Pharmacology & Pharmacy, 2011, 2, 56-66
doi:10.4236/pp.2011.22007 Published Online April 2011 (http://www.SciRP.org/journal/pp)
Polymethylmethacrylate Coated Alginate Matrix
Microcapsules for Controlled Release of Diclofenac
Sodium
Tapas Pal, Shubhajit Paul, Biswanath Sa
Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India.
Received November 24th, 2010; revised January 2nd, 2011; accepted February 9th, 2011.
ABSTRACT
Polymethylmethacrylate (PMMA) coated microcapsules of diclofenac sodium (DFS) were prepared by a modified wa-
ter-in-oil-in-water (W1/O/W2) emulsion solvent evapora tion method u sing so d ium alginate (SAL) as a matrix material in
the interna l aqueous phase (W1). Their performance with respect to controlled release of the drug in simulated gastric
fluid (SGF) and simula ted in testin al flu id (SIF ) were eva lua ted, and compared with non-matrix microcapsules prepared
by the conventional W1/O/W2 emulsion solvent evaporation method. Scanning electron micrographs (SEM) revealed
that all the microcapsules were discrete and spherical in shape; however, the surface porosity of the matrix microcap-
sules appeared to be less than that of the non-matrix microcapsules. In case of no n-matrix microcapsules, an increase
in the volume of water in W1 phas e resulted in decrease in the drug entrapment efficien cy (DEE) along with increa se in
release of the drug in both SGF and SIF. While in case of matrix microcapsules increase in the amount of SAL in W1
phase and concentration of the coating polymer in organic phase led to increase in DEE of the matrix microcapsules
and considerable decrease in the drug release in both SGF and SIF. No interaction between the drug and any of the
polymers used to prepare microcapsules was evident from Fourier transform infra-red (FTIR) analysis. The matrix
microcapsules prepared using higher concentration of SAL and PMMA released the drug following zero order or
Case-II transport model. The matrix microcapsules appeared to be suitable for releasing lesser amounts of DFS in SGF
and providi ng ext ende d release in SIF.
Keywords: Polymethylmethacrylate, Sodiu m Al gi n at e , Matrix Microcapsules, Diclofenac Sodium, Drug Release
1. Introduction
Diclofenac Sodium (DFS), a non steroidal anti-inflam-
matory drug, is widely used in rheumatoid arthritis, se-
vere osteoarthritis and in ankylosing spondilities [1].
However, drug therapy with immediate release formula-
tions like tablet, capsule of this agent is associated with
several adverse effects like gastric irritation, bleeding,
ulceration and eventually wall perforation especially in
chronic dosing [2]. In addition, owing to its short bio-
logical half life (1 h - 2 h), DFS is administered 2 - 3
times a day [1]. A controlled release dosage form main-
tains adequate therapeutic plasma level of drug avoiding
peak-and-valley effect and thereby, minimizes the emer-
gence of adverse effects, prolongs the release of drug
over extended period of time, reduces frequency of ad-
ministration and hence improves patient compliance,
provides therapeutic action during night time no-dosing
period and thus, is suitable for better drug therapy [3,4].
When compared with single unit sustained release
tablets, multiunit controlled release dosage forms such as
microcapsules, microspheres pass through the gut as if a
solution avoiding the vagaries of gastric emptying and
different transit rates and thereby, release drugs more
uniformly [5], and spread over a large area of absorbing
mucosa decreasing dose dumping and preventing expo-
sure to high drug concentration [6,7].
Among the various methods of preparing microcap-
sules, water-in-oil-in-water (W1/O/W2) emulsion solvent
evaporation technique has been widely investigated. In
this method, an aqueous solution or suspension of the
drug (internal aqueous phase, W1) is emulsified in a solu-
tion of polymer in organic solvent. The resulting primary
emulsion (W1/O) is then dispersed in a second aqueous
phase (external aqueous phase, W2) containing suitable
emulsifiers to form multiple emulsion (W1/O/W2). Re-

Polymethylmethacrylate Coated Alginate Matrix Microcapsules for Controlled Release of Diclofenac Sodium57
moval of the volatile organic solvent leads to the forma-
tion of solid microcapsules. Drugs having different
physical properties and diverse solubility have been
microencapsulated by W1/O/W2 emulsion solvent evapo-
ration technique using various polymers like polymethyl-
methacrylate [8], polylactide-co-glycolide [9,10], eudrajit
RS [11], poly-Є-caprolactone [12]. Further modification
of this method includes variation in the volume of inter-
nal aqueous phase [13], pH [14] and concentration of
stabilizers [15] in W2 phase, and addition of NaCl [16],
glycerol [17], phosphate salt [18] in W1 phase for achiev-
ing better physical properties of the microcapsules.
Recently, ranitidine-loaded matrix type microcapsules
have been developed by W1/O/W2 emulsion solvent
evaporation method incorporating chitosan as a matrix
material in W1 phase and cellulose acetate as encapsulat-
ing polymer in organic phase [19]. However, detailed
study on PMMA coated SAL matrix microcapsules pre-
pared by W1/O/W2 emulsion solvent evaporation method
is not available. The objective of this study was to de-
velop PMMA coated alginate matrix microcapsules by
W1/O/W2 emulsion solvent evaporation method, and to
study the effect of concentration of SAL in W1 phase,
and concentration of PMMA in organic phase on the re-
lease of DFS in SGF and SIF.
SAL, a hydrophilic biopolymer obtained from brown
sea-weeds, has been widely used in drug delivery sys-
tems because of its high biological safety [20]. It has
been used to encapsulate various drugs in alginate beads
[21,22] and to prepare matrix tablets [23,24].
One of the rational advantages of using PMMA as a
coating polymer is that it is widely used as a biostable
polymer in biomedical field as bone cement in orthopae-
dics for local delivery of anti-inflammatory or antibiotic
drugs [25]. PMMA beads have been used in Europe over
the years for the management of total joint arthoplasty
and soft tissue infection of abdomen, rectum and neck
[26]. Therefore, an anti-inflammatory drug loaded in
PMMA microcapsules with an inner aqueous phase con-
taining SAL as a matrix material is expected to provide
better control on drug release in both SGF and SIF.
2. Materials and Methods
2.1. Materials
Diclofenac sodium (Indian Pharmacopoeia) was obtained
as gift sample from Plethico Pharmaceuticals Ltd, Indore,
India; Sodium alginate (Mol. Wt. 240 KDa, S.D. Fine
Chemicals, Ltd., Mumbai, India); Polymethyl methacry-
late (low mol. wt., BDH Chemicals Ltd., Poole, England),
Calcium chloride, Dichloromethane, Tween 80R (Merck,
India), Span 80R (Fluka Chemie AG, Bucks, Switzerland)
and all other analytical reagent grade chemicals were
obtained commercially and used as received.
2.2. Preparation of Microcapsules
SAL (0.5% - 2.5% w/v) was dissolved in 3ml at 30˚C -
35˚C water by stirring with a magnetic stirrer for 20 min.
200 mg of DFS was added to the solution and stirred for
further 20 min. The resulting mixture was added through
a 16 gauge needle in 20 ml solution of PMMA (4% w/v)
in dichloromethane containing 1% v/v Span 80 and
emulsified at 4000 rpm for 2 min in a homogenizer
(Eltek Motor, India). The resulting W1/O primary emul-
sion was then added through a 16 gauge needle in 100 ml
of water containing 1.25% v/v tween 80 and 2% w/v
CaCl2 and emulsified at 850 rpm to form W1/O/W2
emulsion. Stirring was continued for 1.5 h with a me-
chanical stirrer (Remi Motor, India) to evaporate off the
organic solvent. Resultant microcapsules were separated
by decantation, washed thrice with water and then, vac-
uum dried at 60˚C for 8 h. The microcapsules were
stored in vacuum desiccator until used. Keeping the
amount of SAL in W1 phase fixed at 2% w/v, matrix
microcapsules were also prepared varying the concentra-
tion (2% - 4% w/v) of PMMA solution. Non-matrix
microcapsules (without containing SAL) were prepared
in the same way using 3, 5 and 7 ml of water as internal
aqueous phase.
Double distilled water was used throughout the prepa-
ration. The composition of the microcapsules has been
shown in Table 1.
2.3. Fourier Transform Infrared Study (FTIR)
FTIR spectra of pure drug, blank (without containing
drug) microcapsules and drug-loaded matrix microcap-
sules were recorded in a FTIR spectrometer (Jasco-FTIR,
model 8300, Japan) in the range between 4000 and 400
cm–1 at a scanning speed 2 mm/sec. Each sample was
mixed with KBr and converted into pellets by applying a
pressure of 300 Kg/cm2 with a hydraulic press.
2.4. Size of Microcapsules
Weighed amount of the microcapsules were placed on
the top of a nest of British Standard Sieves (Gelological
India) of 25 to 150 mesh with the coarsest sieve on the
top, and shaken for 15 min on a mechanical shaker. The
microcapsules retained on each sieve were collected and
weighed. The average diameters of the microcapsules
were determined following the method reported else-
where [27]. The fraction having arithmetic mean diame-
ter of 215 µm was used for further studies.
2.5. DEE of Microcapsules
Accurately weighed 30 mg of microcapsules were dis-
solved in 3 ml dichloromethane; 25 ml of USP phosphate

Polymethylmethacrylate Coated Alginate Matrix Microcapsules for Controlled Release of Diclofenac Sodium 58
Table 1. Composition and characteristics of polymethylmethacrylate coated matrix and non-matrix microcapsules.
Rmulation code Volume of internal aqueous phase
(W1) (ml)
SAL concentration
in internal
aqueous phase (% w/v)
PMMA concentration
in organic phase
(% w/v)
Mean average
diameter (µm) DEE (%)
mean ± SD
A1 3 0 4 213.45 35.12 ± 2.71
A2 5 0 4 221.46 32.56 ± 3.25
A3 7 0 4 226.91 28.71 ± 2.19
B1 3 0.5 4 234.11 58.62 ± 3.88
B2 3 1.0 4 236.80 64.16 ± 2.12
B3 3 1.5 4 270.05 67.46 ± 3.95
B4 3 2.0 4 291.72 72.16 ± 2.44
B5 3 2.5 4 308.60 71.98 ± 4.39
C1 3 2.0 2 213.88 47.25 ± 3.76
C2 3 2.0 3 239.39 62.21 ± 3.37
C3 3 2.0 4 291.72 72.16 ± 2.44
buffer (PB) solution (pH 6.8) was added and stirred for
30 min with a magnetic stirrer. The mixture was heated
at 55˚C in a constant temperature bath with shaking to
evaporate off the organic solvent. The solution was
cooled and the volume was made up to 50 ml with PB
solution. The solution was filtered through Whatmann
filter paper (8 μm). An aliquot, following suitable dilu-
tion, was analyzed at 276 nm using a spectrophotometer
(model UV2400PC series, Shimadzu, Japan) and the
content of the microcapsules was determined using a
calibration curve constructed using PB solution of pH 6.8.
The reliability of the above method was judged by con-
ducting recovery analysis at three levels of spiked drug
solutions in the absence or presence of the polymers for
three consecutive days. The average recovery was found
to be 98.71 ± 3.06%. Drug entrapment efficiency (DEE)
of the microcapsules was calculated using the following
relationship:

Drug entrapment efficiency DEE%
Experimental drug content100
Theoretical drug content

2.6. Scanning Electron Microscopy (SEM)
Microcapsules were mounted on conducting stubs (made
of brass) using double sided adhesive tape and vacuum
coated with gold palladium film using a sputter coater
(Edward S-150, UK). Images were taken using 15 kV
electron beam intensity in a scanning electron micro-
scope (Jeol, JSM-5200, Japan) to examine the surface
morphology of the samples.
2.7. In-vitro Drug Release Study
In vitro drug release study was carried out in SGF (0.1 N
HCl, pH 1.2) for an initial 2 h followed by in SIF (USP,
Phosphate buffer, pH 6.8) for the rest of the period using
USP II dissolution test apparatus (model TDP – 06P,
Electro Lab, Mumbai, India). Microcapsules containing
about 10mg DFS were placed in 400 ml SGF (37˚C ±
0.5˚C) and rotated with a paddle at 100 rpm. After 2 h,
the acidic solution was removed carefully and replaced
with 400 ml SIF. Aliquots were withdrawn at different
times and replenished immediately with the same volume
of fresh solution. The withdrawn samples were filtered
through Whatman filter paper (8 µm), suitably diluted,
and analyzed spectrophotometrically at 273 nm and 276
nm respectively for SGF and SIF. The amount of drug
released in SGF and SIF were calculated from the cali-
bration curves drawn respectively in 0.1 N HCl and PB
(pH 6.8) solutions. Each release study was duplicated.
3. Results & Discussion
PMMA coated matrix and non-matrix microcapsules of
DSF were prepared by W1/O/W2 emulsion solvent evapo-
ration method. Initial experiments revealed that higher
volume of organic phase and external aqueous phase as
well as processing temperature considerably reduced
DEE of the non-matrix microcapsules. Use of large
volume of organic solvent required more time (about 5 h)
for solvent evaporation and formation of microcapsules.
This provided greater opportunity for the drug to parti-
tion from W1 to W2 phase. As a result DEE of the

Polymethylmethacrylate Coated Alginate Matrix Microcapsules for Controlled Release of Diclofenac Sodium59
microcapsules decreased. It has been reported that en-
trapment efficiency of vitamin B12 in poly (Є-caprolactone)
microparticles decreased when the volume of external
aqueous phase was increased and vice-versa [28]. Hence,
20ml of organic phase, 100ml of external aqueous phase
and 30˚C to 35˚C processing temperature were used for
the preparation of all microcapsules. Keeping the above
conditions fixed the effect of the volume of internal
aqueous phase of the non-matrix microcapsules and con-
centrations of SAL and PMMA of the matrix microcap-
sules on the properties of the microcapsules were studied.
3.1. Compatibility of Drug with Polymers
The compatibility of the drug with the polymers was
studied by FTIR analysis. FTIR spectrum of pure DFS
(Figure 1(a)) exhibited distinctive peaks at 3387.51 cm–1
due to N-H stretching of secondary amine, at 1575.63
cm–1 owing to –C═O stretching of carboxyl ion, and
746.86 cm–1 because of C–Cl stretching. As DFS con-
tains aromatic rings, peaks were found just above 3000
cm–1 (at 3076.69 cm–1 and 3034.48 cm–1). Generally 3 to
4 peaks in the range of 1400 cm–1 - 1550 cm–1 indicate
the presence of aromatic ring. The spectrum of DFS
showed peaks at 1401.72 cm–1, 1453.62 cm–1 and
1504.70 cm–1 confirming the presence of aromatic rings.
The FTIR spectrum of blank microcapsule (Figure 1(b))
which was composed of SAL and PMMA displayed a
broad peak at 3449.97 cm–1 due to –OH group of SAL.
The peak at 2927.75 cm–1 is due to C–H aliphatic
stretching of PMMA (aliphatic stretching appears just
below 3000 cm–1). The peak at 1735.04 cm–1 represents
–C═O stretching of carboxyl ion of both SAL and
PMMA. The spectrum of blank microcapsule did not
display any peak characteristics of NH stretching, aro-
matic C–H stretch and C–Cl stretch. FTIR spectrum of
DFS loaded matrix microcapsule (Figure 1(c)) demon-
strated a peak at 3450.98 cm–1 due to –OH stretching of
SAL, 3388.38 cm–1 due to N–H of the drug, 2926.49
cm–1 due to CH aliphatic stretching of PMMA. The peaks
between 1400 cm–1 - 1550 cm–1 are due to aromatic rings
of the drug, a peak at 1736.03 cm–1 represent the –C═O
stretching of carboxyl ions of SAL and PMMA, and a
peak at 1576.50 cm–1 is due to –C═O stretching of car-
boxyl ion of the drug. In addition, the peak at 747.39
cm–1 indicates the presence of C–Cl of the drugs. The
FTIR results thus confirmed the presence of the drug in
the microcapsules that did not interact with any of the
components of the matrix microcapsule.
3.2. Effect of Variables on Size of Microcapsules
Increase in the volume of the internal aqueous phase (W1)
tended to increase the size of the non-matrix microcap-
sules (Table 1). Increase in volume of W1 phase in-
creased the number of dispersed droplets in a fixed vol-
ume of organic phase, and the probability of coalescence
between the dispersed droplets increases. This resulted
increase in size of the non-matrix microcapsules. Similar
results have been reported by various workers [29,30].
Incorporation of SAL as matrix material in the fixed
volume (3 ml) of W1 phase also affected the size of the
matrix microcapsules. Increase in the concentration of
SAL increased the size of the matrix microcapsules (Ta-
ble 1). As the concentration of SAL was increased, the
viscosity of the W1 phase also increased. This hindered
easy breakdown of W1 phase into smaller droplets. In
addition, increase in viscosity of W1 phase made the
primary W1/O emulsion more viscous and formed larger
W1/O/W2 emulsion droplets. As a result, matrix micro-
capsules of bigger size were formed.
Keeping the concentration of SAL in W1 phase con-
stant at 2% w/v, increase in the concentration of PMMA
from 2% to 4% w/v increased the average diameter of the
matrix microcapsules (Table 1). Increase in the concen-
tration of PMMA increases the viscosity of organic phase
that makes it difficult to form smaller W1/O/W2 emulsion
droplets, and thus, leads to the formation of bigger
microcapsules. Although the size of the microcapsules
was confined within 36 - 120 mesh, 40% to 70% of the
microcapsules were retained by 60 to 85 mesh screen.
Hence, the microcapsules having an arithmetic mean
diameter of 215 µm were used for evaluation.
3.3. Effect of Variables on DEE
Increase in the volume of W1 phase decreased the DEE
of non-matrix microcapsules significantly (Table 1).
During the preparation of microcapsules by W1/O/W2
emulsion-solvent evaporation method, the organic poly-
mer phase separates the internal and external aqueous
phases and acts as a diffusion barrier for the drug be-
tween the two aqueous phases. Higher internal aqueous
volume may increase the volume of W1 droplets in the
oil phase and consequently may decrease the thickness of
the organic polymer phase. This promotes more parti-
tioning/leaching of the drug from internal to external
aqueous phase. As a result, the DEE of the microcapsules
decreases. The observation is in agreement with the re-
sults of other researchers [31,32].
DEE of alginate matrix microcapsules was found
higher than that of the non-matrix microcapsules (Table
1). Further, an increase in the concentration of SAL in-
creased DEE upto a limiting value beyond which DEE
decreased. Increase in the amount of SAL increases the
viscosity of W1 phase that minimizes the leaching of the
drug into the external aqueous phase; and thus, increases
DEE. However, when the concentration of SAL exceeded

Polymethylmethacrylate Coated Alginate Matrix Microcapsules for Controlled Release of Diclofenac Sodium 60
Figure 1. FTIR spectra of (a) diclofenac sodium, (b) blank microcapsules, (c) drug loaded microcapsules.

Polymethylmethacrylate Coated Alginate Matrix Microcapsules for Controlled Release of Diclofenac Sodium61
2% w/v, DEE of the microcapsules decreased. High vis-
cosity of the internal aqueous phase results in the forma-
tion of inhomogeneous emulsion with numerous internal
droplets in the W1/O emulsion aggravating leakage of the
inner core material to the external phase [33]. The load-
ing efficiency of ranitidine in cellulose acetate micro-
spheres containing chitosan as matrix material in the in-
ner aqueous phase has been reported to decrease with
increase in the concentration of chitosan in W1 phase
[19].
Using 2% w/v SAL in W1 phase, matrix microcapsules
were prepared with 2% to 4% w/v PMMA solution. In-
crease in the concentration of coating solution increased
DEE of the matrix microcapsules (Table 1). Increase in
the amount of PMMA increases the viscosity of the or-
ganic polymer phase which separates the internal aque-
ous phase from the external aqueous phase, and this is
turn, decreases the leakage of the drug from W1 to W2
phase, and thus, DEE of the matrix microcapsules in-
creases.
3.4. Effect of Variables on Drug Release
3.4.1. Effect of Volume of W1 Phase
The results of in vitro drug release studies which were
carried out initially for 2 h in SGF followed by in SIF
have been represented in Figure 2. The release of drug in
SGF from the non-matrix microcapsules which were
prepared with different volume of inner aqueous phase
was slow. Replacement of the dissolution medium after 2
h with SIF produced a sudden increase in release which
extended for different periods of time depending on the
volume of W1 phase. Such difference in release in the
two dissolution media may be attributed to pH dependent
solubility of the drug which is poorly soluble in acidic
solution and more soluble in aqueous solution of higher
pH. In addition, as the volume of W1 phase was in-
creased, the release of drug in both the dissolution media
increased. Time required for 50% (t50%) and 80% (t80%)
drug release were determined from the cumulative per-
centage release versus time curves. t50% were found to
decrease from 3.72 h to 2.39 h and t80% decreased from
7.87 h to 4.34 h as the volume of internal aqueous phase
Figure 2. Release profile of diclofenac sodium from non-
matrix microcapsules prepared with different volume of W1
phase (3 ml - A1, 5ml - A2, 7ml - A3) and matrix microcap-
sules prepared with different concentration of SAL in W1
phase (0.5% - B1, 1.0% - B2, 1.5% - B3, 2.0% - B4, 2.5% -
B5).
Table 1. Composition and characteristics of polymethylmethacrylate coated matrix and non-matrix microcapsules.
Formulation
code Volume of internalaqueous phase (W1) (ml) SAL concentration in internal aqueous phase (% w/v) PMMA concentration in organic phase (% w/v) Mean average diameter (µm) DEE (%)
mean ± SD
A1 3 0 4 213.45 35.12 ± 2.71
A2 5 0 4 221.46 32.56 ± 3.25
A3 7 0 4 226.91 28.71 ± 2.19
B1 3 0.5 4 234.11 58.62 ± 3.88
B2 3 1.0 4 236.80 64.16 ± 2.12
B3 3 1.5 4 270.05 67.46 ± 3.95
B4 3 2.0 4 291.72 72.16 ± 2.44
B5 3 2.5 4 308.60 71.98 ± 4.39
C1 3 2.0 2 213.88 47.25 ± 3.76
C2 3 2.0 3 239.39 62.21 ± 3.37
C3 3 2.0 4 291.72 72.16 ± 2.44

Polymethylmethacrylate Coated Alginate Matrix Microcapsules for Controlled Release of Diclofenac Sodium 62
Table 2. Parameters of release and release kinetics of DFS from polymethylmethacrylate coated matrix and non-matrix
microcapsules.
Parameters of release kinetics
Formulation code t50% (h) t80% (h) AUC (% mg·h/ml) n R²
A1 3.72 7.87 350.04b 0.702 0.992
A2 2.71 6.21 410.51b 0.707 0.975
A3 2.39 4.34 478.67b 0.767 0.978
B1 4.44 9.03 679.82 0.799 0.990
B2 5.17 10.26 622.37 0.857 0.989
B3 6.10 11.41 557.48 0.924 0.987
B4 6.75 ―a 507.38 1.024 0.988
B5 7.15 ―a 469.92 1.243 0.977
C1 3.30 5.68 399.62b 0.949 0.988
C2 4.78 8.31 291.07b 0.954 0.987
C3 6.75 ―a 206.25b 1.024 0.988
a. Drug release was less than 80% in 12 h. b. AUC was calculated from 0 h to 7.5 h.
was increased from 3 ml to 7 ml (Table 2). For better
comparison among the drug release from non-matrix
microcapsules prepared with different volume of W1 phase,
area under curves (AUCs) were determined from the
cumulative percentage release versus time curves using
“Origin 8.0” software. Since the release of the drugs
from the microcapsules prepared with 7 ml water in W1
phase was complete in 7.5 h, AUCs of the formulations
A1 to A3 were compared upto 7.5 h. Increase in the
value of AUC means a faster release of a drug. The val-
ues of AUCs were found to increase from 350.04 µg/ml/h
to 478.67 µg/ml/h as the volume of W1 phase was in-
creased for 3 ml to 7 ml. Higher volume of W1 phase
increases the porosity of the wall of the microcapsules
and results in faster drug release [34]. SEM photographs
(Figures 3(a-c)) showed the presence of pores on the
surface of the microcapsules. The development of pores
may be due to leakage of water through the organic
phase. During W1/O/W2 emulsion solvent evaporation
method, organic liquid diffuses from W1/O droplets to
external aqueous phase and simultaneously water from
external aqueous phase back diffuses into the droplets.
The back diffusion is related to the difference in the os-
momolarity between the internal and external phases.
The greater the back diffusion, the greater is the leakage
of water [28] and hence, the wall of the microcapsules
becomes more porous providing faster drug release.
3.4.2. Effect of SAL Concentration
The drug release from the matrix microcapsules followed
the same trend as that found from the non-matrix micro-
capsules prepared without SAL. However, the release of
drug from the matrix microcapsules was less than that
from the non-matrix microcapsules. While the non-matrix
microcapsule prepared with 3 ml water in W1 phase re-
leased 100% drug in 12 h, the matrix microcapsules con-
taining 3 ml water and 2.5% w/v SAL released only
76.06% drug in 12 h. For comparison, area under the
curve (AUC) of release versus time curve was calculated.
The value of AUC decreased from 679.82 μg/ml/h (for
non-matrix microcapsules) to 469.92 μg/ml/h (for matrix
microcapsules) containing 2.5% w/v SAL. It was further
noted from the drug release profile that while non-matrix
microcapsules prepared with 3 ml water in W1 phase
released 28.71% drug in 2 h in SGF, the matrix micro-
capsules containing 2% and 2.5% w/v SAL released re-
spectively only 11.26% and 6.12% drug during the same
period. In contact with acid solution, SAL is converted
into insoluble alginic acid which provides resistance to
drug diffusion. When the same microcapsules are brought
in contact with aqueous solution of higher pH, alginic
acid is reconverted into SAL which swells in water to
from a viscous solution inside the matrix microcapsules.
Thus, while the insoluble alginic acid formed inside the
matrix microcapsules provides resistance to drug diffu-
sion in SGF, formation of viscous SAL solution in the
matrix microcapsules is responsible for slower drug re-
lease in SIF. The higher the amount of SAL in the matrix
microcapsules, the higher will be the amount of alginic
acid formed in acidic solution, and the higher will be the
viscosity of SAL solution in SIF. Moreover, SEM photo-
graphs (Figures 3(d-f)) showed that although the gross

Polymethylmethacrylate Coated Alginate Matrix Microcapsules for Controlled Release of Diclofenac Sodium63
morphology of the matrix microcapsules did not change
appreciably, increase in the concentration of SAL tended
to decrease the porosity on the surface of the microcap-
sules. Thus increase in the concentration of SAL in the
W1 phase of the matrix microcapsules decreases the drug
release in both SGF and SIF.
3.4.3. Effect of PMMA Concentration
The effect of PMMA, used as coating polymer, on the
release of drug from the matrix microcapsules have been
represented in Figure 4. The pattern of drug release in
SGF and SIF was same as that found with other micro-
capsules. However, the matrix microcapsules prepared
with lower polymer concentration released the drug
faster than those prepared with higher polymer concen-
tration. Comparison of the AUC upto 7.5 h indicated a
decrease in AUC values with increase in concentration of
PMMA. Increase in the amount of coating polymer leads
around the matrix (Figures 3(g-i)), and thus, results in a
decrease in drug release. This result is consistent with the
report that release of protein from polylactide-co-glycolide
microcapsules decreases as the concentration of the
coating polymer is increased [35].
3.4.4. Kinetics of Drug Release
The release pattern of the drug from all the microcap-
sules appeared to be biphasic. The drug release was slow
in SGF. When the microcapsules were placed in SIF after
2 h dissolution study in SGF, a sudden increase in drug
release was observed following which the drug release
increased steadily. To obtain an idea of the mechanism of
drug release from various microcapsules, the release data
were fitted in the classical power law expression [36].
n
t
M
K
t
M


(a) (b) (c)
(d) (e) (f)
(g) (h) (i)
Figure 3. Scanning e lectron mic rographs of: non-matrix microcapsules prepared with different volume of W1 phase (3 ml - a,
5 ml - b, 7 ml - c); matrix microcapsules prepared with 4% w/v PMMA and different concentration of SAL (0.5% - d, 1.5% -
e, 2.5% - f); matrix microcapsules prepared with 2% w/v SAL in W1 phase and different concentration of PMMA (2% - g,
3% - h, 4% - i).

Polymethylmethacrylate Coated Alginate Matrix Microcapsules for Controlled Release of Diclofenac Sodium 64
Figure 4. Release profiles of diclofenac sodium from matrix
microcapsules prepared with 2% w/v SAL in W1 phase and
different concentration of PMMA (2% - C1, 3% - C2, 4% -
C3).
Where t
M
and
M

are respectively the amount of
drug released at time ‘t’ and at infinite time; ‘K’ repre-
sents a constant incorporating structural and geometrical
characteristics of the dosage form, ‘n’ denotes the diffu-
sion exponent indicative of the mechanism of drug re-
lease. Values of ‘n’ ranging from 0.45 to 0.5 indicate
Fickian or diffusion controlled release; values of ‘n’
ranging from 0.5 to 0.89 indicate non-Fickian or anoma-
lous release, and values of ‘n’ from 0.89 to 1 indicate
Case-II transport or zero order release. Table 2 shows
that the release of drug from non-matrix microcapsules
followed non-Fickian mechanism as the values of ‘n’
were confined within 0.70 to 0.77. The release of drug
from matrix microcapsules containing lower concentra-
tion of SAL in W1 phase also followed non-Fickian
model. However, increase in the concentration of SAL
shifted the drug release from the matrix microcapsules
towards Case-II transport or zero order model. Similarly,
the release of the drug from matrix microcapsules pre-
pared with increasing concentration of coating polymer
followed Case-II transport.
4. Conclusions
PMMA coated non-matrix and matrix microcapsules of
DFS, a non steroidal anti-inflammatory drug, were pre-
pared by W1/O/W2 emulsion solvent evaporation method.
DEE of the matrix microcapsules were found to be con-
siderably high than those of non-matrix microcapsules
and increased with increase in the concentration of the
matrix material. However, after a certain concentration of
the matrix material, DEE tended to decrease probably
due to the formation of inhomogeneous emulsion. Re-
lease of the drug from all the microcapsules appeared to
be biphasic releasing less amount of drug in SGF and
higher amount of drug in SIF. However, drug release
from the matrix microcapsules in SGF was considerably
less when compared with that from non-matrix micro-
capsules. In addition, the drug release from matrix micro-
capsules in SIF was more prolonged than that from non-
matrix microcapsules and extended over a longer period
of time depending on the concentration of SAL and
PMMA. The release of the drug from most of the micro-
capsules appeared to follow non-Fickian model. Increase
in the concentration of SAL in W1 phase and PMMA in
organic phase shifted the release kinetics towards zero-
order model. The results of this study indicated that ma-
trix microcapsules prepared with SAL as matrix material
could be a suitable multiunit controlled release dosage
form of DFS having high DEE that may release less
amount of drug in stomach minimizing the emergence of
gastric adverse effects and at the same time may provide
prolonged release in the intestine to achieve better drug
therapy.
5. Acknowledgements
One of the authors (T. Pal) received financial assistance
from State Government Departmental Fellowship Scheme
of Jadavpur University.
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