Development of Indomethacin Sustained Release

Microcapsules using Ethyl Cellulose and Hydroxy

Propyl Methyl Cellulose Phthalate
by O/W Emulsification
Md. Abu Hena Mostafa Kamal1, Maruf Ahmed1, Mir Imam Ibne Wahed1,
Md. Shah Amran2, Sharif Md. Shaheen1, Mamunur Rashid1
and Md. Anwar-Ul-Islam1
1
Department of Pharmacy, University of Rajshahi, Rajshahi-6205, Bangladesh
2
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Dhaka,
Dhaka-1000, Bangladesh

ABSTRACT: Indomethacin (IM) sustained release microcapsules were successfully prepared using ethyl cellulose
(EC) and hydroxy propyl methyl cellulose phthalate (HPMCP) by o/w emulsification-solvent evaporation technique.
The prepared microcapsules were evaluated for size, shape, drug content and in vitro drug release. The microcapsules
show sustained release curves at pH 7.2 phosphate buffer for up to 6 h. The data obtained from the dissolution
profiles were compared in the light of different kinetics models and the regression coefficients were compared. The
in vitro dissolution study confirmed the Higuchi-order release pattern. Particle size and release data analysis from five
consecutive batches prepared in the laboratory indicated suitable reproducibility of the solvent evaporation process.
The release rate increased exponentially with the addition of HPMCP in EC. IM release rate was observed highest
with the highest concentration of HPMCP (3:7 ratio of EC:HPMCP), used in the present studies. On the other hand,
IM release rate was lowest when EC and HPMCP combination was used at the ratio of 10:0. When percent of
HPMCP was increased, the particle size of microcapsules was decreased.
Key words: Indomethacin, sustained release, microcapsule, HPMCP, EC, Higuchi-order

INTRODUCTION
Sustain action dosage forms are designed to individual drug particles in inert polymeric material,
achieve a prolonged therapeutic action by through which the drug would diffuse at a controlled
continuously releasing medication over an extended and predictable rate to the surrounding medium.
period of time after administration of single dose. Other techniques used colloidal polymer dispersions
Microencapsulation is a process for coating of small in a completely aqueous environment as an
solid particle; liquid droplets or dispersions using alternative to conventional microencapsulation
polymeric material to produce small particles of 1 to techniques, which use organic solvents.2
5000 micrometer in size. It is a rapidly expanding Encapsulation and sustained release of
technology for achieving sustained release dosage indomethacin (IM), using CO2-based microencapsu-
forms. Microencapsulation is used to modify and lation was studied by Liu and co-workers.3 The CO2
retard drug release.1 It involves the coating of the plasticizes the biodegradable polymers, increasing
Correspondence to: Maruf Ahmed the drug diffusion rate in the particles so that drug
Tel: +88-0721-750041-49/4110
Fax: +88-0721-750064
loading is enhanced. Rowe and Carless studied the
Email: amaruf2003@yahoo.co.jp comparison of the in vitro dissolution behaviour of
various indomethacin formulations with their in vivo
Dhaka Univ. J. Pharm. Sci. 7(1): 83-88, 2008 (June)
84 Kamal et al.

bioavailability. The effects of the core to colloid wall Five batches of microcapsules were prepared. In each
ratio and particle size of the core on the in vitro batch amount of IM was 1 gm. and total amount of
release of indomethacin microcapsules prepared by polymer was 2 gms. The details of the polymer
the gelatin-acacia complex coacervation process have proportion and their amount in different batches are
been examined.4 Dissolution behaviour of sustained shown in Table 1.
release formulations of indomethacin with Eudragit
Table 1. Formulation of indomethacin microcapsules.
RS was also studied by Khanfar and co-workers.5 In
another study, complex coacervation of chitosan and Polymer Average
IM Amount size
carboxymethylcellulose was prepared to control the Batch Ratio (EC :
(g) (EC+HPMCP) (µm)
HPMCP)
release of indomethacin from microcapsule. The (g)
1 1 10 : 0 2.0 + 0.0 87.7
mechanism lies in crosslinking between chitosan and
2 1 8:2 1.6 + 0.4 65.5
carboxymethylcellulose with glutaraldehyde.6 3 1 7:3 1.4 + 0.6 40.0
Indomethacin, a nonsteroidal anti-inflammatory 4 1 5:5 1.0 + 1.0 22.9
5 1 3:7 0.6 + 1.4 18.6
agent, has a short biological half-life of 2.6-11.2
hours.7 The usual oral dosage for adults is 25 or 50 Each microcapsule batch weighs 3gms. The polymer ratio and
amounts in the microcapsules containing EC and HPMCP prepared
mg, 2 to 3 times a day. Controlled release by emulsification and organic solvent evaporation technique.
preparations of this drug are to increase patient
compliance and to reduce adverse effects, fluctuation Continuous phase was gelatin gel in distilled
in plasma concentration and dosing frequency. water and dispersed non-aqueous phase consisted of
Therefore, the objective of this study was to polymers (EC and HPMCP) and IM solution in
investigate the preparation of microcapsules using dichloromethane. At first 2% w/v gelatin solution in
ethyl cellulose (EC) and hydroxy propyl methyl 500 ml of distilled water was prepared. Then one
cellulose phthalate (HPMCP) by o/w emulsification- gram IM and required amounts of polymers were
solvent evaporation technique. The effects of EC and dissolved in 20 ml of dichloromethane. Two percent
HPMCP ratio on the physical properties and drug (2%) gelatin solution was diluted with distilled water
release pattern of the pharmaceutical microcapsule to obtain 0.5% gelatin solution.
were studied. A flat bottomed glass cylinder was partially
immersed in a thermostatic water bath at 40°C. 50 ml
of 0.5% gelatin solution was taken into that glass
MATERIALS AND METHODS
cylinder and kept for 10 minutes to equilibrate the
Materials. Ethyl Cellulose (EC), Hydroxy temperature. The dispersed phase was then added and
Propyl Methyl Cellulose Phthalate (HPMCP) and stirred with a stainless steel propeller at 2000 rpm.
Gelatin were purchased from Fluka, Switzerland. Agitation was continued for 45 minutes to ensure
Indomethacin (product grade) was a kind gift from complete evaporation of the volatile solvent and
Novartis (BD) Ltd. The solvents and reagents were of formation of microcapsules. Finally microcapsules
analytical grade. were separated by vacuum filtration. They were
Preparation of indomethacin microcapsules. washed four times with 20 ml of distilled water and
Microcapsules were prepared by an emulsification dried in a desiccator.
and organic solvent evaporation technique reported Percentages of drug entrapment and drug
earlier by Jalil and Nixon.8 The apparatus used in this recovery. The percentage of drug entrapment was
technique was very simple, consisting of stirrer, a flat calculated from the content of indomethacin in
bottomed glass vessel and thermostatically controlled microcapsule determined according to the monograph
water bath. of Indomethacin Extended Release Capsule in the
Development of Indomethacin Sustained Release Microcapsules 85

USP XXIV. The percentage of drug recovery was calculated with the help of appropriate calibration
computed from the following equation. curves constructed from reference standards. Data
% Recovery = Mt.Dm100/Ma Di analysis and statistical calculations were performed
using a computer program GraphPad Prism version
where Dm, Mt, Di and Ma were the drug content
3.00 for Windows (GraphPad Software, San Diego,
in microcapsule, the weight of total microcapsule
CA, USA).
yield and the initial amount of drug used in the
microencapsulation process and weight of the
determined microcapsule, respectively. RESULTS AND DISCUSSION
In vitro Dissolution Studies. Microencapsulated Microcapsule size. IM microcapsules were
IM showed better drug release profile with USP prepared from EC and HPMCP by emulsification-
paddle method than that of USP basket method. solvent evaporation technique in which different
Simulated intestinal fluid (pH 7.2) was an appropriate ratios of EC and HPMCP were used keeping the drug
medium to use for dissolution studies on prolonged- load constant. Microcapsules of same formulation
release microcapsules.9 In our study, the dissolution were more or less uniform in size with spherical or
studies of approx. 200 mg of microcapsules from oval shape when observed in a light microscope. The
each formulation were carried out using an average sizes of IM microcapsules are given in Table
''Electrolab Dissolution Tester USP (XXI) TDT-06''. 1. This observation clearly indicates that when
The paddle rotation was set at 50 rpm and the percent of HPMCP was increased, the particle size of
temperature was controlled at 37 ± 2°C using 1 litre microcapsules was decreased. Figures 1a, 1b, 1c, 1d
of dissolution medium of pH 7.2 as chamber volume and 1e show the IM microcapsules of five batches
containing potassium dihydrogen phosphate, KH2PO4 respectively.
(0.2M); sodium hydroxide, NaOH (0.2M) and water.
Time was recorded as soon as the microcapsules
were put into the dissolution vessels. A five ml
sample solution was withdrawn from each vessel at
appropriate time intervals (5, 10, 20, 30, 40, 60, 90,
120, 150, 180, 210, 240, 270, 300, 330, 360 minutes)
for the analysis of drug release. Five ml of fresh
phosphate buffer solution previously heated to 37°C
was immediately added to the dissolution medium for
compensating the sampling. The dissolution study
was carried out for three samples from each Figure 1(a), Microphotograph of EC and HPMCP combination
formulation. microcapsules ratio 10 : 0

Size and size distribution. The size and size

distribution were determined using light microscopy.
The particle size was determined by measuring the
Martin’s diameter.10
Analysis of drug release. Drug released in the
sample solution was determined spectrophoto-
metrically by measuring the absorbance at 318 nm
using a UV-visible spectrophotometer, the reference
being the fresh dissolution medium of pH 7.2. The
Figure 1(b), Microphotograph of EC and HPMCP combination
amounts of drug present in the samples were microcapsules ratio 8 : 2
86 Kamal et al.

Table 2 was obviously varied between 54.87 to

86.33%. It could be seen that the drug recovery was
influenced by the EC solution. It was also noted that
high drug recovery could be achieved by increasing
the concentration of EC solution. This might be due
to increased thickness of EC coating of the
microcapsules. However, the drug entrapment did not
show any relationship with the concentration of EC,
since it depends on the processing of microcapsule
rather than on any ingredient of the formulation.

Table 2. Formulation variable affecting drug entrapment and

drug recovery in indomethacin microcapsules

Figure 1(c), Microphotograph of EC and HPMCP combination EC % Drug entrapment % Drug recovery
microcapsules ratio 7 : 3 Batch
(gm) ± SEM ± SEM
1 2.0 89.67 ± 0.55 (3) 86.33 ± 0.72 (3)
2 1.6 78.00 ± 0.67 (3) 76.95 ± 0.43 (3)
3 1.4 84.45 ± 1.02 (3) 77.23 ± 0.65 (3)
4 1.0 75.86 ± 0.47 (4) 63.37 ± 1.23 (4)
5 0.6 66.17 ± 0.18 (4) 54.87 ± 0.88 (4)
Numbers in parentheses indicate number of determinations

Drug release kinetics from EC-HPMCP

microcapsules. IM release kinetics from
microcapsules were studied using phosphate buffer
(pH 7.2) at 37°C temperature and 50 rpm paddle
speed using a USP dissolution test apparatus. The
Figure 1(d), Microphotograph of EC and HPMCP combination release rate was slower when the content of EC was
microcapsules ratio 5 : 5 increased. A linear relation exists between the rate of
release and the reciprocal amount of EC used for
coating, indicating that the drug release was
controlled by the coating thickness. When percent
release was plotted against time (Figure 2), no
straight lines were obtained indicating that IM release
did not follow the zero order kinetics. First order plot
(log % remaining vs. time) also showed curved
released pattern (Figure 3).
In contrast, when percent release was plotted
against square root of time (Figure 4), release profile
showed linear relationship. The Higuchi square root
Figure 1(e), Microphotograph of EC and HPMCP combination equation describes the release from systems where
microcapsules ratio 3 : 7 the solid drug is dispersed in an insoluble matrix, and
the rate of drug release is related to the rate of drug
Drug entrapment and drug recovery. Drug
diffusion.11,12 This confirms that EC-HPMCP
entrapment in EC-HPMCP microcapsules was within
microcapsules were released in a Higuchian diffusion
a range of 66.17 to 89.67 % as listed in Table 2. In
fashion.
contrast, the percentage of drug recovery shown in
Development of Indomethacin Sustained Release Microcapsules 87

Figure 2. Zero order release profile of IM from polymeric

microcapsules. Batch formulation is available in Table 1
Figure 5. Release rate of IM from different proportion of HPMCP
in microcapsules

Figure 3. First order release profile of Ibuprofen from polymeric

microcapsules. Batch formulation is available in Table 1

Figure 6. Particle size of IM microcapsules from different

proportion of EC:HPMCP in microcapsules

The reason for gradually decreasing release rate

may be due to the plasticization of the EC polymer
thereby forming smooth and nonporous films around
the core IM crystal. The increase in ''Higuchian''
release rate constant with the increase of HPMCP
proportion to EC was due to higher rate of
permeability of HPMCP in the dissolution medium of
Figure 4. Higuchi release profile of IM from polymeric pH 7.2 as well as increased surface area due to
microcapsules. Batch formulation is available in Table 1
decreased particle size. Another study with the
surface morphology of the microcapsules of IM,
The slope values (Higuchi release rate constants,
microencapsulated with EC, was examined using
Kh) obtained from the straight line portion of the
scanning electron microscopy, the microcapsules
Figure 4 were 2.68, 3.17, 4.33, 5.86, and 6.92 for the
were found porous and spherical, and their porosity
formulation of 1, 2, 3, 4, and 5 respectively. These
increased with increasing viscosity of EC.12 So, EC
values were plotted against the percent of HPMCP
might have created porosity in its coating in this
content in the EC-HPMCP microcapsules and Figure
formulation also. The release rate of the drug from
5 was obtained. This figure indicated that the release
microcapsules decreased as the viscosity of EC
rate was increased with the increase of percent of
decreased. The release rate also decreased with
HPMCP.
increasing microcapsule size.
88 Kamal et al.

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