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Formulation and Evaluation of Mucoadhesive Microcapsules of Diltiazem HCl and Diclofenac Sodium
by Orifice-Ionic Gelation Method

T. M. Rasala*, V.V.Kale, M. R. Bhalekar, J. G. Avari

Department of Pharmaceutical Sciences, R. T. M. Nagpur University,

Nagpur-440033. India.
E-mail:
Corresponding Author : Mr Tirupati Rasala Email address: tirupati_rasala@yahoo.co.in

Abstract
Purpose: The aim of investigation was to formulate and evaluate microcapsules of freely
soluble drug (diltiazem HCl) and sparingly soluble drug (diclofenac sodium). Methods: In the
present work, microcapsules of diltiazem HCl and diclofenac sodium were prepared by orifice-
ionic gelation technique using mucoadhesive polymers HPMCK 15 and Carbopol 934 in
combination with sodium alginate. The formulated microcapsules of diltiazem HCl and diclofenac
sodium were evaluated for the following parameters viz. Particle size, entrapment efficiency, In-
vitro drug release and % mucoadhesive strength. FT-IR and SEM were used to characterize
microcapsules.
It was observed that the evaluated parameters for both the drugs were within the
desired limits. However, the entrapment efficiency was found to differ for diltiazem HCl (15%)
and diclofenac sodium (69%). The drug release from the microcapsules were found to be slow and
spread over extended period of time, drug release depends on the percent of coat material, wall
thickness and size of microcapsule. Microcapsule with a coat comprised sodium alginate and
HPMC, carbapol exhibited good mucoadhesive properties as observed in in-vitro wash-off test.
From the present investigation, it was concluded that the orifice-ionic gelation method is more
suitable to entrap sparingly soluble drug than freely water soluble drugs.

Keywords: Mucoadhesive, Microcapsules, orifice-ionic gelation method, DDS, DEE,

HPMCK15, Carbapol 934, Sodium alginate.
Vol 1: 1 (2010) IJPI’S Journal Of Pharmaceutics And Cosmetology

1. INTRODUCTION

Oral bioavailability of certain drug can be limited by the residence time of the pharmaceutical formulations in
the upper gastrointestinal tract. Gastric emptying plays an important role in the dynamics of drug absorption and can
lead to variable and unpredictable availability. The ability to maintain an oral delivery system at the target absorption
location for an extended period of time has great appeal for treatment of both local conditions as well as for sustained
systemic absorption. Several strategies have been proposed to modify the GI transit of oral pharmaceutical
formulations such as floating, high-density system, expandable, swelling system etc. Mucoadhesive drug delivery is
one of the approaches to design a formulation, which can adhere to the lining of the stomach, thus retaining the drug at
the target absorption site for a prolonged period. This approach involves the use of bioadhesive polymers, which can
adhere to the epithelial surface in the stomach (1, 2).
Drug delivery systems (DDS) that can precisely control the release rates or target drugs to a specific body site
had an enormous impact on the healthcare system. Carrier technology offers an intelligent approach for drug delivery
by coupling the drug to a carrier particle such as microspheres, nanoparticles, liposomes, etc. which modulates the
release and absorption characteristics of the drug. Bioadhesive microspheres include microparticles and microcapsules
(having a core of the drug) of 1–1000µm in diameter and consisting either entirely of a bioadhesive polymer or having
an outer coating of it, respectively. Microparticles constitute an important part of these particulate DDS by virtue of
their small size and efficient carrier characteristics. However, the success of these novel DDS is limited due to their
short residence time at the site of absorption. It would, therefore, be advantageous to have means for providing an
intimate contact of the DDS with the absorbing membranes. It can be achieved by coupling bioadhesion characteristics
to microparticle and developing novel delivery systems referred to as “bioadhesive microparticle” (1,3).

2. MATERIAL AND METHOD

Materials:
Diltiazem HCl and Diclofenac sodium were generous gift sample from ZIM Labs (Nagpur). Sodium alginate
was gift sample from TIC Gums USA, HPMC K15 (Colorcon Asia PVT, LTD. Goa India), Carbopol (Noveon USA)
and all other chemicals used were of analytical grade.
Methods:
Preparation of Mucoadhesive Microcapsule of Diltiazem HCl and Diclofenac Sodium(4,5,6).
Microcapsules were prepared by orifice-ionic gelation method. Sodium alginate and mucoadhesive polymer
such as HPMC K15 and Carbopol 934 were dissolved in purified water to form a homogeneous polymer solution. The
core material as fine powder was passed through mesh no. 120, added to the polymer solution and mixed to form a
smooth viscous dispersion. This dispersion was added drop wise into 10%w/v CaCl 2 solution through a syringe with a
needle of diameter 0.55mm. The added droplets were retained in CaCl2 solution and allowed to cure for 20 minutes at
200 rpm to produce spherical rigid microcapsules. The microcapsules were collected and dried in an oven at a
temperature 450C for 12 h.
Table1: Core coat ratio and coating composition of microcapsules
Batch code Core (w/w) Coat
Coat (w/v) Ratio Composition (w/v)
MH1 1:1 Na Alginate: HPMCK15 (1:1)
MH2 1:2 Na Alginate: HPMCK15 (2:1)
MH3 1:3 Na Alginate: HPMCK15 (3:1)
MC1 1:1 Na Alginate: Carbopol 934 (1:1)
MC2 1:2 Na Alginate: Carbopol 934 (2:1)
MC3 1:3 Na Alginate: Carbopol 934 (3:1)

T. M. Rasala et al Page 2
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Estimation of Diltiazem HCl and Diclofenac Sodium

Diltiazem and Diclofenac were estimated spectrophotometrically at 236nm and 276nm respectively using
shimadzu 1601(Japan) spectrophotometer.

Size Analysis and Percentage Encapsulation Efficiency

The microcapsules size was determined by using optical microscopy method. The entrapment efficiency was
calculated by sonicating 100 mg of microcapsules in 100 ml of pH 6.8 buffer for a period of 2 hours to facilitate the
complete dissolution of the microcapsules. The drug released was spectrophotometrically analysed. The entrapment
efficiency in percentage was calculated as per the following formula.
Practical drug content
DEE   100
Theoretical drug content
Scanning Electron Microscopic Analysis
The morphology and the surface texture of the microcapsules were studied using Scanning electron
microscopy (SEM).
In-vitro drug release studies
The Highest encapsulation efficiency of Diltiazem HCl was found to be 15%; so there is no significance to
perform in-vitro dissolution study.
In vitro release rate studies were carried out using USP dissolution apparatus Type II (Veego Scientific, 6 ST).
Simulated gastric fluid of pH 1.2 with SLS (1%W/V) was used as dissolution medium (900 ml) and was maintained at
37oC ± 0.5oC. The paddle speed was controlled at 75 rpm. Aliquots of 10 ml were withdrawn at different time intervals
up to 12 h and a 10 ml of fresh medium was added to replace the sample that was withdrawn. Drug content of the
microcapsule was determined by UV spectroscopy at 276 nm, after suitable dilution of the samples. Dissolution studies
were performed three times and the mean values were taken.
Measurement of Percent mucoadhesive Strength (5, 6, 9)
The mucoadhesive properties of the microcapsules were evaluated by in-vitro wash off test as reported by Lehr
et al. A 1cm by 1cm piece of rat stomach mucosa was tied onto a glass slide (3 inch by 1 inch) using thread.
Microcapsules were spread (50) onto the wet, rinsed, tissue specimen and the prepared slide was hung onto one of the
groves of a USP tablet disintegrating test apparatus. The disintegrating test apparatus was operated such that the tissue
specimen was given regular up and down movements in a beaker containing 1.2 pH and pH 6.8 buffer solution. At the
end of every hour the number of microcapsules still adhering onto tissue was counted.

3. RESULTS AND DISCUSSION

Morphological characteristics of microcapsules:
The mucoadhesive microcapsules of Diltiazem HCl and diclofenac sodium prepared by orifice-ionic gelation
method were found to be discret, spherical, free flowing. The microcapsules were uniform in size, with size range of
806.9 μ to 927.7 μ and 851.0 μ to 918.3 respectively. The SEM Photograph indicated that the microcapsules were
spherical and completely covered the coat polymer (Figure 2). The microencapsulation efficiency was in the range of
6.7-15.68 % and 50.09-69.77% respectively.

T. M. Rasala et al Page 3
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Table 2: Values of physical parameters and drug content for mucoadhesive microcapsule of diltiazem HCl and
diclofenac sodium prepared by orifice- ionic gelation method

Batch code Particle size Drug content (Diltiazem) of % % Microencapsulation

( Mean+ SD)µm microcapsules Efficiency
Theoretical Practical
MH1 806.95± 5.51 50.0 3.35 6.7
MH2 844.45 ± 4.43 33.33 3.71 11.13
MH3 886.56 ± 5.44 25.0 2.71 10.80
MC1 901.13 ± 8.39 50.0 6.3 12.60
MC2 921.03 ± 7.67 33.33 5.61 16.83
MC3 927.73 ± 8.49 25.0 3.92 15.68

Batch code Particle size Drug content (Diclofenac) % Microencapsulation

(Mean+ SD)µm of % microcapsules Efficiency
Theoretical Practical
MH1 851.2 ± 5.84 50.0 25.04 50.09
MH2 885.9 ± 4.86 33.33 20.12 60.38
MH3 914.6 ± 6.66 25.0 14.76 59.04
MC1 882.6 ± 9.40 50.0 30.52 61.05
MC2 948.9 ± 8.38 33.33 23.68 71.05
MC3 953.3 ± 7.67 25.0 3.92 69.77

80
DICLOFENAC
% Entrapment efficiency

DILTIAZEM
60

40

20

0
MH1 MH2 MH3 MC1 MC2 MC3
Batch Code

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Vol 1: 1 (2010) IJPI’S Journal Of Pharmaceutics And Cosmetology

In-vitro release of diclofenac sodium

The encapsulation efficiency of diltiazem HCl was very low (6.7-15.68 %) so, there is no in-vitro dissolution
data for diltiazem HCl mucoadhesive microcapsules.
The in-vitro dissolution studies of the formulated mucoadhesive Diclofenac sodium microcapsules were
carried out in simulated gastric fluid(0.1M HCL, pH 1.2 with SLS 1% ) and simulated intestinal fluid( phosphate
buffer 6.8) using USP type II (paddle) apparatus in 900ml of pH 1.2 pH and 6.8 buffer for the 12 hours. The batch
MH1 has shown 98.74% drug release in 10 hr and MH3 (96.36%) in 12 hr. Batch MC2 and MC3 released 97.41% and
91.90 % drug release in 12 hr respectively. The Diclofenac release from the microcapsules was slow and depended on
the composition of coat. Microcapsules of alginate-HPMC K15 gave relatively fast release as compared to alginate-
carbapol 934. The diclofenac release from microcapsules MH3 and MC2 was slow and extended over a period of 12 h.
so, MH3 and MC2 found suitable for oral sustained release (figure 3, 4).

Figure 3: Cumulative % drug release of diclofenac sodium in PH 1.2 with SLS 1%

120
MH1
% cumulative drug release

100 MH2
80 MH3
60 MC1
MC2
40
MC3
20
0
0 5 10 15
Time (hrs)

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Vol 1: 1 (2010) IJPI’S Journal Of Pharmaceutics And Cosmetology

% cumulative drug release

120
MH1
100
MH2
80
MH3
60
MC1
40 MC2

20 MC3

0
0 5 10

Time (h)

Figure 4: Cumulative % drug release of diclofenac sodium in PH 6.8 buffer Drug release models

To describe the kinetics of the drug release from the microcapsules, mathematical models such as zero-order,
first order, Higuchi, Hixon-crowell, Korsmeyer-Peppas models were used. The criterion for selecting the most
appropriate model was chosen on the basis of the goodness-or fit test.
Table 3: Mechanism of drug release from optimized formulations

r value
Models n value
MH3 MC2 MC3
Korsmeyer-peppas 0.9975 0.9965 0.9975 0.9368
Zero order 0.9974 0.9962 0.9977 0.8702

On the application of different release models, it was found that the optimized formulation of diltiazem and
diclofenac sodium (batch MH3 and MC2) follows the Korsmeyer-peppas model. The value of „n‟ was found to be
0.9368 which indicates that it follows non-fickian diffusion. This observation coincides with swelling study i.e. drug
release was controlled by an intermediate of both diffusion and erosion mechanism. The formulation batch MC3
follows the zero order release which show constant drug release rate with time.

Figure 5: Mucoadhesion behaviour of Diltiazem HCl Figure 6: Mucoadhesion behaviour of Diltiazem HCl
microcapsules in PH 1.2 microcapsule in 6.8 buffer

T. M. Rasala et al Page 6
Figure 7: Mucoadhesion behaviour of diclofenac Figure 8: Mucoadhesion behaviour of diclofenac
sodium microcapsules in pH 1.2 sodium microcapsule in 6.8 buffer

4. CONCLUSION

Diltiazem and diclofenac sodium loaded mucoadhesive microcapsule were prepared by orifice-ionic gelation
method. The method employed gave, discrete, spherical, free flowing (sodium alginate and mucoadhesive polymers)
microcapsules, it was observed that in case of diltiazem HCl, the entrapment efficiency was very poor (≤ 15%) due to
diffusion of the drug into the gelation medium because of the free solubility of the drug in the aqueous external ionic
gelation medium. Whereas the entrapment of diclofenac sodium is relatively higher due to its sparingly soluble nature
of drug in aqueous media (50.09 to 69.77%), from the result it was concluded that orifice ionic gelation method
suitable to entrap sparingly soluble drug than freely soluble drug.
The drug releases from the microcapsules were found to be slow and spread over extended period of time. The
wash-off was faster at simulated intestinal pH (6.8) than that at simulated gastric pH (1.2). The solubility, hydration
and mucoadhesivity of the polymers depend on the pH of the medium. The rapid wash-off observed at simulated
intestinal pH may be due to the ionization of carboxyl acid group and other functional groups in the polymers, which
increase their solubility and reduce adhesive strength. The results of the wash-off test indicated that the microcapsules
had fairly good mucoadhesive properties. The mucoadhesive microcapsules are thus suitable for oral sustained release
of dosage form.

5. ACKNOWLEDGMENTS

The authors are very much thankful to ZIM Lab, Colorcon, Noveon and TIC gums for providing gift sample and
also to UGC for providing financial assistance.

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