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1 s2.0 016836598790037X Main
1 s2.0 016836598790037X Main
1 s2.0 016836598790037X Main
A new kinetic model is developed for free radical monomethacryl-dimethacryl monomer copoly-
merization/crosslinking reactions. The steps of initiation, propagation, crosslinking and termi-
nation have been included in the kinetic description of the model. The kinetics is described in
terms of the concentrations of three species: the monomethacryl, the dimethacryl and the pendent
methacryl entities. The gel point, the average number of effective crosslinks per linear chain and
the number-average molecular weight between crosslinks of the polymer network are calculated
from the moments of the molecular weight distribution of the crosslinked copolymer.
nique has also been used in our laboratory by typical copolymerization reactions) but instead
Robert et al. [ 121 and Barr-Howell [ 131 to the crosslinking ratio, X, defined as the ratio of
produce microparticles of controlled structure the initial concentration of the dimethacryl
and study their swelling behavior in water. Sev- monomer (the crosslinking agent EGDMA) to
eral of these studies have shown that the pen- the initial concentration of the monomethacryl
etrant swelling and solute (drug) release are monomer (HEMA), as one would do for typi-
related to the crosslinked structure and size of cal crosslinking reactions.
these microparticles. Due to the reaction of relatively long polymer
The reaction mechanism of monomethac- chains, beyond the gel point the termination and
ryl-dimethacryl monomer copolymerization/ crosslinking reactions become diffusion con-
crosslinking reactions (CCR) is an addition trolled [ 191. The high viscosity of the reacting
polymerization, the basic reactions of which are system beyond the gel point slows down the dif-
shown in Fig. 1. Clearly due to the copolymeri- fusion of the growing polymer chains.
zation reaction, linear polymer chains are The recent studies of Mueller and his asso-
formed with pendent methacryl groups. These ciates [ 71 for the production of crosslinked
groups further react with other propagating PHEMA microparticles for controlled release
(living) chains to give highly branched and applications has rekindled our interest in
eventually crosslinked polymer chains (net- examining the kinetics of these reactions dur-
work). In reality, these copolymerization and ing suspension polymerization. This is impor-
crosslinking reactions occur simultaneously tant, since a reliable kinetic model is needed to
[ 14-171. predict the effect of various reaction parame-
As the CCR proceeds, the formation of a net- ters on the structure of the final polymer. Of the
work can be observed when at least two cross- various structural parameters, the effective
links (junctions) are formed per chain. The number of crosslinks, v,, and the number-aver-
reaction time when this occurs is known as the age molecular weight between crosslinks, A?&,
gelation time, or more commonly as the gel point are probably the most important ones [ 3,20,21],
[ 181. The gel point is affected by the relative since they control both the mechanism and rate
reactivity ratios of the methacryl groups of the of the water transport during swelling [ 8,22-261
dimethacryl monomer and depends on the and the mechanism and rate of drug release
crosslinking ratio, X. Since in CCR crosslink- during the delivery process [ 2,8,25-271.
ing is observed, it is common not to use the The reaction-engineering aspects of suspen-
comonomer feed ratio, fi, as the defining sion polymerization have been studied in an
parameter of the system (as one would do for earlier publication [ 281. There, we investi-
AH
I 2
hH2 LH
I 2
&I
I 2
OH A OH 0
h.0
CH2 =; CH2 .:
ki,
KINETIC MECHANISM
Mz+A - POAO
The kinetic mechanism includes the follow- ki:,
ing steps: initiation, propagation and crosslink- Pp,q.r
+A- Pp,q-l,r+ 1 + Po,o,l
ing, and termination by combination. In the
development of the kinetic model we make use ki.3
of the following terminology: I is the initiator, Mp,q,r+ A - Mp,q-l,r+ I + Po,o,l
A is the initiated radical, M1 is the monome-
For the propagation and crosslinking steps:
thacryl monomer (HEMA) and M, is the
dimethacryl monomer (EGDMA). We con-
P P.97 + M1 ?+ Pp+l,q,r
sider primary polymer chains, i.e., the polymer
chains which would result if all crosslinks were
kP,
severed [ 291. The definition of a primary pol-
+ Mz -
Pp,q.r Pm+1,r
ymer chain within a polymer network is shown
in Fig. 2. The symbols Pp,p,r and Mp,q,r represent
living and dead polymer chains, respectively. +pxy,t-2pp.q.r+R,-
pp.q.r 1 + 1.*+ 1
Three subscripts are used to describe a primary
chain; they refer to the number of monome-
thacryl units, p, pendent methacryl groups, q, P p.q.r + Mxy,r 2 %q,r+ I+ I%,- I,r+ I
and crosslinks per chain, r, respectively. Thus,
It must be noted that the crosslinking reac-
the following basic reactions can be written:
tion between a growing polymer chain and a
For the initiation step:
pendent methacryl group of a second polymer
kd
chain (living or dead) results in the formation
I-2A
of a crosslink at each chain and in the reduction
of a pendent methacryl group of the second
chain. For the termination step by combination
we may write:
56
p= f f 2 pp,q.r (7)
REACTION KINETICS AND MOLECULAR p=oq=or=o
WEIGHT DISTRIBUTIONS
The reaction rate for total living polymer is
Based on the previous reactions we may now given by eqn. (8).
write the fundamental rate expressions for the
disappearance of various species, assuming no (8)
volume change, and we can subsequently cal-
culate the molecular weight distribution of the The rate equation for the first and the zeroth
initially branched, and beyond the gel point moment of the molecular weight distribution of
crosslinked HEMA-EGDMA copolymer. total polymer can be written as:
The reaction rate of the initiator, I, may be
written as:
(9)
dz
%= -k,J (1)
dy/
The rate of reaction of initiated radicals, A, is y=kplPM, (10)
given by:
dA
(2) dv
x=2fkdI- (ki,M, +2ki,Mz + k,Ms)A a=2k,,,,PM2 -k,,PM3 (11)
dt
where f is the initiator efficiency and MS is the and
concentration of pendent methacryl groups,
defined as: dvoo,
--==2h,,PM, (12)
dt
(3)
where P is given by eqn. (13)) invoking the
steady state approximation for total living
Invoking the steady state approximation for the
polymer:
initiated radicals we obtain
(kilM,+2ki,Mz+ki,M3)A=2fkdI (4) pJ~11’2
Ml
-= -k,,PMI
are used to evaluate important averages such
(5)
dt as: the number-average molecular weight (lin-
ear polymer), a,.,, and the average molecular
dM‘i! weight between crosslinks, i@C (see Fig. 2).
-=--2&,PM, (6)
dt Recalling the definition of li;i, as the ratio of the
57
first to the zeroth moment of the distribution At high conversions vitrification may occur,
of molecular weights, we may write since the remaining monomer becomes a plas-
ticizer for the produced polymer, thus lowering
Wl w1,o.o + P2 ( cyO,l,O + mvo,o,1>
iii,= (15) the glass transition temperature of the swollen
‘yo,o,o system to the reaction temperature. Theoreti-
Here w1 and wa are the molecular weights of cally, the vitrification can occur before or after
HEMA and EGDMA, respectively. the gelation point. At the glass transition, the
The number average molecular weight monomer diffusion coefficient falls approxi-
between crosslinks, MC, can be calculated as: mately four orders of magnitude, which results
essentially in the cessation of the polymeriza-
(16) tion reaction [ 29,311. The important feature of
the HEMA-EGDMA system is that for poly-
where the average number of effective cross- merization reactions in the temperature range
links per chain, v,, (i.e., the crosslinks resulting from 60 to 90” C total conversion can be
from intermolecular crosslinking reactions) is achieved, because of the low glass transition
expressed as: temperature of PHEMA ( 55’ C ) [ 321.
In the case where some of the water of the
Iy0,O.l suspending phase enters the droplets of HEMA
v, = (17)
(vo.o,o during the reaction, one should expect a further
drop of the value of the glass transition tem-
As discussed before, the formation of an infi-
perature due to the additional plasticizing effect
nite network of PHEMA occurs at the gel point,
of the water on the PHEMA microparticles.
which corresponds to the reaction time when
This phenomenon is further discussed by
the average number of effective crosslinks per
KopeEek et al. [ 141.
linear chain of PHEMA is equal to two:
In suspension polymerization the model may
v, =2 (13) be solved to determine the conversion as a func-
tion of time by using the appropriate initial
Beyond the gel point the polymerization rate
conditions. For example, the conversion for
constants of the diffusion-controlled steps
component 1 (HEMA) is written as
change. This change can be described using a
mobility factor, flu,defined as:
p,=+ (22)
polymerization rate of crosslinked chains 1,o
polymerization rate of primary chains where the subscript 0 indicates initial
conditions.
(19)
The mobility factor depends on the average
number of crosslinks per chain, v,, as shown by
Mikos et al. [ 291: RESULTS AND DISCUSSION
TABLE 1
f = 0.6 (AIBN) 18
kd = 2.67x10i5exp( -31.1 kcalmoll’/RT) s’ 33
kPI = 7.35 X 10’ exp ( -4.8 kcal mol-‘/RT) ml mall’ s-’ 33
rl = k,, @k,,a,=0.916 34
k, = 1.8x 10” exp( - 1.3 kcal mol-‘/RT) ml mall’ s-i 33
12
I-
9
a- 6 I
1 ,
A I
I 1 I J
L1
0 I
,.?I
3 4
‘\
1 \
\ \
- wlooo
75000 - - 15000
--_
Fig. 7. Variation of the number-average molecular weight Fig. 8. Variation of the number-average molecular weight
of a chain, fin (curves 1, 2, 3)) and the number-average of a chain, & (curves 1, 2, 3), and the number-average
molecular weight between crosslinks, @= (curves 1 I, 2’, 3’) molecular weight between crosslinks, I& (curves 1’ ,2 ’ ,3’ ) ,
in a crosslinked PHEMA system produced by reaction of in a crosslinked PHEMA system produced by reaction of
HEMA and EGDMA at 70°C using 0.005 mol AIBN/mol HEMA and EGDMA using 0.01 mol EGDMA/mol HEMA
solution. Three different crosslinking ratios were used: and 0.005 mol AIBN/mol solution. Three different reaction
X=0.005 (curves 1 and l’), X=0.010 (curves 2 and 2’) temperatures were used: T= 70°C (curves 1 and 1’))
and X=0.020 (curves 3 and 3’). T=80”C (curves 2 and 2’) and T=90"C (curves 3 and
3’).
tion temperature ( 70 ’ C ) significant crosslink-
ing may be achieved with the addition of only must be recalled that low values of ii& signify a
0.5 mol % EGDMA (X=0.005) to the mon- densely crosslinked network.
omer HEMA. The effect of reaction temperature on the
In controlled release applications the cross- values of A?&,and & is shown in Fig. 8. In gen-
linked structure of the final microparticles eral, as the reaction temperature is increased
obtained is of utmost importance, since it is this the crosslinked network becomes denser. After
network structure that controls the release rate 4 hours of reaction, networks with l& varying
of any previously incorporated drug. Figure 7 from 9,100 to 16,000 are obtained.
shows the change of the number-average Finally, the effect of the polymerization tem-
molecular weight of a polymer chain, n;r,, and perature on the HEMA conversion is shown in
the number-average molecular weight between Fig. 9 for three different temperatures: 70, 80
two consecutive crosslinks, fi=, in the cross- and 90°C. It is observed that the higher the
linked PHEMA structure as a function of reac- temperature, the higher the monomer conver-
tion time for a HEMA-EGDMA reaction sion. Monomer conversions larger than 99% are
carried out at 70” C using 0.01 mol AIBN per observed after 4 hours of polymerization at 80
mol of solution and for three different cross- and 90°C.
linking ratios: 0.005,O.OlO and 0.020. It is seen
that as the reaction time increases the number
average molecular weight between crosslinks CONCLUSIONS
passes through a maximum (rearrangement of
the branched chains to form a network with The reaction of HEMA with EGDMA is very
minimum crosslinking density) and then it important in controlled release applications
decreases approaching an asymptotic value. It because it produces microparticles of PHEMA
61
1 .oo
as related to the development of new materials, in: J.
Hartstein (Ed.), Extended Wear Contact Lenses for
Aphakia and Myopia, C.V. Mosby Co., St. Louis, 1982,
0.75 pp. 6-43.
2 N.A, Peppas and R. Gurny, Relation entre la structure
des polymeres et la lib&ration control& de principes
a: 0.50
actifs, Pharm. Acta Helv., 58 (1983 ) 2-8.
3 N.A. Peppas, H.J. Moyni~n and L.M. Lucht, The
structure of highly crosslinked PHEMA hydrogels, J.
Biomed. Mater. Res., 19 (1985) 397-411.
0.25 4 D.E. Gregonis, C.M. Chen and J.D. Andrade, The
chemistry of some selected methacrylate hydrogels, in:
J.D. Andrade (Ed.), Hydrogels for Medical and
0.00
Related Applications, ACS Symposium Series, Vol. 31,
American Chemical Society, Washington, DC, 1976,
t. h pp. 88-104.
5 S. Wisniewski and S.W. Kim, pe~eation of water-
soluble drugs through PHEMA and PHEMA cross-
Fig. 9. Effect of the temperature on the HEMA conversion,
linked with EGDMA, J. Membrane Sci., 6 (1980)
p,, for the HEMA-EGDMA copolymerization/craeslink-
299-311.
ing reaction using 0.01 mol EGDMA/mol HEMA and 0.005
6 W.R. Good and K.F. Mueller, A new family of mono-
mol AIBp/mol solution, Three different reaction temper-
lithic hydrogels for controlled release applications, in:
atures were used: T==?O”C (curve l), T=8O”C (curve 2)
R.W. Baker (Ed.), Controlled Release of Bioactive
and T=90”C (curve 3).
Materials, Academic Press, New York, NY, 1980, pp.
155-175.
which can be loaded with drugs and serve as 7 K.F. Mueller, S. Heiber and W. Flank& Process for
swelling-controlled release systems, By appro- preparing hydrogels as spherical beads of large size,
priate control of the reaction conditions it is U.S. Patent 4,224,472, 1978.
8 P.I. Lee, Dimensional changes during drug release from
possible to produce microparticles of specific
a glassy hydrogel matrix, Polym. Commun., 24 (1983)
structural characteristics. 45-48.
A kinetic model has been developed which can 9 P.I. Lee, Effect of non-uniform initial drug concentra-
be used to predict the number-average molec- tion distribution on the kinetics of drug release from
ular weight between crosslinks, li;lc, the gel point glassy hydrogel matrices, Polymer, 25 (1984) 973-978.
10 P.I. Lee, Novel approach to zero-order drug delivery
and the progress of the reaction as functions of
via immobilized nonuniform drug distribution in glassy
the reaction temperature and time, the cross- hydrogels, J. Pharm Sci., 73 (1984) 1344-1347.
linking ratio and the concentration of initiator. 11 K.F. Mueller and S.J. Heiber, Gradient-IPN-modified
hydrogel beads: Their synthesis by diffu-
sion-~lyconden~tion and function as controlled drug
delivery agents, J. Appl. Polym. Sci., 27 (1982)
ACKNOWLEDGMENTS
4043-4064.
12 C.C.R. Robert, P.A. Buri and N.A. Peppas, Effect of
This work was presented in a preliminary degree of crosslinking on water transport in polymer
form at the 12th International Symposium of microparticles, J. Appl. Polym., Sci., 30 (1985)
Controlled Release of Bioactive Materials, 301-306.
13 B.D. Barr-Howell, Characteristics of diffusion of highly
Geneva, Switzerland, July 10, 1985.
crosslinked macromolecular networks, MS. Thesis,
School of Chemical Engineering, Purdue University,
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