Academic Sciences

International Journal of Pharmacy and Pharmaceutical Sciences

ISSN- 0975-1491

Vol 5, Suppl 4, 2013

Research Article

DESIGN & IN-VITRO EVALUATION OF GASTRORETENTIVE, SUSTAINED RELEASE TABLET

FORMULATION OF ACYCLOVIR USING HYDROPHILIC POLYMERS
CHAUDHARI SHILPA P.*, KAMBLE SHRENIK C., SALVANKAR SHAILENDRA S.
Department of Pharmaceutics, Marathwada Mitra Mandals College of Pharmacy, Thergaon (Kalewadi), Pune, India 411033.
Received: 19 July 2013, Revised and Accepted: 02 Oct 2013
ABSTRACT
The purpose of this research was to develop a gastroretentive sustained release delivery system with swellable and mucoadhesive properties for a
drug like acyclovir. Hydrophilic polymers like poly ethylene oxide, and Hydroxypropyl methylcellulose were tried in combinations and statistically
optimized. A 32 factorial design was used to optimize the formulation to get the release profile for up to 12 h. Concentrations of HPMC K15 and
Polyox WSR301 was used as independent variables and in vitro drug release profile, swelling characteristics and in vitro mucoadhesive strength as
dependent variables. The optimized formulation (F3) showed the maximum drug release (95.2 4.5%), highest swelling index (182.47) and
maximum mucoadhesive strength in 12 h. The in vitro drug release mechanism was found to be of anomalous or non-Fickian type. The high water
uptake leading to higher swelling of the tablet supported the anomalous release mechanism of acyclovir. A formulation developed using swellable
mucoadhesive polymers, show excellent adhesion and gastroretention and desired release profiles thus providing absolute control.
Keywords: Acyclovir, Gastroretentive, Mucoadhesion, Polyethylene oxide, Hydroxypropyl methylcellulose.

INTRODUCTION

MATERIALS AND METHODS

The absorption of drug from the gastrointestinal tract is a complex

procedure. A number of variables are directly or indirectly affecting
the drug absorption. It has been reported that the extent of
gastrointestinal tract drug absorption is related to contact time with
the small intestinal mucosa [1]. Gastro retentive systems can remain
in the gastric region for several hours and therefore significantly
prolong the gastric residence time of drugs. Many approaches have
been reported in the literature for the formulation of such systems
viz. mucoadhesion [2], floatation [3], swellable/expansion [3,4],
sedimentation [5], modified shape systems [6,7] or by the
simultaneous administration of pharmacological agents [8,9] which
delay gastric emptying. Both single unit systems (tablets or
capsules) [3] and multiple unit systems (multi particulate systems)
have been reported in the literature [10,11]. Swellable and
mucoadhesive drug delivery offers a number of applications for
drugs having absorption window in the upper part of
gastrointestinal tract and also for localized action. It retains the
dosage form at the site of absorption and thus enhances the
bioavailability [12].

Acyclovir
was received as gift sample
from
Glen
mark Pharmaceuticals Ltd. (Mumbai, India). Hydroxypropyl
methylcellulose (HPMC) K15M, Poly (ethylene oxide) WSR 301(Polyox) and all other chemicals and ingredients used were
either of analytical or pharmaceutical grades.

Acyclovir [9-(2-hydroxyethoxylmethyl) guanine], a synthetic

purine nucleoside analogue derived from guanine is the most
widely used antiviral agent. It is effective in the treatment of
herpes simplex virus (HSV), mainly HSV-1 and HSV-2 and varicella
zoster virus. According to the biopharmaceutical classification
system acyclovir is categorized as a class- III drug i.e. having high
solubility and less permeability [13]. The pharmacokinetic
parameters of acyclovir, following oral administration, are
generally highly variable. It has an average plasma half-life of
about 3 hours on average in adults with normal renal function. Its
absorption in the GIT is slow, variable and incomplete. The
bioavailability of acyclovir after oral administration ranges from
10-30%. Approximately 80% of an oral dose is never absorbed
and excreted through feces. Also the frequency of administration
of acyclovir is high, depending upon the type of infection
[14].Among a variety of hydrophilic polymers, Polyethylene oxide
(Polyox), and Hydroxypropyl methylcellulose (HPMC) are
frequently used candidates in pharmaceutical formulation, mainly
because of its non-toxicity, high water-solubility and swellability,
mucoadhesive strength, insensitivity to the pH of the biological
medium and ease of production [15-16]. The aim of the present
study was to prepare a swellable, mucoadhesive type of
formulation giving sustained delivery of acyclovir using
hydrophilic polymers. Swelling, mucoadhesive properties and
drug release of the tablets with different proportions of polymers
in formulations was conducted applying experimental design.

Compatibility studies
Sample of pure drug, physical mixture of polymers and drug in (1:1)
ratio was placed at accelerated stability condition 402 C and
755% relative humidity for a period of 3 month. At the end of 3
month samples were evaluated for drug-Excipients compatibility
using Differential scanning calorimeter (DSC) (Mettler Toledo DSC
822e, Japan) and Fourier transformed infrared spectroscopy (FT-IR)
(Shimadzu Corporation, Japan, 8400s).
Preparation of tablet
Oral gastroretentive sustained release tablets containing acyclovir
were prepared by direct compression technology. The composition
of different formulations prepared using varying amounts of
polymers (i.e. Polyethylene oxide and HPMC K15M).
Microcrystalline cellulose was added as the compressing agent with
a fixed quantity of magnesium stearate (1%) as lubricant. Drug and
the Excipients were homogeneously blended and subsequently
compressed into tablet (12 mm Punch) using 12 station multi
tooling rotary tablet punching machine.
Table 1: It shows factor combinations as per the chosen
experimental design
Formulations
F1
F2
F3
F4
F5
F6
F7
F8
F9

Coded level
X1 HPMC 15K (mg)
X2 Polyox (mg)

X1
0
-1
-1
+1
-1
0
0
+1
+1

-1
50
50

X2
0
0
+1
0
-1
-1
+1
-1
+1

0
100
100

+1
150
150

Shilpa et al.
Int J Pharm Pharm Sci, Vol 5, Suppl 4, 111-116
Factorial design
A 32 full factorial design was constructed, where the independent
variables were concentration of HPMC K15M (X1) and Polyox (X2)
respectively selected as the factors. The levels of the two factors
were selected on the basis of preliminary studies carried out before
implementing the experimental design. The dependent variable
were Y1 (Swelling index), Y2 (mucoadhesive strength) and Y3 (%
Drug release). Table 1 summarizes the experimental runs, their
factor combinations and the translation of the coded levels to the
experimental units used in the study.

and weighed (Wt). Then swelling index was calculated by using the
formula given in equation:
SI =

Wt W0
X 100
W0

Where,
SI =Swelling index
Wt = Weight of swollen tablet at each time interval
W0 = Initial weight of tablet.

Evaluation of formulations

In-vitro mucoadhesion studies [23]

Thickness
The thickness of the tablet was measured using Vernier caliper.
Thickness of five tablets from each batch was measured and mean
was calculated.
Friability and Hardness
Twenty tablets from each formulation were examined for friability
[18], using the Veego friabilator and hardness using a Monsanto type
hardness tester.
Drug Content
Ten tablets from each formulation were powdered individually and a
quantity equivalent to 100 mg of acyclovir was accurately weighed
and extracted with a suitable volume of 0.1 N HCl. Each extract was
suitably diluted and analyzed spectrophotometrically at 255 nm [19].
Weight variation test

The mucoadhesive forces of tablets were determined by means of

modified analytical two pan balance (Fig.1). The pieces of stomach
(Fundus) tissue of sheep were taken in saline solution to 37 0C
before use. At the time of testing a section of tissue was attached,
keeping the mucosal side out, on to upper glass vial using a rubber
band. Then, the vial with a section of tissue was connected to the
balance and the other vial was fixed on a height-adjustable pan. To
the lower vial, a tablet was applied with the help of double-sided
adhesive tape. The height of the vial was adjusted so that the tablet
could adhere to the mucosal tissues of upper vial. After which the
upper vial was then connected to the balance. On the other side of
the modified balance an empty beaker was placed on pan and then
water was added at a constant rate to the beaker until the tablet gets
detached from tissue. The mucoadhesive force in dyne/cm2 was
determined from the minimal weights required for the detachment
using the following equation:
mg
A

Weighing 20 tablets individually, calculating the average weight and

comparing the individual tablet weight to the average USP weight
variation test.

Where,

Swelling study

m = the weight added to the balance in gm

The Swelling studies were carried out by determining the swelling

index using USP Type- II Apparatus (Paddle). Tablets were initially
weighed (W0) and then placed in the basket and revolved at 50 rpm
for 12 hrs. At intervals of 1 hr., tablets were removed from basket

g = acceleration due to gravity taken as 980 cm/sec 2

Mucoadhesive Force =

A = area of tissue exposed and is equal to r

(r-the radius of the tablet attached to tissue).

Fig. 1: Modified analytical two pan balance for Mucoadhesion Test

In vitro drug release studies

Dissolution studies were performed on all the formulations
prepared, in triplicate, employing Tablet dissolution test apparatus
(VEEGO-VDA-6D USP Standards) and 0.1 N HCl as the dissolution
medium at 50 rpm and 37C 0.5C. 0.1 ml aliquots of each test

sample were withdrawn periodically at suitable time intervals and

the volume was replaced with an equivalent amount of the plain
dissolution
medium.
The
samples
were
analyzed
spectrophotometrically at 255 nm.
Kinetic data analysis

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Shilpa et al.
Int J Pharm Pharm Sci, Vol 5, Suppl 4, 111-116
To analyze the in vitro release data various kinetic models were
used to describe the release kinetics, the dissolution profiles were
analyzed according to the zero-order, first-order[20], Higuchis
square root equations[21] and Korsmeyer - Peppas Model[22]. A
high value of correlation coefficient suggested good correlation
between in vitro-in vivo data. In case of tablets a value of n<0.45
indicates Fickian or Case I release; 0.45<n<0.89 for non-Fickian or
anomalous release; n=0.89 for Case II release; and n>0.89 indicates
Super Case II release[23].

RESULTS AND DISCUSSION

Compatibility study
1) FTIR spectra
The FTIR spectra of Acyclovir and optimized formulation of
Acyclovir tablet are shown in Figure 2. It suggested that there was
no interaction between the drug and polymers because principle
peaks of optimized formulation were nearly similar to that of pure
drug.

Fig. 2: It shows FTIR spectra (A - Acyclovir Drug, B- Optimized Formulation).

2) DSC Thermo grams
DSC thermo grams of the pure Acyclovir and the optimized
formulation of Acyclovir tablet (Fig.3). The DSC analysis of pure

Acyclovir showed a sharp endothermic peak at 251.470C,

corresponding to drugs melting point. The DSC analysis of the
optimized formulation showed a negligible change in melting point
of Acyclovir in the presence of polymer mixture studied.

Fig. 3: It shows DSC thermo grams (A - Acyclovir Drug, B - Optimized Formulation)

[

Factorial Design
A 32 full factorial design was constructed, where the amounts of
HPMC K15M (X1) and Polyox (X2) selected as the factors. The levels
of the two factors were selected on the basis of preliminary studies
carried out before implementing the experimental design.

interaction terms (X1 X2) show how the response changes when two
factors are simultaneously changed. The polynomial terms (X12 and
X22) are included to investigate non-linearity. The responses
swelling index (Y1), mucoadhesive strength (Y2), and % drug release
(Y3) for nine formulations (F1-F9) prepared according to 32 factorial
designs are as follows (Table 2).

The design was evaluated by following interactive model.

The fitted equation relating the response Y1, Y2, Y3, are shown below,

Y = b0 +

b1 X1+b2X2+b12X1X2+b12X12+b22X22

Where, Y is the dependent variable, b 0 is the arithmetic mean

response of the nine runs, and b1 is the estimated coefficient for the
factor X1. The main effects (X1 and X2) represent the average result of
changing one factor at a time from its low to high value. The

Y1 = 181.80 4.56 X1 + 0.37 X2 4.66 X1 X2 7.61 X12 4.07 X22.. (1)

Y2 = 5591.82 37.07 X1 + 1201.64 X2 8.99 X1 X2 + 74.05 X12 +
192.56 X22.(2)

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Int J Pharm Pharm Sci, Vol 5, Suppl 4, 111-116
Y3 = 89.54 5.01 X1 + 3.12 X2 3.32 X1 X2 3.77 X12 3.41
X22.(3)
Effect of formulation variables on swelling index
The swelling index values of all the formulations were increased
with increasing amounts of polymer concentration. Maximum
swelling index value was observed with the formulation F 3. The
mucoadhesion and drug release profile are dependent upon
swelling behavior of the tablets. As the proportion of these
polymers in the matrix increased, there was an increase in the

amount of water uptake and proportionally greater swelling

leading to a thicker gel layer supported the anomalous release
mechanism of acyclovir. An increase in polymer concentration
causes an increase in the viscosity of the gel as well as formation
of a gel layer with a longer diffusion path. This could cause a
decrease in the effective diffusion coefficient of the drug and
therefore a reduction in the drug release rate. The result of
regression analysis and ANOVA clearly shows that the coefficient
of X1, X2 and X1X2 were found to be significant at P < 0.05 hence
they were retained in polynomial equation(1).

Table 2: It shows Summary of Results of Regression Analysis for Response Y 1, Y2, Y3

Response
Y1
Y2
Y3

Models
Quadratic
Quadratic
Quadratic

F value
12.80
281.33
24.36

Prob > F
0.0021
0.0001
0.0003

R2
0.9014
0.9950
0.9457

Adjusted R2
0.8310
0.9915
0.9060

Predicted R2
0.2990
0.9648
0.6135

S.D
3.36
91.74
1.94

Remarks
Suggested
Suggested
Suggested

Fig. 4: Response surface plot of swelling index

Effect of formulation variables on Mucoadhesive strength
The Polynomial equation(2) and the figure 5 obtained using Design
Expert software DX8 shows an increasing trend in mucoadhesive
strength, with an increase in the amount of single polymer. The

maximum mucoadhesive strength was exhibited by formulation F 3

that contains polymer (i.e. Polyox) at their highest concentrations.
However, formulation F5 containing the least amount of the Polyox
showed the lowest mucoadhesive strength.

Fig. 5: Response surface plot of Mucoadhesive strength

Effect of formulation variables on % Drug release
According to polynomial equation 3, Increasing the amount of HPMC
K15M (X1) resulted in retardation of drug release of tablet as
suggested by the negative sign of the coefficient of X1, however
Increasing the amount of Polyox (X2) resulted in increases the drug

release of tablet. The optimized formulation (F3) showed the

maximum drug release (95.2 4.5%) in 12 h whereas the formulation
F4 showed lowest drug release (73.3 1.5%) in 12 h. The in vitro drug
release mechanism was found to be of anomalous or non-Fickian type.
The high water uptake leading to higher swelling of the tablet
supported the anomalous release mechanism of acyclovir.

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Int J Pharm Pharm Sci, Vol 5, Suppl 4, 111-116

Fig. 6: Response surface plot of % Drug release

Kinetic data analysis
The release data was fitted to various mathematical models to
evaluate the kinetics and mechanism of the drug release is shown in
Table 3. Results of in-vitro drug release kinetics study suggests that,

all formulations follows Higuchi model with r2 value in range of 0.99

and fitting the release data to Korsmeyer equation release exponent
(n) ranged from 0.788 to 0.883 this indicated that the nature of drug
release from the tablets followed non-Fickian diffusion mechanism
(anomalous transport)[24].

Table 3: It shows Release Kinetic Parameters of Sustained Release Tablet.

Formulation No.
F1
F2
F3
F4
F5
F6
F7
F8
F9

Zero order
(r2)
0.986
0.982
0.989
0.982
0.984
0.982
0.986
0.982
0.987

First order
(r2)
0.971
0.982
0.933
0.996
0.984
0.994
0.984
0.990
0.983

Higuchi
(r2)
0.990
0.991
0.992
0.995
0.989
0.995
0.995
0.991
0.991

CONCLUSION
This study suggests that the polymers Polyox and HPMC K 15M can
produce a controlled pattern of drug release in the prepared
acyclovir tablets. The high mucoadhesive strength of this
formulation is likely to increase its residence time in the
gastrointestinal tract, which eventually improves the extent of
bioavailability. However, an appropriate balance between various
levels of the two polymers is needed to acquire proper release and
mucoadhesion. In this formulation the amount of Polyox mainly
affects on the Mucoadhesion and Swelling of tablets. It can be
concluded that by formulating gastroretentive sustained release
tablets of acyclovir, its complete release can be ensured prior to
absorption window and hence the problem of incomplete drug
release and erratic absorption can be solved by increasing the
retention time of drug in GIT for a longer duration of time.
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