ARTICLE

pubs.acs.org/IECR

Drug Delivery Using Stimuli-Responsive Polymer Gel Spheres

Pravin R. Ninawe and Satish J. Parulekar*
Department of Chemical and Biological Engineering, Illinois Institute of Technology, Chicago, Illinois 60616, United States
ABSTRACT: Polymeric gels that undergo deformation upon appropriate changes in pH or temperature have considerable promise
as drug delivery vehicles. Uptake of drug macromolecules into swelling and nonswelling gel spheres and release of drug
macromolecules from deswelling and nondeforming gel spheres into a target uid are investigated here. A mathematical model
for gel
solution composite, a composite of a distributed parameter system (gel spheres) and a lumped parameter system
(surrounding solution), is developed. The polymer network displacement in swelling/deswelling gels is described by a stress
diusion coupling model. The analytical solution for network displacement is used to predict solvent intake by swelling gels, solvent
eux from deswelling gels, and changes in pressure, porosity, and eective drug diusivity resulting from network displacement.
These in turn inuence drug uptake during and after gel swelling and drug release from gel during and after gel deswelling.
Numerical results illustrate benets of gel swelling for drug loading and merits of dierent modes of drug release. Comparisons are
made, as concerns drug uptake and drug release, with gels not subject to deformation.

1. INTRODUCTION
Biodegradable and nonbiodegradable polymers have been used
for the past few decades for encapsulating drugs and their subsequent delivery,1,2 with the encapsulation protecting drug macromolecules from biological degradation prior to their release.3,4
Polymeric gels are solid
liquid systems in which a polymeric
matrix is physically or chemically cross-linked to form a threedimensional network, which is swollen by uptake of liquids but is
not dissolved in these.5 The degree of swelling depends on the
nature of polymer and its cross-link density.6,7 Hydrogels are a
cross-linked network of hydrophilic polymers, which can swell by
absorbing water and shrink (deswell) upon release of water when
in contact with aqueous solutions, such as biological uids.8,9
Hydrogels have broad applications in drug delivery, tissue engineering, medical devices, and regenerative medicine due to their tunable
chemical and three-dimensional physical structure, high water
content, good mechanical properties, biocompatibility, ability to
respond to external stimuli under various physiological conditions, and easy control of drug transport.7,9
13 The ability of
drug molecules of dierent sizes to diuse into (drug loading)
and out of (drug release) hydrogels allows the use of these as
drug delivery systems for various routes of administration. 2,8
Polymers from natural, synthetic, or semisynthetic sources,
containing hydroxyl, amine, amide, ether, carboxylate, and
sulfonate as functional groups in their side chains, are used for
synthesizing hydrogels for delivery of both hydrophilic and
hydrophobic drug macromolecules.7,8,10,13
19 Cylindrical and
spherical hydrogels are commonly used for various routes of
drug administration.2,8
Physical entrapment is the simplest method for incorporating
drug macromolecules into hydrogels,15,20,21 synthesis of which
should be tailored considering physical properties of the drug,
loading level, and desired release kinetics.2,22 There are two
general methods of physical entrapment used for loading hydrogels with drug macromolecules.20,21 The rst involves placing a
preformed hydrogel in a suitable drug solution until it swells to
equilibrium. In the second approach, the hydrogel monomer(s)
r 2011 American Chemical Society

are mixed with drug, an initiator, with or without a cross-linker,

and allowed to polymerize, thus trapping the drug within the
matrix.20,21,23
Hydrogels can exhibit dramatic reversible and repeatable changes
in their swelling behavior, network structure, permeability, or
mechanical strength in response to dierent stimuli.2,6,8,24 Depending on the polymer, the environmental stimulus can be pH,
temperature, ionic strength, magnetic and electrical elds, or a
combination of these, and the hydrogel can either shrink or swell
upon a change in any of these environmental factors leading to
release or uptake of drug, as appropriate.2,6,11,12,25
30 Stimulisensitive hydrogels possess ionizable functional groups and their
sensitivity depends on the polymer units and the type, composition, and number of functional groups present on the polymer
backbone.11,14,26 A hydrogel is described as smart or intelligent
when a sharp transition in the gel is induced by a small change in
environmental conditions.7 Hydrogels that respond to changes
in temperature or pH are most widely used.7,28,30,31 Many polymers
and copolymers of acrylamides, acrylic acid, and their various
derivatives belong to this group.
The most well-known thermal-responsive polymer is poly(Nisopropylacrylamide) (PNIPAAm), which exhibits a lower critical solution temperature (LCST) around 32
C in an aqueous
solution. PNIPAAm hydrogels swell after absorbing water into
the gel network below the LCST and shrink upon expelling water
from the gel network above LCST.6,10,11,20,21,23,32 The phase
behavior and mechanical properties of PNIPAAm hydrogels can
be modied by the addition of more hydrophobic or hydrophilic
monomers for desired drug delivery.15,20,21,23,33
Special Issue: Nigam Issue
Received: January 18, 2011
Accepted: June 2, 2011
Revised:
May 26, 2011
Published: June 02, 2011
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pH-Responsive hydrogels are composed of polymeric backbones with ionic pendant groups. Small changes in pH around a
critical value can result in signicant change in the mesh size of
the polymeric networks. Pendant groups of anionic hydrogels are
un-ionized below and ionized above the pKa of the polymeric
network, leading to swelling of the hydrogel at a pH above the
polymer pKa because of a large osmotic swelling force by the
presence of ions.8,31 The reverse is the case for cationic hydrogels, which swell at lower pH.8 Peroral controlled delivery
requires uniform drug release with an increase in pH gradient
in dierent segments of the gastrointestinal tract.8 Delivery of
therapeutic proteins to the small intestine requires that these
should not be released in the stomach (low pH) but be released
in the small intestine (high pH).2,13,14,31,34,35 Delivery of chemotherapeutics in colon requires their retention in the hydrogels
in intestine (pH 7
8) and their release in colon (pH =
5.5
7).13,36
A majority of smart hydrogels deal with response to a single
stimulus. Gels that respond to two or more stimuli have also been
studied.11,26,27,29,37,38 Injectable environmentally sensitive hydrogels formed by in situ chemical polymerization or by sol
gel
phase transition are receiving considerable attention. These
material systems are owable aqueous solutions before administration, but once injected rapidly gel under physiological
conditions7,9,27,39
42 and become drug delivery deposits in
pharmaceutics or cell-growing depots for tissue regeneration.
In much of the reminder of the manuscript, hydrogel is referred
to as gel and solvent denotes water.
Whereas smart hydrogels hold considerable promise as vehicles for controlled drug release, as evidenced by several experimental studies in the past few years, there has been very limited
eort in mathematical modeling of stimuli-responsive hydrogels.
Most of this eort has been focused on swelling behavior and
swelling kinetics of gels that respond to one or more stimuli.43
50
Multiphasic mathematical models have been developed to describe transient deformation of gels responding to the following
stimuli: (1) temperature,44,47,51
54 (2) electric eld,46,48,55 (3)
pH,55,56 (4) ions,43 and (5) glucose.49 Kinetics of drug release has
been investigated in few studies.57
60 The overall drug release
proles have been described empirically using rst-order release
kinetics,57 drug diusion in hydrogels,45,60 and partitioning of
drug between hydrogel and the surrounding medium,59 without
getting into details of hydrogel deformation during drug release.
There currently are no mathematical models available to describe
the design and functioning of stimuli-responsive hydrogels for
drug loading and drug release. This is not surprising since the
development of such models is a considerable challenge58 as a
swelling or deswelling hydrogel involves a moving boundary
due to displacement of polymer network of the hydrogel,
which in turn inuences pore network, porosity, and transport
of drug and solvent in the hydrogel. With this in mind, a
composite mathematical model for drug loading into gel
spheres from a well-mixed drug solution and subsequent
release of the drug from gel into a well-mixed medium
(target uid) is developed and presented next.
The composite mathematical model accounts for (i) polymer
network displacement in gels undergoing swelling (drug loading)
and deswelling (drug release), (ii) solvent intake by gels
(swelling gels), solvent eux from gels (deswelling gels), and
changes in pressure, porosity, and eective drug diusivity resulting
from network displacement, and (iii) drug uptake during and after
gel swelling and subsequent drug release from gel during and

ARTICLE

Figure 1. Schematics of drug uptake and drug release operations.

(a) Gel spheres in contact with (surrounded by) a well-mixed solution
drug solution in the case of loading of gel with drug and target uid for
drug delivery from gel. (b) Transport of solvent and drug from drug
solution into a gel sphere subject to swelling. (c) Transport of solvent
and drug from a gel sphere subject to deswelling into target uid.
(d) Transport of solvent from target uid into a gel sphere subject to
swelling accompanied by drug release from gel into target uid. Dashed
circles denote gel spheres deformed upon swelling or deswelling, as
appropriate. Not shown here are nondeforming gel spheres wherein
drug transport (drug uptake or drug release) in porous space of gel
occurs by diusion.

after gel deswelling. The results of model simulations pertaining

to spatiotemporal proles of network displacement, hydrogel
porosity, eective drug diusivity, and drug concentration in
the hydrogel, as well as temporal proles of drug concentration
in and volume of bulk, well-mixed solution in contact with
hydrogel, total rate of drug transport, and amount of drug
transferred are presented and discussed in Section 3, rst for
drug uptake by hydrogel particles and next for drug release
from these.

2. PROBLEM FORMULATION
Subjecting pH-responsive or thermally responsive gels to
appropriate changes in pH or temperature can lead to stretching
or contracting of polymer chains in these, leading thereby to
swelling or deswelling of gels. This can aid in drug loading
(swelling gels) and subsequent drug release (deswelling gels).
When a virgin (devoid of drug) gel in contact with a drug solution
is subjected to appropriate pH or temperature change that
causes gel swelling, there is solvent inux into the gel and an
accompanying transport of drug macromolecules in the same
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direction (Figure 1b). Transport of drug in the gel is due to
solvent motion and diusion in porous space of the gel. The
former persists as long as the gel is swelling. Swelling terminates
when there is equilibrium between the gel and the surrounding
drug solution as concerns solvent. Transfer of drug in the gel
occurs solely by diusion after swelling terminates. Swelling
increases the capacity of gel as concerns drug macromolecules.
Transport of drug in a gel not undergoing swelling occurs purely
by diusion in porous space of the gel.
Drug release from gels can occur via three dierent modes.
When a drug-laden gel in contact with a bulk solution (target of
drug delivery) is subjected to appropriate pH or temperature
change that causes gel deswelling, there is solvent eux from the
gel into the surrounding bulk solution and an accompanying
transport of drug macromolecules in the same direction
(Figure 1c). Transport of drug in the gel is due to solvent motion
and diusion in porous space of the gel. The former persists as
long as the gel is undergoing deswelling. Deswelling terminates
when there is equilibrium between gel and the surrounding bulk
solution as concerns solvent. Transfer of drug in the gel occurs
solely by diusion after deswelling terminates. Deswelling allows
quicker delivery of drug macromolecules. Transport of drug in a
gel not subject to deswelling (second mode) occurs purely by
diusion in porous space of the gel. The third mode involves
subjecting a drug-laden gel in contact with a bulk solution (target
of drug delivery) to appropriate pH or temperature change that
causes gel swelling. There is solvent inux into the gel from the
bulk solution and transport of drug from the gel into bulk
solution by diusion in porous space of gel. The solvent transport
and transport of drug macromolecules occur in opposite directions (Figure 1d), leading to hindered diusion of drug macromolecules in the gel. Transport of solvent persists as long as the
gel is swelling. Release of drug accelerates after swelling terminates as diusion is unhindered. Gel swelling enables slower
release of drug macromolecules, allowing for drug delivery over
an extended period.
In both drug loading and drug release operations, we consider
spherical gels to be surrounded by a well-mixed solution containing the solvent present in the gel (Figure 1a). A well-mixed drug
solution for loading gel spheres with drug macromolecules is an
ecient and natural setting for uniform and rapid drug
uptake.2,8,20,21 The drug-laden gel particles may be transported
to target uid in an organ or implanted in target tissues for drug
delivery. In the former situation, which is of interest to this study,
the target uid may be well-mixed owing to uid ow. In the
latter case, drug transport in gel implants and the surrounding
tissue occurs by diusion. In compartmental models reported in
biomedical engineering and pharmacokinetics literature, however, it is a common practice to consider the surrounding tissue
to be equivalent to a well-mixed region.61,62 Gel spheres suspended in a well-mixed solution is a popular setting for laboratory
drug delivery studies.2,8,20,21
2.1. Network Displacement During Gel Swelling and
Deswelling. We consider a small deformation of a spherical
gel and employ the linear constitutive equation for the stress
tensor of the polymer network. Denoting the displacement of a
point in the gel network in the reference state as u(r, , , t), with
3
2
u1 r, , , t
7
6
7
ur, , , t 6
4 u2 r, , , t 5
u3 r, , , t

ARTICLE

the elements of the stress tensor are63,64

!
!
3
3
uk
ui uj 2
uk
ij K

3Re ij + G
+

ij
,
xj xi 3 k 1 xk
k 1 xk
(
1 if i j
ij
i, j 1
3
0 if i 6 j

with x1 = r, x2 = , x3 = , u1 = ur, u2 = u, and u3 = u, K being the

osmotic bulk modulus of the gel, G being the shear modulus of
the gel, and Re representing the equilibrium swelling ratio of the
gel for particular initial and final solvent conditions. If the solvent
condition, such as pH or temperature, has not been changed, Re
can be considered to be zero. A change in the solvent condition,
such as change in pH or temperature, will lead to change in
equilibrium volume and in this case, Re will be nonzero. In the
polymer network, the stress is transmitted by the displacement of
polymer network and solvent pressure p, the net stress, net
ij ,
being
ijnet ij
pij ,

i, j 1
3:

The stress diusion coupling model63,64 accounts for force

balance on the gel and solvent diusion in the gel. The force
balance can be stated concisely as


G
1
3 u + G2 u p
K+
3
The permeation of solvent through the polymer network is
dictated by the gradient in pressure p and leads to the following
diusion equation:
3

u
k2 p
t

In the above, k is the Darcys constant. Temporal variations in

displacements of the gel network and pressure in the gel are thus
described by eqs 1 and 2.
For the solvent to permeate freely across the external surface
D of the gel, the pressure must be continuous on the external
surface of the gel, i.e.,
p p0 on
The force balance on the external surface of gel is

pI 3 n f
with I being the unit tensor (idem matrix) and n being the unit
vector normal to the external surface.
We consider a gel sphere of initial radius a. Both u(r, , , t)
and u(r, , , t) are zero. Further, ur(r, , , t) is independent of
and and is denoted henceforth as u(r, t). For this deformation, the o-diagonal components of the stress tensor , ij, i 6 j,
are deduced to be zero. As a result, from the and components
of eq 1, we deduce that p is independent of and . The force
balance in eq 1 then reduces to


 
p
4G 1 2
K+
r u , 0 < r < a
3
r
3 r r 2 r
and the solvent diusion equation, eq 2, reduces to




2 p
2 u
r
r
k

, 0 < r < a, t > 0

r
r
r
t
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The reference pressure of the solvent external to the gel, p0, is

considered to be zero. Because the solvent can permeate freely
across the gel surface at r = a, there is no force acting on the
external surface of the gel sphere at r = a. The boundary
conditions at the external surface therefore reduce to

with

p 0 and rr 0 at r a





4G u
2G u
+2 K


3KRe
rr K +
3 r
3 r

The prole of pressure in the gel can be obtained by integrating

eq 3 from r to a and employing the boundary condition for p in
eq 5 as

 #

"
4G 1 2
1 2
r u
2 r u
pr, t K +
7
3
r 2 r
r r
ra
Integration of eq 4 with respect to r and substitution of eq 3 into
the resulting relation leads to


 
u
4G 1 2
k K+
r
u
, 0 < r < a, t > 0 8
t
3 r r 2 r
One of the boundary conditions for eq 8 is that at the center of
the gel sphere, r = 0, there is no displacement, the other boundary
condition being provided in eq 5, with rr being dened in eq 6.
The boundary conditions for eq 8 therefore are
r 0 : u 0, r a




4G u
2G u
+2 K


3KRe 0
: K+
3 r
3 r

The initial condition for eq 8 typically is

ur, 0 0,

0<r<a

10

The boundary value
initial value problem for deformation of

the polymer network is as a result described by eqs 8
10. As the
problem involves linear mathematical operators, its closed-form
solution can be obtained using properties of linear operators. The
details of this and the nal form of the solution are relegated to
the Appendix. The analytical solution is particularly useful for
obtaining insight into spatial and temporal proles of network
displacement, pressure, porosity, and eective diusivity of drug
in gel spheres subject to swelling or deswelling. Further, the
solution is obviously computationally more ecient than its
iterative numerical counterpart.
2.2. Porosity Distribution in Gel. Let denote the gel
porosity or the volume fraction of fluid in the gel. The conservation of solid phase (polymer) requires that65



u
fFs 1
Eg + 3 Fs 1
E
0
t
t
with Fs being the solid density. Because Fs is constant, is
independent of and , and u(r, , , t) and u(r, , , t) are
zero, the conservation equation above reduces to


p
1 2 u
r p
2
11
, p 1
E
r r
t
t

The initial conditions for eq 11 are

r 0:

p
0,
r

t 0 : p r, t pi r

12

2.3. Transport of Drug. The transport of drug macromolecules in hydrogels occurs through diffusion in the pores of the
polymer matrix.2 As the drug release continues, the rate normally
decreases, since the drug molecules have a progressively longer
distance to diffuse and a lower concentration gradient.2,11 The
desired period for drug release varies from application to
application. A fast drug release (for 12
24 h) is required, while
maintaining the biological activity of drug, for antibiotics and
pain-relief medications administered after surgery or organ
transplantation and for once- or twice-a-day oral formulations
administered to patients suffering from diseases such as malaria
and typhoid.34 A pulsed or triggered release is required for certain
drugs and is achieved in response to appropriate external
stimuli.28 Most of the pH-sensitive drug-delivery systems release
the entrapped drugs into intestine and colon for considerably
longer duration, from few days to weeks or even months.34
The pores in a hydrogel are a series of tortuous, interconnecting paths of pore bodies and pore throats with varying crosssectional areas and lengths. It is not convenient or computationally ecient to describe diusion of drug macromolecules in each
and every one of the tortuous pathways. As is done with
diusion-reaction processes in porous solid phase catalysts, we
represent the drug transport in a spherical porous hydrogel
particle by drug transport by diusion in a spherical particle of
identical size that is totally porous (p = 0) and using the eective
diusivity De in place of molecular diusivity. The eective
diusivity accounts for varying cross-sectional areas and lengths
of pores, tortuous paths, and nonavailability of entire area normal
to the direction of diusion (radial direction in the case of gel
spheres) due to presence of polymer. Let C denote the drug
concentration in the gel and De represent the eective diusivity
of the drug in the gel. The eective diusivity is related to the
volume fraction of polymer in the gel, p, as66
!2
1
p
De D 0
13
1 + p

with D0 being the drug diusivity in solvent. The conservation

equation for the drug is
C
+ v s 3 C 3 De C
t
with the solvent velocity vector, vs, being obtained as65
vs

k
p
s p

In the above, k is the hydraulic permeability of the polymer

network. For nondeformable media such as porous solid phase
catalysts, where pore network is time-invariant, the eective
diusivity is considered to be unform in the entire medium.
For deformable media, such as gel spheres undergoing swelling
or deswelling, there are changes in the pore network with time
and the gel porosity varies with radial location and time. At a
particular time, the eective diusivity of drug in a deforming gel
particle as a result will not be uniform. The spatial and temporal
variation in De is described by eq 13.
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The analytical solution to the network displacement problem

presented in the Appendix enables explicit computation of spatial
and temporal proles of network displacement and pressure,
followed by noniterative computation of porosity and eective
diusivity of drug in gel spheres subject to swelling or deswelling.
The spatial basis for these variables is the initial radius of gel
spheres, a. The spatial and temporal variations in drug content in
the gel are dictated by transport of drug in the gel due to diusion
and solvent motion, which in turn are inuenced by proles of
network displacement, pressure, porosity, and eective drug
diusivity. For this reason, the convenient spatial basis for drug
concentration in gel is the initial radius of gel particle. The drug
transport problem for gel
solution composite, described later
by eqs 14
16 and 18, reects this basis. For the spherical
geometry under consideration, since C and p are independent
of and , the drug conservation equation reduces to


C
1 2 C
C
2
r De

vsr , 0 < r < a, t > 0 14
t
r r
r
r
with sr being
vsr

k p
s p r

15

re = keCb. The conservation equation for the drug can be

rearranged as
dCb
Cb dVb N dmg





re ,
Vb dt
dt
Vb dt
Z a
mg t 4 r 2 Cr, tdr, Cb 0 Cbi

When there is no drug elimination in the solution surrounding

the gel spheres (re = 0), which is the case during loading of the
drug into the gel, conservation of the drug in the system requires
that
Z a
Z a
2
Cb Vb + 4N r Cr, tdr Cbi Vbi + 4N r 2 Ci rdr
0

C
0; r a : C Cb ;
r 0:
r
Cr, 0 Ci r, 0 < r < a

16

Let there be N hydrogel spheres of initial radius a in contact with

a drug solution of volume Vb and drug concentration Cb, with the
initial values of these being Vbi and Cbi, respectively. Further, let
the solvent density be constant. The basis for drug concentration
in solution exterior to gel particles is solution volume. Conservation of solvent in the system requires that

19
When there is drug elimination in the solution surrounding the
gel spheres (re > 0), which is the case during drug release from the
gel spheres, depletion of drug due to elimination implies that

 

Z a
Z a
Cb Vb + 4N r 2 Cr, tdr < Cbi Vbi + 4N r 2 Ci rdr
0

4N 3
a f1 + Rtg3
1 Vbi ,
3
ua, t
Rt
a

The boundary value
initial value problem that describes the

distribution of drug in the hydrogel, eqs 14
16, with the
expressions for p(r, t) and u(r, t) being provided in eqs 7, A9
and A10, must be solved in conjunction with the constraints in
eqs 17 and 18 (gel deswelling) or in eq 17 and eq 18 (re = 0) or
eq 19 (gel swelling) for conservation of solvent and drug.
In the case of drug uptake during and after gel swelling, the
drug concentration will be uniform in the gel at large times and
will be in equilibrium with that in the bulk solution outside the
gel. Let this concentration be denoted as Cbe. It follows then from
eq 19 that

Vb t +

Cbe
17

At large times, the relation above reduces to

4N 3
a 1 + Re 3
1,
3

20

Equation 14 is subject to the boundary and initial conditions

Vbe Vbi

18

Vbe lim Vb t
tf

After sucient time, the porosity in the gel will be uniform. The
equilibrium porosity can be obtained by invoking conservation of
polymer in the gel, which leads to the relation
pi
, pe lim p t
pe
tf
1 + Re 3
As anticipated, pe < pi when Re > 0 (gel swelling), and pe > pi
when Re < 0 (gel deswelling).
When the drug is released from the gel, it may undergo
elimination in the surrounding liquid. The conservation equation
for the drug in the environment outside the gel is
Z a
dmg
d
Cb Vb
re Vb
N
, mg t 4 r 2 Cr, tdr
dt
dt
0
with re being the volume-specic rate of drug elimination and
mg being the amount of drug in each gel sphere. It is customary
to consider drug elimination to follow rst-order kinetics, i.e.,

Cbi Vbi + 4Na3 Ci =3

Vbe + 4Na3 =3

21

for uniform initial drug concentration in the gel, Ci. The

fractional uptake of drug during drug loading in a gel can be
expressed as


mg
Cb V b
1

f
22
Cbi Vbi
Cbi Vbi
The upper limit on f for drug loading is (1
CbeVbe/CbiVbi). The
fractional release of drug from gel spheres loaded with drug
during deswelling and postdeswelling periods is expressed as
0
1
Z a
2


r Crdr
mg 0
mg t
B
C
C
Z 0a
B
1


f
23
@
A
mg 0
r 2 Ci rdr
0

Total depletion of drug in the gel and the surrounding solution is

assured at large times when drug release from a gel is followed by
drug elimination.
2.4. Model Solution. The solution of the composite model for
drug loading into gel particles and subsequent drug release from
these proceeds as follows. The network displacement profiles are
computed numerically employing expressions in eqs A9 and A10.
Profiles of pressure, p(r, t), are computed next as per eq 7.
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ARTICLE

Table 1. Values of Parameters in the Composite Mathematical Model

general

D0 = 2.895  10
7 cm2/s, k = 3.68  10
11 cm2/{N.s}, N = 1, k = 3.022  10
19 m2, s = 10
3 N.s/m2

swelling

K = 13 500 N/m2, G = 9000 N/m2, K/G = 1.5, Ti = 36
C, Tb = 30
C, a = 0.48 cm, Re = 0.2912, (1
pi) = 0.91

deswelling

K = 150 000 N/m2, G = 20 000 N/m2, K/G = 7.5, Ti = 30
C, Tb = 36
C, a = 0.62 cm, Re =
0.2255, (1
pi) = 0.958

drug loading

Ci = 0, Cbi = 1.264 mg/cm3, Vbi = 2 cm3

drug release

Ci = 1 mg/cm3, Cbi = 0, Vbi = 5 cm3, ke = 10
6 s
1

Variation in volume of surrounding solution, Vb, is computed as

per eq 17. Knowledge of polymer network displacement permits
computation of spatiotemporal variations in gel porosity,
(1
p), by solving eqs 11 and 12. This permits computation
of profiles of effective diffusivity of drug as per eq 13. The drug
transport problem for gel
solution composite, an initial value
boundary value problem described by eqs 14
16 and 18
is solved next to compute profiles of drug concentration in gel,
C(r, t), and surrounding well-mixed bulk solution, Cb(t), and
related parameters, such as profiles of amount and rate of drug
transported.

3. RESULTS AND DISCUSSION

The results to be presented next involve swelling and deswelling of gel spheres induced by subjecting these to appropriate
temperature change. Qualitatively similar results can be obtained
for pH-responsive gels where swelling/deswelling is induced by
appropriate change in pH. In drug loading operation, gel spheres
devoid of drug are immersed in a drug solution (Figure 1a). The
initial temperatures of gel spheres and drug solution are dierent
and are such that gel spheres are subject to swelling leading to
uptake of solvent and drug by gel (Figure 1b). In drug delivery
operation, gel spheres loaded with drug are immersed in a
medium (target uid) devoid of drug (Figure 1a). The initial
temperatures of gel spheres and medium are dierent and are
such that gel spheres are subject to deswelling leading to release
of solvent and drug from gel (Figure 1c). Unless mentioned
otherwise, the values of key parameters listed in Table 1 were
used to obtain the results presented and discussed next. These
parameters are representative of immunoglobulin G (IgG) (drug
macromolecule, molecular mass = 150 kDa) and poly(Nisopropylacrylamide) (PNIPAAm) gel, which has LCST of
32
C.62,67
69 In both drug loading and drug release operations,
the dierence in the initial temperatures of gel particles and the
surrounding solution will lead to change, increase or decrease as
appropriate, in the temperature of gel, causing thereby swelling
or deswelling of gel.
3.1. Gel Swelling and Drug Uptake. Gel spheres, initially at
36
C and devoid of drug (Ci = 0), are brought in contact with a
drug solution at a lower temperature (less than 30
C), with the
equilibrium temperature being 30
C, with Cbi = 1.264 mg/cm3
(Table 1). The reduction in gel temperature upon this contact
leads to swelling of the spherical gel. Spatial profiles of network
displacement at different t are displayed in Figure 2a. Earlier in
the transient operation, the rate of swelling, as indicated by the
rate of network displacement, increases as one moves away from
the center of the gel particle (Figure 2a). The solvent is therefore
able to penetrate the polymer network in the gel better as one
moves away from the gel center to the gel exterior. The network
displacement is sluggish in the gel interior. Profiles of gel
porosity, (1
p), depicting spatial variation in the same due
to polymer network displacement are presented in Figure 2b.
The initial porosity of the gel particles (at 36
C) is 0.91. The

Figure 2. Proles of (a) displacement of polymer network, u(r, t),

(b) gel porosity, and (c) eective diusivity of drug in gel, De, during
swelling of gel spheres at 30
C.

positive network displacement leads to penetration of the gel by

the solvent leading to gel swelling and increase in gel porosity. At
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Figure 3. Proles of (a) Cb and (b) Vb/Vbi during and after swelling
of gel spheres at 30
C. Curves 1, 2, and 3 represent conditions in the
bulk solution for (i) gel spheres subject to swelling with Vbi = 2 cm3,
(ii) nonswelling gel spheres with Vbi = 2 cm3, and (iii) gel spheres
subject to swelling with Vbi = 10 cm3, respectively. The dashed
vertical lines indicate termination of gel swelling in the case of curves
1 and 3.

low t, solvent penetration is limited to outer portion of the gel.

The porosity increases gradually in the gel interior as solvent
permeates further. After 82 h, the gel porosity is very close to its
new equilibrium value, 0.958. The effective diffusivity of drug
molecules in the gel, De, increases commensurate with increase in
gel porosity upon solvent penetration into gel (Figure 2c, eq 13).
Because the drug solution in which gel particles are immersed
(bulk solution) has volume, Vb, comparable to initial volume of
gel particles, there is substantial drop in Vb upon solvent uptake
by gel particles (curve 1 in Figure 3b).
Proles of drug concentration in gel spheres, C(r, t), are
presented in Figure 4a and variation in drug concentration in the
bulk solution surrounding gel spheres, Cb, is depicted in Figure 3a
(curve 1). Transport of drug macromolecules from the external
solution into gel spheres follows solvent penetration. Although
drug transport lags solvent transport in the beginning, drug
concentration becomes nearly uniform and close to its equilibrium value, Cbe (eq 21), in 96 h which is little more than that
required for gel porosity to achieve its equilibrium value. The
characteristic time constants for solvent penetration and drug
transport aided by solvent uptake are therefore comparable.
Because the volume of the bulk solution in which the gel particles
are immersed is comparable to initial volume of gel particles, the

Figure 4. Proles of (a) drug concentration in gel, C(r, t), (b) amount
of drug in gel, mg, and (c) fractional uptake of drug, f, during drug loading
in gel spheres at 30
C. Curves 1, 2, and 3 in parts b and c correspond to
(i) gel spheres subject to swelling with Vbi = 2 cm3, (ii) nonswelling gel
spheres with Vbi = 2 cm3, and (iii) gel spheres subject to swelling with
Vbi = 10 cm3, respectively. The dashed vertical lines in parts b and c
indicate termination of gel swelling in the case of curves 1 and 3.

decrease in Cb upon drug uptake by gel particles is signicant

(curve 1 in Figure 3a).
The prole of amount of drug loaded into gel particles, mg(t),
is displayed in Figure 4b (curve 1, Vbi = 2 cm3). For comparison,
proles of amount of drug loaded (i) into gel spheres subject to
swelling when Vbi = 10 cm3 (curve 3) and (ii) in a hypothetical
case where drug uptake in gel occurs purely by diusion in the
absence of gel swelling (curve 2, Vbi = 2 cm3) are also displayed
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in Figure 4b. The corresponding proles of Cb and Vb are provided
by curves 2 and 3 in Figure 3. For case (ii), since drug transport
occurs only by diusion in gel spheres of xed radius, one needs
to solve eqs 14, 16, and 18 with p = p0, vsr = 0, re = 0, and p = pi.
The proles of fractional drug uptake, f (dened in eq 22),
corresponding to proles of mg in Figure 4b, are shown in
Figure 4c. When the volume of the bulk solution in which the
gel particles are immersed and the initial volume of gel particles
are of the same order of magnitude, an increase in the initial
amount of drug in the bulk solution due to an increase in Vbi leads
to increased drug loading, mg. As a result, for gels undergoing
swelling, mg is higher for Vbi = 10 cm3 compared to Vbi = 2 cm3
(Figure 4b). For identical gel spheres, the fractional variation in
volume of bulk solution, (1
Vb/Vbi), is reduced as Vbi is
increased (Figure 3a). When the initial volume of drug solution
in which gel particles are immersed is in large excess vis-a-vis
initial gel volume, i.e., when Vbi . 4Na3/3, one can reason that
Vbe = Vbi and Cbe = Cbi. The drug uptake at large, mg(), is
maximum under these conditions and f f 0 [eq 22]. The lack of
gel swelling in drug uptake by diusion-only operation severely
restricts the amount of drug loaded. A comparison of curves 1
and 2 in Figure 4, parts b and c, reveals a tremendous (5:2)
advantage that swelling gels have over gels not subject to swelling
in terms of drug uptake. The proles of rates of drug uptake in
gels subject to and not subject to swelling are close (corresponding
to curves 1 and 2 in Figure 4, parts b and c, data not shown). One
can deduce from curves 1
3 in Figure 4b that the rate of drug
uptake decreases monotonically with time, the rate being highest
at t = 0 when the gel is devoid of drug macromolecules. Most of
the drug uptake in a gel sphere subject to swelling occurs during
its deformation (curves 1 and 3 in Figure 4, parts b and c).
The impact of the ratio of osmotic bulk modulus of gel and
shear modulus of gel (K/G) on the solvent and drug permeation
in gel spheres was also studied, by keeping G xed and varying K.
For a particular change in temperature or pH, dierent sets of K
and G will lead to dierent values of Re. However, we do not have
any exact expression relating Re to K/G. The results in Figure 5
are for appropriate combinations of K and changes in pH or
temperature such that Re remains the same. Temporal variations
in radius of gel spheres, ad(t) [= a + u(a, t)], are displayed in
Figure 5a for K/G = 0.15, 0.75, 1.5 (base value), 3, and 15. It is
evident that an increase in K/G leads to more rapid displacement
of the polymer network in gel, causing in turn faster uptake of
solvent and faster swelling of the gel. All other parameters, such
as initial gel radius, initial bulk solution conditions (volume and
drug concentration), and pH or temperature of bulk solution,
being unaltered, an increase in K/G as a result leads to faster
uptake of drug, mg (eq 18, Figure 5b). The prole of mg for the
hypothetical case of very large bulk solution volume (Vb f ) is
also shown in Figure 5b, with K/G = 1.5. When Vbi . 4Na3/3,
it follows that Vb(t) = Vbi (eq 17), Cb(t) = Cbi (eq 19), and
Cbe = Cbi (eq 21), and the drug uptake, mg(t), is at its upper limit
(Figure 5b).
3.2. Gel Deswelling and Drug Release. Drug-loaded gel
spheres, initially at 30
C, are brought in contact with a medium
devoid of drug at a higher temperature (greater than 36
C), with
the equilibrium temperature being 36
C. The increase in gel
temperature upon this contact leads to deswelling of gel particles.
Spatial profiles of network displacement at different t are
displayed in Figure 6a. The negative displacement of polymer
network in the gel is indicative of deswelling of gel spheres, i.e.,
shrinkage of these. Earlier in the transient operation, the rate of

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Figure 5. Temporal proles of (a) radius of gel spheres, ad(t) [= a +

u(a, t)], and (b) amount of drug in gel, mg, during drug loading in gel
spheres for xed Re (= 0.2912). Legends 1, 2, 3, 4, and 5 represent proles
for K/G = 0.15, 0.75, 1.5, 3, and 15, respectively, and the dashed curve in
(b) corresponds to very large bulk solution volume (Vb f , K/G = 1.5).

deswelling, as indicated by the rate of network displacement,

increases as one moves away from the center of the gel particle
(Figure 6a). The solvent is able to permeate out of the gel better
as one moves away from the center to the gel exterior. The
network displacement is sluggish in the gel interior. Profiles of gel
porosity, (1
p), depicting spatial variation in the same are
presented in Figure 6b. The initial porosity of the gel particles (at
36
C) is 0.958. The negative network displacement leads to
depletion of solvent in the gel due to its transport from the gel
particle into medium (solution) in contact with gel spheres,
leading to a decrease in gel porosity. At very low t, solvent efflux
from the gel is limited to the portion of the gel near its exterior.
The porosity decreases gradually in the gel interior as solvent is
transported out of gel spheres. At 12 h, the gel porosity is very
close to its new equilibrium value, 0.91 (Figure 6b). The effective
diffusivity of drug molecules, De, in the gel decreases commensurate with decrease in gel porosity upon solvent efflux from gel
(Figure 6c, eq 13). Because the medium in which gel spheres are
immersed (bulk solution) has volume, Vb, comparable to initial
volume of gel spheres, there is substantial increase in Vb upon
solvent efflux from gel spheres into the surrounding medium
(curve 1 in Figure 7b).
Proles of drug concentration in gel spheres, C(r, t), are
presented in Figure 8a and variation in drug concentration in the
medium surrounding gel spheres, Cb, is depicted in Figure 7a.
Transport of drug macromolecules from gel spheres into external
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Figure 7. Proles of (a) Cb and (b) Vb/Vbi during and after deswelling
of gel spheres at 36
C. Curves 1, 2, and 3 represent conditions in the
surrounding medium for (i) gel spheres subject to deswelling with Vbi =
5 cm3, (ii) nondeswelling gel spheres with Vbi = 5 cm3, and (iii) gel
spheres subject to deswelling with Vbi = 50 cm3, respectively.

Figure 6. Proles of (a) displacement of polymer network, u(r, t),

(b) gel porosity, and (c) eective diusivity of drug in gel, De, during
deswelling of gel spheres at 36
C.

medium follows solvent eux from the gel particles. There is a

signicant lag in drug transport vis-a-vis solvent transport.
Therefore, at 12 h, while the proles of network displacement,
gel porosity, and eective diusivity of drug macromolecules are
very close to their new equilibrium values, the drug concentration
prole is highly nonuniform, with drug transport in the inner
core of gel spheres being much less signicant. Up to 12 h,
transport of drug molecules is aided by solvent eux resulting
from deswelling of gel spheres. For t > 12 h, transport of drug
molecules in gel spheres is solely due to pore diusion. The drug
concentration proles remain nonuniform much longer after
termination of deswelling of gel spheres and drug release from gel

spheres continues over extended time period. This is attractive

for sustained delivery of drug macromolecules. The characteristic
time constants for solvent eux and drug transport are therefore
very dierent, the latter being much greater than the former. This
is in contrast to gel swelling operation where the characteristic
time constants for the two counterpart rate processes, solvent
penetration into gel and drug transport into gel, are comparable.
Because the volume of the bulk solution in which the gel
particles are immersed is comparable to initial volume of gel
particles, there is substantial variation in Cb upon drug release
from gel particles and elimination of the released drug in the
medium (curve 1 in Figure 7a). In the beginning, since the
medium is devoid of drug, there is an increase in Cb. The drug
accumulated in the medium is subject to elimination. As release
of drug into medium and its elimination in the medium are
consecutive (series) rate processes, Cb exhibits a maximum at a
critical t, tm, which is characteristic of rate processes in series. For
t < tm, the rate of drug release exceeds the rate of drug elimination
and drug accumulates in the medium, causing an increase in Cb.
For t > tm, the rate of drug elimination exceeds the rate of drug
release and drug depletes in the medium, resulting in a decrease
in Cb. For the elimination constant under consideration, Cb
declines gradually over extended period (Figure 7a).
The prole of amount of drug released from gel particles
into the surrounding medium, mg(t) [= mg(0)
mg(t)], is
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Figure 8. Proles of (a) drug concentration in gel, C(r, t), (b) amount
of drug released from gel, mg, (c) fractional release of drug, f, and
(d) rate of drug release, rrel, during drug delivery from gel spheres at
36
C. Curves 1, 2, and 3 in parts b, c, and d correspond to (i) gel spheres
subject to deswelling with Vbi = 5 cm3, (ii) nondeswelling gel spheres
with Vbi = 5 cm3, and (iii) gel spheres subject to deswelling with Vbi =
50 cm3, respectively. The dashed vertical lines in parts b, c, and d indicate
termination of gel deswelling in the case of curves 1 and 3.

ARTICLE

displayed in Figure 8b (curve 1, Vbi = 5 cm3). For comparison,

proles of amount of drug released (i) from a gel subject to
deswelling when Vbi = 50 cm3 (curve 3) and (ii) in a hypothetical
case where drug release from gel occurs purely by diusion in the
absence of gel deswelling (curve 2, Vbi = 5 cm3) are also displayed
in Figure 8b. For case (ii), since drug transport occurs solely by
diusion in gel spheres of xed radius, one needs to solve eqs 14,
16, and 18 with p = p0, vsr = 0, and p = pi. The proles of
fractional drug release, f (dened in eq 23), corresponding to
proles of mg in Figure 8b, are shown in Figure 8c. There is a
slight increase in the amount of drug released upon a 9-fold
increase in Vbi, from 5 cm3 to 50 cm3. Higher Vbi implies higher
Vb and therefore lower Cb, which leads to increase in the driving
force for drug transport out of gel spheres. For identical gel
particles, the relative variation in volume of bulk solution,
(Vb/Vbi
1), is reduced as Vbi is increased (Figure 7b), as
anticipated. When the initial volume of medium in which gel
particles are immersed, Vbi, is in large excess vis-a-vis initial
gel volume, i.e., when Vbi . 4Na3/3, one can reason that
Vbe = Vbi and Cbe f 0. The lack of gel deswelling in drug release
by diusion-only operation signicantly reduces the amount
of drug released. A comparison of curves 1 and 2 in Figure 8,
parts b and c, reveals a 3:2 advantage that deswelling gels have at
t = 12 h over gels not subject to deswelling in terms of drug
release.
The proles of rates of drug release, rrel, in gels subject to and
not subject to deswelling are shown in Figure 8d. One can deduce
from curves 1
3 in Figure 8b and curves 1 and 2 in Figure 8d that
the rate of drug release decreases monotonically with time, the
rate being highest at t = 0 when the medium is devoid of drug
macromolecules. When compared to gels not subject to deswelling, the rate of drug transport in gels undergoing deswelling is
higher in the beginning due to drug transport aided by solvent
eux. The decline in the rate of drug release is slower in diusiononly drug transport. As a result, there is crossover between
proles 1 and 2 at t = 4.3 h (inset of Figure 8d).
The impact of the ratio of osmotic bulk modulus of gel and
shear modulus of gel (K/G) on solvent eux and drug release
from gel spheres was also studied, by keeping G xed and varying
K. Temporal variations in radius of gel spheres, ad(t) [= a +
u(a, t)], are displayed in Figure 9a for K/G = 0.75, 3.75, 7.5 (base
value), 15 and 75. It is evident that an increase in K/G leads to
more rapid displacement of the polymer network in gel, causing
in turn faster deswelling/shrinking of the gel and faster loss of
solvent from gel spheres. All other parameters, such as initial gel
radius, initial volume and pH, or temperature of the surrounding
medium, being unaltered, an increase in K/G as a result leads to
faster release of drug, as revealed by proles of f (eq 23,
Figure 9b). The prole of f for the hypothetical case of very
large medium volume (Vb f ) is also shown in Figure 9b, with
K/G = 7.5. When Vbi . 4Na3/3, it follows that Vb(t) = Vbi
(eq 17), Cb(t) and Cbe are very low (eqs 20 and 21), and the
drug release, total[mg(0)
mg(t)] and fractionalf(t)
(eq 23), is at its upper limit (Figure 9b).
In experimental studies employing smart gels as drug delivery
vehicles, far more attention has been given, as one may anticipate,
to drug release than drug loading. Dynamics of drug release
has therefore been studied extensively. The rates of release
are computed from the proles of Cb, which have been reported
in these studies. The values of the key parameters listed in
Table 1 and used to obtain the results presented earlier
are representative of immunoglobulin G (IgG) (drug) and
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Figure 9. Temporal proles of (a) radius of gel spheres, ad(t) [= a +

u(a, t)], and (b) fractional release of drug, f, during drug delivery from
gel spheres for xed Re (=
0.2255). Legends 1, 2, 3, 4, and 5 represent proles for K/G = 0.75, 3.75, 7.5, 15, and 75, respectively, and the
dashed curve in (b) corresponds to very large bulk solution volume
(Vb f , K/G = 7.5).

poly(N-isopropylacrylamide) (PNIPAAm) gel. The swelling/

deswelling times for PNIPAAm hydrogel predicted by the model
(Figures 2 and 6) are in agreement with those reported in
experimental studies employing the hydrogel. The proles of
Cb in Figure 7a and the rate of drug release, rrel, in Figure 8d are
qualitatively similar to those reported in experimental studies
with this and other drug-gel systems. When the drug solution
(drug loading) or the surrounding medium (drug release) in
which gel particles are immersed has initial volume, Vbi, comparable (not in large excess) to initial volume of gel particles, it was
seen earlier that there are substantial variations in Vb upon
solvent uptake (gel swelling) or solvent eux (gel deswelling).
The estimates of drug loaded, mg, or drug released, [mg(0)

mg(t)], must take into account these variations. Estimates of
amount of drug loaded or released based just on variations in Cb,
ignoring variations in Vb, as has been done in most experimental
studies, will be in signicant error.

4. CONCLUSIONS
A mathematical model for processes involved in drug loading
into gel spheres from a well-mixed drug solution and drug
delivery from gel spheres into a well-mixed medium (target
uid) was developed. Polymeric gels that undergo deformation
upon appropriate changes in pH or temperature were considered

ARTICLE

as drug delivery vehicles. A stress diusion coupling model was

employed to compute polymer network displacement in swelling/deswelling gels and an analytical solution for network
displacement was obtained. When the drug solution (drug
loading) or the surrounding medium (drug release) in which
gel particles are immersed has initial volume, Vbi, comparable
(not in large excess) to initial volume of gel particles, there are
substantial variations in Vb upon solvent uptake (gel swelling) or
solvent eux (gel deswelling). The estimates of drug loaded, mg,
or drug released, [mg(0)
mg(t)], must take into account these
variations. Estimates of these based just on variations in Cb, as is
done frequently in experimental studies, will be erroneous.
Future experimental investigations must avoid this pitfall. The
characteristic time constants for solvent penetration and drug
transport aided by solvent uptake in swelling gels are comparable.
Most of the drug uptake therefore occurs during gel swelling.
Drug uptake in swelling gels was compared to that in nonswelling
gels and the tremendous superiority of the former as concerns
drug capacity of each gel particle was demonstrated via suitable
numerical illustrations. Two dierent modes of drug release from
drug-laden gels were considered: deswelling gels and gels not
subject to deformation. Numerical illustrations revealed distinct
features of each mode. Deswelling gels are suited well for rapid
drug delivery and nondeforming gels are suited better for drug
delivery over extended period. For deswelling gels, the characteristic time constant for drug transport is much greater than that
for solvent eux. Drug release from gel spheres, initiated during
deswelling operation, therefore continues over extended time
period much after termination of deswelling. This is attractive for
sustained delivery of drug macromolecules. For a particular
equilibrium swelling ratio, Re, an increase in K/G leads to more
rapid displacement of the polymer network in gel, causing in turn
faster uptake of solvent and drug in swelling gels and faster
release of solvent and drug from deswelling gels. The drug
loading can be increased, up to certain extent, by increasing the
amount of drug in the drug solution in contact with virgin gel
spheres. Because most of the drug loading occurs during gel
swelling, drug loading operation will be of much shorter duration
vis-a-vis drug release operation, duration of which can be tailored
as desired through appropriate selection of properties of gel and
drug molecule.

APPENDIX
A.1. Boundary Value
Initial Value Problem. The equilibrium (steady-state) solution of the boundary value
initial value
problem described by eqs 8 and 9, ue(r), is

ue r lim ur, t Re r,
tf

0<r<a

In terms of the deviation variable

vr, t ur, t
ue r
the boundary value
initial value problem described by eqs 8
10
can be recast as


v
4G

k K+
L v,
t
3


1 2
r v , 0 < r < a, t > 0
A1
Lv

r r 2 r
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subject to the boundary and initial conditions

r 0 : vr, t 0; r a :




4G v
2G v
+2 K

0; vr, 0
Re r
K+
3 r
3 r
A2

with A, B, C, D, E, and F being yet to be determined constants.

Because f(0, ) = 0 and J
3/2(()1/2r) and I
3/2((
)1/2r)
become unbounded as r f 0, B, D, and F are zero. For = 0, the
boundary condition at r = a requires that KC = 0. Because K is
positive, f(r, 0) is zero. An eigenfunction of L must be non-zero.
As a result, = 0 is not an eigenvalue of L. When < 0, the
boundary condition at r = a requires that

p



 
7
1 4G

a2m + 3=2
E
2m + K + 2m +
0
2
2 3 22m + 3=2 m!fm + 5=2g
m0

A.2. Properties of Differential Operator L. An analytical

solution to the boundary value
initial value problem can be
obtained using the properties of the differential operator L, which
is comprised of the Sturm
Liouville differential expression L ,
with the domain of L being function vectors f satisfying the
boundary conditions in eq A2, viz.,

r 0 : f 0, r a :



4G df
2G f
+2 K

0
K+
3 dr
3 r

A3

The inner product between two function vectors f and g

belonging to the domain of L is defined as
Z a
f , g r 2 f rgrdr
A4
0

Further, for arbitrary function vectors f and g belonging to the

domain of L, we have
Z

 



d 1 d 2
d 1 d 2
r2 f
g


g
f

dr
r
r
dr r 2 dr
dr r 2 dr

Becaue E must be non-zero and a, K, and G are positive, the

requirement above cannot be satisfied. Eigenvalues of L cannot
therefore be negative. All eigenvalues of L are thus positive and L
is positive-definite. Because
r

p
2 sinx

cosx , x r
J3=2 x
x
x
by suitable choice of A in eq A5, the eigenfunctions are restated as
( p
p
1 sin r
p
cos r g, 0 < r < a
f r,
A6
r
r
The characteristic equation for L is obtained from the boundary
condition at r = a as


p
F
3K
2G
, a, F 2
tan 2
A7
+F
2
3K + 4G

Lf , g
f , Lg
0

The normalization factor for eigenfunction fj [= f(r, j)] is

)2
Z a( p
p
sin r
p
cos r dr
Nj f j , f j
r
0
"
#
q
sin2j
sin2 j
a
A8

2

j a
1+
,

j
2
j2
2j

 

dg
df r a
r2 f
g
0
dr
dr r 0

in view of the boundary conditions in eq A3 for f(y) and g(y). The

differential operator L is therefore self-adjoint, ensuring that its
eigenvalues are real. For an arbitrary function vector f belonging
to the domain of L, it follows that




Z a
1 d 2
d 2 ra
2 d
r f dr
f r f
Lf , f
r f
dr r 2 dr
dr
0
r0
2


Z a 
1 d 2
df
r f dr g
2rf 2 + r 2 f
+
2 dr
r
dr r a
0
12aG
f a2


3K + 4G

Because eigenvalues of L are distinct, eigenfunctions of L form an

orthogonal set of function vectors. This follows as
Lf i , f j
f i , Lf j i
j f i , f j 0
w f i , f j 0 for i 6 j
The eigenfunctions are therefore linearly independent and form
a basis for expansion of function vectors. An arbitrary function
vector q (q(r), 0 < r < a) can be expanded in terms of eigenfunctions
of L as

The lower bound on L is therefore negative, implying that some

eigenvalues of L may be negative. Let be an eigenvalue of L and
f(r, ) the corresponding eigenfunction of L. The eigenfunctions
of L are subject to the boundary conditions in eq A3 and satisfy
the relation Lf = f, which is restated as
r2

d2 f
df
+ 2r + r 2
2f 0,
dr 2
dr

0<r<a

q, f j
f r, j ,
Nj
( p
)
q
1 sin j r
p
cos j r
f r, j
r
j r
qr

j1

where

The eigenfunctions are expressed as

8
p
p
p
>
< AJ3=2 r + BJ
3=2 r= r , > 0
Cr + D=r 2 , 0
f r,
p
p
>
: EI3=2
r + FI
3=2
r=pr , < 0
A5

Z
q, f j
0

)
p
q
sin j r
p
cos j r dr
rqr
j r

is the integral transform of q with respect to fj.

A.3. Solution to Boundary Value
Initial Value Problem.
The properties of L can be used to obtain solution to the
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Industrial & Engineering Chemistry Research

ARTICLE

boundary value-initial value problem described by eqs A1 and A2

as follows. Taking the integral transform of each term in eq A1,
one obtains

Z a 
d

vt, f j r 2
vr, t f r, j dr
Lv, f j
dt
t
0

v, Lf j
j vt, f j ,


4G
k K+
3
as v(r, t) and f(r, j) are subject to identical boundary conditions.
The initial conditions for the relations above are
)
Z a ( p
q
2 sin j r
p
cos j r dr
v0, f j
Re r
j r
0
q
Re
3=2 j2
3sinj + 3j cosj , j j a
j
The solution of the initial value problem stated above is



4G
vt, f j v0, f j exp
j k K +
t
3

Greek Symbols

The radial displacement of the gel network, u(r, t), therefore has
the expression
ur, t vr, t + Re r,

0 < r < a,

t>0

mg = amount of drug in single gel sphere, dened in eq 18, g

N = number of hydrogel spheres
Nj = normalization factor for eigenfunction f(r, j), dened in
eq A8
n = unit vector normal to the external surface
p = solvent pressure, p(r, t), dened in eq 7
p0 = external solvent pressure
re = volume-specic rate of drug elimination, g/{cm3 3 h}
t = time, h
Tb = temperature of bulk solution,
C
Ti = initial gel temperature (prior to its transfer to bulk
solution),
C
u(r, t) = ur(r, , j, t), cm
ue(r) = displacement prole at equilibrium, cm
ui = deformation in direction xi, i = 1
3, u1 = ur, u2 = u, u3 = u
u = deformation vector
vs = solvent velocity vector, cm/s
Vb = volume of bulk solution, cm3
vsr = solvent velocity in radial direction, dened in eq 15, cm/s
xi = spherical coordinate (direction) i, i = 1
3, x1 = r, x2 = , x3 =

A9

with




v0, f j
4G
exp
j k K +
t f r, j A10
vr, t
3
Nj
j1

AUTHOR INFORMATION
Corresponding Author

*Tel.: (312) 567-3044. Fax: (312) 567-8874. E-mail: parulekar@

iit.edu.

NOMENCLATURE
a = radius of spherical gel at the start of gel swelling or gel
deswelling, as appropriate, cm
C = drug concentration in gel, g/cm3
Cb = drug concentration in bulk solution, g/cm3
D0 = drug diusivity in solvent, cm2/s
De = eective diusivity of drug in gel, dened in eq 13, cm2/s
(f, g) = inner product between function vectors f and g, dened in
eq A4
f = fractional uptake (eq 22) or release (eq 23), as appropriate
f(r, ) = eigenfunction of L, dened in eq A6
f = f(r), 0 < r < a
f = external force vector
G = shear modulus of gel, N/m2
I = unit tensor (idem matrix)
Jn, In = Bessel functions of order n, n = ( 3/2
K = osmotic bulk modulus of gel, N/m2
k = hydraulic permeability of the polymer network
ke = kinetic coecient for drug elimination, h
1
L = dierential expression dened in eq A1
L = dierential operator
LCST = lower critical solution temperature,
C

R(t) = dened in eq 17
Re = equilibrium swelling ratio of gel
D = external surface of gel
= gel porosity
s = solvent viscosity
k = Darcys constant, cm2/{N.s}
= eigenvalue of L satisfying eq A7
, = angular coordinates, 0 e j, e 2
p = volume fraction of polymer in gel
F = dened in eq A7
Fs = solid (polymer) density, g/cm3
= stress tensor
ij = component of stress tensor , i, j = 1
3 or i, j = r, ,
net
net
ij = component of the net stress tensor , i, j = 1
3 or
i, j = r, ,
Subscripts

b = bulk solution outside gel spheres

e = equilibrium
i = value at t = 0

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