the swelling
behaviour appreciably. Owing to the reactivity parameters of this pair of monomers, a relatively high MMM
molar triad fraction in the copolymer can only be
obtained for a feed composition very rich in the hydrophobic monomer.
The di†erences of swelling found for any copolymer
composition at di†erent pH values may be due to di†erent conformational arrangements through hydrogen
bond interactions at di†erent pH values.21h23 In the
copolymers very rich in methyl methacrylate, the presence of MMM sequences might favour a coil conformation through hydrophobic interactions at acidic
pH by comparison with that of the pure
poly(ethoxytriethyleneglycol monomethacrylate), since
lower hydration degrees are obtained for these hydrogels. However, in the copolymers with a molar fraction
of methyl methacrylate lower than 0É7, the presence of
alternating sequences may favour the extended conformation of the polymeric chains at basic pH giving rise
to no signiÐcant di†erences in the swelling ratio.
CONCLUSIONS
(1)
The copolymerization reaction of ethoxytriethyleneglycol monomethacrylate and methyl
(2)
(3)
methacrylate gives random copolymers with reactivity ratios of 0É18 and 0É75, respectively.
These copolymer systems provide an e†ective route
for the design and application of polyacrylic hydrogels with swelling extent controlled by average
composition, as well as by the distribution of T
and M sequences along the copolymer chains.
In addition, these systems present an interesting
globular transition in a relatively narrow interval
of pH, just in the range of physiological conditions,
which o†ers enormous possibilities in the Ðeld of
drug delivery systems, or even for the design of biomembranes for dermal applications.
ACKNOWLEDGEMENT
We thank the CICYT (Mat96-0981) for the facilities
granted to have this work performed.
REFERENCES
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POLYMER INTERNATIONAL VOL. 43, NO. 2, 1997
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