RESEARCH ARTICLE

Preparation and In vitro Evaluation of Captopril Loaded

Microspheres for Gastroretention
C Nithya Shanthi1*, Rakesh Gupta2, Arun Kumar Mahato1
Abstract: Captopril, an effective anti hypertensive drug, faced various limitations in preparation of sustained or controlled
delivery system due to the fact that the drug is not stable in intestine. Thus the objective of the present study was to prepare
gastro retentive microspheres using poly methacrylate polymers to retain the drug in the stomach for longer period.
Microspheres prepared by solvent evaporation method were analyzed to sustain the release of captopril in gastric region. The
drug and polymer compatibility analysis were done to determine possible interactions between them using FTIR, DSC and TG
analysis. The compatible polymers were selected for further formulations. Microspheres of captopril were prepared using
Eudragit RLPO, RL100, RSPO and RS100 and its combinations. The process was optimized for the drug polymer ratio, speed of
rotation and concentration of surfactant. The various parameters such as percentage yield, drug content, buoyancy percentage,
particle size analysis and bulk density was determined. The in vitro release study was carried out for the prepared
microspheres. The bulk densities of the microspheres were less than one and the results of buoyancy showed that the prepared
microspheres float in the acidic medium upto 8 hr. The microspheres gave sustained release of drug upto 24 hr. The kinetic
modeling showed that release follows first order and the mechanism was by both dissolution and diffusion. Thus the
formulation and in vitro evaluation of captopril loaded microspheres using eudragit polymers found to retain in the gastric
region upto 8 h and the drug release was also found to sustained upto 24 hr.

INTRODUCTION Captopril was kindly procured from Akums Pharma,

Captopril, an antihypertensive has been widely used for
the treatment of hypertension and congestive heart
failure. [1] The duration of antihypertensive action after
single oral dosing of captopril is only 6-8 hr, so
clinical use requires the daily dose of 37.5-75 mg to be
taken at 3 times. [2] The drug is freely water soluble and
has elimination half-life after an oral dose of 1.7 hr. It is
stable at pH 1.2, and as the pH increases, the drug
becomes unstable and undergoes a degradation reaction.
[3, 4] Therefore it would be advantageous to formulate
captopril as a gastroretentive dosage forms so that the
system can be retained in the stomach for a longer period
of time.
Numerous efforts were made on the drug to sustain and
control the release from different delivery systems. The
various works includes preparation of matrix tablets,
osmotic delivery systems, microparticulate systems
prepared from different polymers, pellets etc., Sintov et al
prepared extended release formulations for absorption
enhancement of Captopril in the rat colon. [5] Hsuisu et al
worked on the controlled delivery of captopril from
granulated excipients as matrix material. [6] Stulzer et al
developed captopril granules for control release by fluid
bed drier. [7] Meka et al researched on multiple unit mini
tabs based on gas formation to prolong the gastric
residence time. [8]
The objective of our present study is to develop
microspheres to be retained in the gastric region for
prolonged period.
MATERIALS AND METHODS
Materials
1Department of Pharm Sciences, Sardar Bhagwan Singh PG institute of
Biomedical Sciences and Research, Dehradun, Uttrakhand, India.
E-mail: nithya.pharm@gmail.com
*Corresponding author
2 LBS College of Pharmacy, Jaipur, Rajasthan, India.
Haridwar. Eudragit grade RLPO, RL100, RSPO and RS100
was kindly obtained as a gift sample from Degussa India
Pvt. Ltd. Mumbai. All the reagents and chemicals used for
the study were of analytical grade.
Methods
1. HPLC Analysis
Captopril was assayed by employing a C-18, 250mm
column. The HPLC system included an isocratic pump
(Waters, model 2350) with a manual injector with an UV
detector (Waters, model 484) and software (Breeze 2) was
used. The drug was analyzed in the wavelength of 220 nm.
The mobile phase consisted of a 70:30 mixture of 0.1%
phosphoric acid and methanol. The peak areas obtained
from chromatograms were used to calculate the
concentration values of captopril in the tested sample
solutions. [9]
2. Fourier Transform Infra Red Spectral Analysis
FTIR spectroscopic studies were carried out to analyze the
possible interactions between drug and polymers used. The
IR spectra of pure drug and polymers, and of microspheres
and physical mixtures, were obtained with an FTIR
spectrophotometer, (Shimadzu 8201 PC) using KBr disks
(about 10 mg sample for 100 mg drug KBr). The scanning
range used was 4000 to 400 cm-1 at a scan period of one
minute.
3. Thermal Analysis
a. Differential Scanning Calorimetry
The thermal properties of the pure drug, physical mixtures
and microspheres were studied using a differential
scanning calorimeter (Perkin Elmer-Pyris Diamond).
Approximately 10 mg of sample was accurately weighed
into a 40 l alumina pan and sealed with a punched lid. The
samples were heated from 28 C to 400 C using a heating
rate of 10 C/min. A nitrogen purge of 200 ml/min was
used in the oven. Reference used was alumina powder.

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 RESEARCH ARTICLE
b. Thermogravimetric Analysis
TG curves were obtained with a Perkin Elmer-Pyris
Diamond thermo balance in the temperature range of 25
400C, using platinum crucibles with 10.00.1mg of
sample, under dynamic Nitrogen atmosphere (200 ml min
1) and at a heating rate of 10C min1. TG analysis has been
performed using pure drug, physical binary mixtures and
microspheres.
4. Preparation of Microspheres
Captopril microspheres were prepared by solvent
evaporation technique. Different amounts of polymer were
dissolved in acetone by using a magnetic stirrer. Drug was
then dispersed in the polymer solution. The resultant
dispersion was then poured into liquid paraffin while
stirring. A cylindrical vessel and a mechanical stirrer with a
blade were used. Stirring was continued for an hour, until
acetone evaporated completely. The same procedure was
followed with different types of polymer, polymer: drug
ratio, Stirring speed and concentration of surfactant to
optimize the process parameters. After evaporation of
acetone, the microspheres formed were collected by
filtration after centrifugation, washed 45 times with
Petroleum ether and dried at room temperature for 24 hrs.
[10-12]
EVALUATION OF FORMULATION
Percentage Yield
The yields were calculated by dividing the weight of the
microspheres by the total weight of added ingredients.
Percentage Yield
 Preparation of Microspheres

Drug Content
Drug content of microspheres was determined by HPLC
method as described in the above section. 25mg of drug-
loaded microspheres were dissolved in ethyl alcohol and
extracted in 0.1N hydrochloric acid and was analyzed. The
experiments were done in triplicate.
Actual drug content
 stretching band at 2563.4cm-1 and carbonyl vibration

Buoyancy Percentage
The buoyancy of the microspheres was determined using
the paddle method in a dissolution tester. One hundred mg
microspheres were introduced into the vessels and the
paddles were rotated at 50 rpm in 900 ml of hydrochloric
acid (pH 1.2) at 370.5C. After 2 hrs, the floating
microspheres were counted. The buoyancy was determined
by the ratio of the number of floating microspheres to the
total number of microspheres. [13]
 melting endotherm of drug could be due to the mixing of
 drug and excipient, which lowers the purity of each
 
Wf Floating microspheres and Ws Sink microspheres.
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Determination of Bulk Density
The determination of bulk density was established by
tapping method. 100mg of dried microspheres were taken
in 10ml measuring cylinder and the volume was noted. The
bulk density was calculated from the ratio of mass and
volume of the microspheres occupied in the measuring
cylinder as follows. [14]

 

Particle Size Analysis and Scanning Electron
Microscopical Studies
Particle size of microspheres was determined by optical
microscopy and dynamic light scattering. The diameter of
microspheres from each formulation was determined. The
surface morphology and internal structure of the
microspheres were analyzed and imaged by Scanning
electron microscopy.
In vitro Drug Release Studies
The in vitro drug release studies of microspheres were
performed in USP apparatus II (paddle) using 900ml of
0.1N HCl (simulated gastric fluid) as media at 37C0.5
rotated at 50rpm. After suitable dilution, the samples were
analyzed by injecting samples in HPLC. The data obtained
from the dissolution studies were fitted to various kinetic
models such as zero, first, Peppas, Higuchi and Hixson-
Crowell models. [15]
RESULTS AND DISCUSSIONS
The microspheres were prepared by emulsification-solvent
evaporation method. Different batches of microspheres
were prepared using polymers such as eudragits alone and
in combination in an attempt to enhance the gastro
retention of the system.
Evaluation of Microspheres
1. Fourier Transform Infra Red Spectral Analysis
The drug shown the characteristic peak at 2978cm-1 and
2877.79cm-1 corresponding to CH2CH3 group, -SH
bands of COOH at 1747.5cm-1 and amide at 1593.34cm-1
as shown in Figure 1. The spectra obtained from the binary
mixtures of drug with polymethacrlate polymers found to
be superimposible. There was no shifting, broadening,
appearance or disappearance of peak found. This confirms
that there is no possible incompatibilities establish
between them.
2. Thermal Analysis
It has been reported that the quantity of material used,
especially in drugexcipient mixtures, affects the peak
shape and enthalpy. Thus, these minor changes in the
component in the mixture and may not necessarily indicate
potential incompatibility. ERL100 and ES100 are beadlets
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 RESEARCH ARTICLE

1,730
1,729
1,728
1,727

105

%T
%T
F
90

75
E

60
D

45

30
C
2877.79
2981.95

15
2563.40

0
.51

4000 3500 3000 2500 2000 1750 1500 1250 1000 750 500 4000 3500 3000 2500 2000 1750 1500 1250 1000 750 500
Dichloramine-T 1/cm Dichloramine-T 1/cm

Figure 1: FTIR spectra of pure drug Figure 2: FTIR spectras of binary mixture of drug with C- Eud
RLPO, D- Eud RL100, E- Eud RSPO, F- Eud RS100

Figure 3: DSC curves of binary drug and binary mixtures Figure 4: TG curves of drug and binary mixtures

or granules made from them. The thermograms of binary 50-85%. The microspheres prepared with combination of
mixture of drug with eudragits obtained from DSC and TG eudragit shown markedly buoyant than the individual ones.
are shown in Figure 3, 4. In the DSC curve of physical The bulk density was also determined to ensure the
mixture of drug and Polymethacrylates, the original floating of system in gastric environment. The criteria is
endothermic peak of the drug was well preserved. that the system whose density will be less than one floats in
the stomach. Hence bulk density was studied for all the
3. Percentage Yield and Drug Entrapment Efficiency formulations and the results showed that bulk density of all
The microspheres were evaluated for the following the formulations were less than one. This indicates that all
parameters such as: % yield, drug content entrapment the microspheres may float in the gastric environment. The
efficiency and particle size. The percentage yield of all the results are tabulated in the Table 2.
formulations was 63-88%. The microspheres prepared
from combined eudragits gave better yield and was about 5. Particle Size Analysis and Scanning Electron
73.66 and 74.5% respectively. The percentage yield was Microscopical Studies
increased by collecting microspheres after centrifugation. The SEM analysis showed that microspheres formed were
The drug entrapment efficiency studies showed that the discrete, spherical and uniform. The roughness on the
value was in the range of 68.64-87.84%. The percentage surface showed the adherence of crystalline drug on its
yield and drug entrapment efficiency increased with surface. The particle size analysis indicated that the
increase in drug-polymer ratio. This was due to the fact the microspheres were in the particle range of 27.92-79.47m.
increase in ratio increased the microsphere size that
entrapped more drug. The results are shown on the Table 1. 6. Process Optimization
The process parameters such as type of polymer, drug
4. Buoyancy Percentage and Bulk Density polymer ratio, percentage of surfactant used for
Buoyancy percentage was calculated to study the floating emulsification and stirring speed were varied
ability of the prepared microspheres. The microspheres appropriately and the process was optimized. Among the
those that float in the stomach reduces the emptying of Eudragit RL and RS, RS gave different results than that of
system into intestine. The buoyancy percentage was about RL as well the combinations. The results of different

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 RESEARCH ARTICLE

Table 1: Percentage Yield And Entrapment Efficiency of Different Formulations

Drug-polymer Theoretical Drug Actual Drug Content Entrapment Efficiency

Formulation Code % Yield
Ratio Content (mg) (mg) (%)
ER1 63.3 17.160.11 68.64
ER2 67.5 17.310.185 69.24
ER3 69.67 18.460.038 73.84
1:1
ER4 65.8 17.900.059 71.6
ER5 73.66 19.040.41 76.16
ER6 74.45 18.210.56 72.84
25
ER7 82.84 21.960.121 87.84
ER8 84.50 20.890.189 83.56
ER9 88.56 20.830.139 83.32
1:2
ER10 88.24 21.630.185 86.52
ER11 85.74 23.050.083 92.2
ER12 86.84 23.550.038 94.2

Table 2: Bulk Density and Buoyancy Percentage of Different Formulations

Bulk Density Bulk Density

Formula Code Buoyancy % Formula Code Buoyancy %
(g/cm3) (g/cm3)
ER1 0.580.09 50.230.139 ER7 0.4270.002 77.760.436
ER2 0.580.08 55.400.252 ER8 0.4320.007 70.810.397
ER3 0.670.08 51.580.265 ER9 0.440.005 70.420.420
ER4 0.660.003 58.060.241 ER10 0.4370.006 75.620.212
ER5 0.720.02 81.000.280 ER11 0.4200.008 84.850.270
ER6 0.550.007 77.450.120 ER12 0.440.009 81.600.342

Table 3: Results of Process Optimization Variables

Optimization Drug Content Entrapment Efficiency Average Microsphere Size

% Yield
Parameters (mg) (%) (m)
Drug-Polymer ratio
1:1 74.45 18.210.56 72.84 30.242.06
1:2 86.84 23.550.38 94.2 62.483.09
% of surfactant
0.5 64.76 12.830.357 51.32 60.721.786
1 74.45 18.210.56 72.84 30.242.06
1.5 63.36 14.490.179 57.96 Not formed properly
Stirring speed (rpm)
500 48.32 14.630.356 58.52 50.731.625
1000 74.45 18.210.56 72.84 30.242.06
1500 52.9 12.960.598 51.84 25.322.786

parameters are shown in the Table 3. As the drug polymer
ratio was increased, yield, entrapment efficiency and
particle size also increased. These changes might be due to
increase in concentration of polymer increased viscosity
thereby formed larger microspheres. Thus these larger
microspheres entrapped drug in large amount. When the
concentration of surfactant was either increased or
decreased from 1% the yield was reduced. This might be
due to insufficiency of surfactant for emulsification or
excess of surfactant might have solubilized the system. The
average microsphere size was inversely proportional to
surfactant concentration as well as the stirring speed. The
increase or decrease in stirring speed also reduced the
yield.
7. In-vitro Release Studies
The in-vitro release of microspheres was performed in
simulated gastric fluid, 0.1N HCl. The results of different
formulations are shown in the Figure 7, 8. The results
showed that the prepared microspheres released drug upto
24hrs. In contrast to the release of RL microspheres, RS
microspheres showed slightly slower release. This was due
to the structural difference between them as well because
of the fact that RL is highly permeable whereas RS is less
permeable. The variation in drug polymer ratio also varied
the release.
8. Release Order/Mechanism Studies
The dissolution profiles were fitted into different models
and the order and mechanism of release was studied. The
correlation coefficient values were found to be
approximately one for first order, Higuchi and Hixson
Crowell model. This explained that release followed first
order and mechanism was by dissolution and diffusion.
CONCLUSION
Thus the gastro retentive microspheres whose density less
than one was prepared using emulsion-solvent evaporation

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 RESEARCH ARTICLE

Figure 5: Average particle diameters of different formulations

Figure 6: SEM images of formulation ER6

120

100
% cumulative drug release

80 ER1
ER2
60
ER3
40 ER4
ER5
20
ER6
0
0 5 10 15 20 25 30
Time (h)
Figure 7: In vitro release profiles of microspheres of 1:1 ratio
Figure 8: In vitro release profiles of microspheres of 1:2 ratio

method. The buoyancy percentage and bulk density
determination studies showed that these systems can be
retained in the stomach for longer period. The
microspheres prepared by eudragits showed slow and
prolonged release of drug upto 24h. These optimized
microspheres could be incorporated suitably into most
acceptable dosage forms such as tablets and capsules.
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Acknowledgments
The authors are thankful to the central instrumentation
facility of IIT Roorkee, IIT Delhi and IIT Kharagpur for
evaluation of the samples. We are also thankful to Degussa
India Pvt. Ltd. Mumbai for providing gift sample of polymers
necessary for the study.
Cite this article as: C Nithya Shanthi, Rakesh Gupta,
Arun Kumar Mahato. Preparation and In-vitro Evaluation
of Captopril Loaded Microspheres for Gastroretention.
Inventi Rapid: Pharm Tech, 2013(3): 1-6, 2013.
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