Influence of Solvents on Entrapment
Efficiency and Drug Release rate of Propranolol Hydrochloride from Ethyl Cellulose
Microcapsules
B. Ashok Reddy*, S. Satish, G. Sankara,
Adithya Sarma and V. Sai Kishore
Bapatla College of Pharmacy,
Bapatla -522101
*Corresponding Author E-mail: adityasarma893@gmail.com
ABSTRACT:
The influence of solubility of drug in the
dispersed phase (Acetone: Water Mixtures) employed in the preparation on the
entrapment efficiency and drug release from ethyl cellulose microcapsules was
studied. Propranolol hydrochloride was used as core and microcapsules were
prepared by an emulsion solvent evaporation method. All the solvents gave discrete,
large sized, free flowing spherical microcapsules. The microcapsules were
evaluated for size analysis, drug content, microencapsulation efficiency, wall
thickness, drug release characteristics, influence of solvent employed on
entrapment efficiency and Propranolol hydrochloride release from microcapsules,
surface characteristics. Propranolol hydrochloride release from the
microcapsules, followed zero order kinetics and influenced by the size of the
microcapsules and the solvent employed in their preparation. The Propranolol
hydrochloride release rate from the microcapsules was found to be decreased
with increased proportion of water in the dispersed phase. Among the solvents
employed acetone: water mixture (92.5% v/v : 7.5% v/v) was found to be more suitable
for slow release of Propranolol hydrochloride from ethyl cellulose
microcapsules.
KEYWORDS: Propranolol hydrochloride,
microcapsules, emulsion solvent evaporation, entrapment efficiency
INTRODUCTION:
Though ethyl cellulose microcapsules have
been extensively studied1-3 for controlled release, no attempts were
made to study the influence of solubility of the drug in the dispersed phase on
entrapment efficiency and on drug release from the microcapsules. In a few
reports4,5 the permeability coefficient of ethyl cellulose
microcapsules prepared by different coacervation methods and relationship
between physical properties such as size and density on the permeability and
drug release from the microcapsules was studied. The solvent employed in the
preparation of microcapsules is likely to influence both the entrapment
efficiency and drug release from the microcapsules. In the present study the
influence of dispersed phase employed in the preparation on entrapment
efficiency and drug release from the ethyl cellulose microcapsules was studied.
Propranolol hydrochloride6, which requires oral controlled release
because of its short biological half-life of 3.9 h and are either given more
frequently or are for formulated in various slow release preparations to permit
once daily dosing was used as core in the micro encapsulation.
MATERIALS AND METHODS:
Ethyl cellulose with a viscosity of 14 CPS
(5% w/w solution in 80:20 toluene:ethanol by weight at 25O) and
containing not less than 46.5% ethoxyl groups was provided by S. D. Fine
Chemicals, Mumbai. Propranolol hydrochloride IP was provided by Natco Pharmaceuticals,
Hyderabad. All solvents and reagents used were of AR grade and procured from
commercial sources. The spectrophotometer used was an Elico UV/Vis model.
Preparation of microcapsules:
Ethyl cellulose microcapsules of
Propranolol hydrochloride were prepared by an emulsion solvent evaporation
method employing, acetone: water mixtures (97.5%: 2.5%, 95%: 5% and 92.5%: 7.5%
v/v) with coat: core ratio 3:7. The polymer (1.5 g) was dissolved in the
polymer solvent (25 ml) to form a homogeneous polymer solution. Core material,
propranolol hydrochloride (1.4g) was added to the polymer solution (10 ml) and
mixed thoroughly. The resulting mixture was then added in a thin stream to 100
ml of heavy liquid paraffin contained in a 450 ml beaker while stirring at 200
rpm to emulsify the added droplets. A Remi medium duty stirrer with speedometer
(Model RQT 124) was used for stirring. Stirring was continued to disperse the
added mixture as fine droplets. The solvent was then removed by evaporation at
RT (28°) to produce spherical microcapsules. The microcapsules were collected
by decantation and washed with petroleum ether. The product was then dried at
45° for 4 h to obtain discrete microcapsules.
Characterization of microcapsules:
For size distribution analysis, different sizes in a batch were
separated by sieving, using a range of standard sieves. The amounts retained on
different sieves were weighed. Microencapsulation efficiency was calculated
using the formula, microencapsulation efficiency = (estimated percent drug
content/theoretical percent drug content)X100. The microencapsulation
efficiency values are reported in Table 1. Wall thickness of microcapsules was
determined by using the equation7, h = 
(1 P)d1/3[Pd2
+(1-P)d1], where h is the wall thickness; r is the arithmetic mean
radius of the microcapsules; d1 is the density of the core material;
d2 is the density of the coat material; P is the proportion of
medicament in the microcapsules. The wall thickness of different microcapsules
is reported in Table 1.
Estimation of Propranolol hydrochloride:
Propranolol hydrochloride content in the
microcapsules was calculated by an UV spectrophotometric method based on the
measurement of absorbance at 290 nm8. The method was validated for
linearity, accuracy and precision. The method obeyed Beers law in the
concentration range 0-10 g/ml. When a standard drug solution assayed
repeatedly (n=6), the mean error (accuracy) and relative standard deviation
(precision) were found to be 0.8% and 1.2%, respectively. A sample of
microcapsules equivalent to 80 mg of Propranolol hydrochloride were dissolved
in 25 ml acetone: water (1:1) and the volume was adjusted to 100 ml using
water. The solution was suitably diluted and the absorbance was measured at 290
nm. The amount of Propranolol hydrochloride estimated from different samples
and sizes are depicted in Table 1.
Drug release studies:
Release of Propranolol hydrochloride from
the microcapsules of size 22/30 and 30/44 was studied in water (900 ml) using
an USP XXXIII dissolution rate test apparatus (M/s. Campbell Electronics,
Mumbai) with a paddle stirrer at 100 rpm and at 37±0.5°. A sample of
microcapsules equivalent to 80 mg of Propranolol hydrochloride were used in
each test. Samples were withdrawn through a filter (0.45 ) at different
time intervals and were assayed at 290 nm for Propranolol hydrochloride using
an Elico double beam UV spectrophotometer. The drug release experiments were
conducted in triplicate. The dissolution profiles are shown in fig. 1.
RESULTS AND DISCUSSION:
Ethyl cellulose microcapsules containing
Propranolol hydrochloride were prepared by an emulsion solvent evaporation
method employing acetone: water mixtures as dispersed media. Propranolol
hydrochloride was not found to be dispersible in acetone. To achieve
dispersibility, co solvent water was tried at various concentrations.
Preliminary experiments indicated that the concentration of water exceeding
7.5% v/v caused the coacervation of the polymer ethyl cellulose. Hence water
was incorporated as a co solvent in the preparation of all microcapsules at a
concentration ranging from 2.5% v/v to 7.5% v/v. All the microcapsules prepared
were found to be discrete, spherical and free flowing. The sizes could be
separated and a more uniform size of microcapsules could readily be obtained.
The size analysis of different microcapsules showed that generally about 8%,
38% and 34% were in the size range of 16+22, 22+30 and 30+44 mesh size
respectively. A lognormal size distribution of the microcapsules was observed
in all the batches prepared. The microencapsulating efficiency was found to be
increased by increasing the proportion of water up to 5% and then the micro
encapsulation efficiency was not changed with the alterations in the dispersed
phase. Low CV (<2.0) in the percent drug content indicated uniformity of
drug content in each batch of microcapsules (Table 1). Drug content of the
microcapsules was found to be the same in different sieve fractions.
Propranolol hydrochloride release from the
pure drug and from the microcapsules was studied in water for a period of 12h.
Propranolol hydrochloride release from the pure drug was found to be within 5
min where as Propranolol hydrochloride release from the microcapsules was slow
and spread over an extended period of time.
TABLE 1: Propranolol Hydrochloride Content,
Microencapsulation Efficiency, Wall Thickness and Release Rate Constant of
Ethyl Cellulose Microcapsules
|
Parameter
|
Solvent employed
|
|
Acetone: water
(97.5%:2.5% v/v)
|
Acetone: water
(95%:5% v/v)
|
Acetone: water
(92.5%:7.5% v/v)
|
|
22/30 size(F1)
|
30/44
size (F2)
|
22/30 size(F3)
|
30/44 size(F4)
|
22/30
Size (F5)
|
30/44
Size (F6)
|
|
Percent drug content
|
62.87
|
61.66
|
65.44
|
64.86
|
67.32
|
65.54
|
|
Micro encapsulation efficiency (%)
|
89.81
|
88.08
|
93.48
|
92.65
|
96.17
|
93.62
|
|
Wall thickness ()
|
85.26
|
58.63
|
85.34
|
59.42
|
85.17
|
59.68
|
Fig. 1: Release Profiles of Propranolol
Hydrochloride from Ethyl Cellulose Microcapsules.
(♦) F1 - Microcapsules
having 22/30 size formulated with acetone : water(97.5% :2.5%v/v)
(¡) F2 - Microcapsules
having 30/44 size formulated with acetone : water(97.5% :2.5%v/v)
() F3 - Microcapsules having
22/30 size formulated with acetone : water(95% :5%v/v)
(Í) F4 - Microcapsules having
30/44 size formulated with acetone : water (95% :5%v/v)
(à) F5 - Microcapsules having
22/30 size formulated with acetone : water(97.5% :2.5%v/v)
(Å) F6 - microcapsules having
30/44 size formulated with acetone : water(97.5% :2.5%v/v)
TABLE 2 :Correlation Coefficient (R) Values
Of Ethyl cellulose Microcapsules
|
Formulation
|
Correlation Coefficient (R) Values
|
|
ZeroOrder Model
|
First Order Model
|
Higuchi Model
|
Peppas Model
|
|
F1
|
0.9868
|
0.9476
|
0.9754
|
0.9948
|
|
F2
|
0.9779
|
0.8988
|
0.97847
|
0.9966
|
|
F3
|
0.9630
|
0.8878
|
0.9834
|
0.9969
|
|
F4
|
0.9696
|
0.93228
|
0.9835
|
0.9986
|
|
F5
|
0.9614
|
0.9038
|
0.9818
|
0.9998
|
|
F6
|
0.9645
|
0.8986
|
0.9826
|
0.9996
|
TABLE 3: Dissolution Parameters of Ethyl
Cellulose Microcapsules
FORMULATIONS
|
DISSOLUTION PARAMETERS
|
|
DIFFUSION EXPONENT (n)
|
ZERO ORDER RATE CONSTANT
(mg/h)
|
T50 (h)
|
T90 (h)
|
F1
|
0.5656
|
6.75
|
5.18
|
12.16
|
|
F2
|
0.626
|
7.61
|
4.59
|
13.72
|
|
F3
|
0.6116
|
6.56
|
5.33
|
11.81
|
F4
|
0.5942
|
6.86
|
5.10
|
12.35
|
|
F5
|
0.5912
|
5.74
|
6.09
|
10.34
|
|
F6
|
05876
|
5.82
|
6.01
|
10.48
|
To ascertain the mechanism of drug release,
the dissolution data was analyzed by zero order, first order, and higuchi and
peppas equations. The correlation coefficient values (r) were reported in Table
2. These values revealed that the dissolution profile follows zero order
kinetics and the mechanism of drug release was governed by peppas model. The n
values are found to be more than 0.5 (n>0.5) indicted that the drug release
was predominantly controlled by non fickian diffusion9. The time
required getting 50% drug release (T50) and 90% drug release (T90)
was calculated and reported in Table 3. The zero order release rate constants
are reported in Table 3.
The drug release depended on size of the microcapsules and the
solvent employed for the polymer in their preparation (fig. 1). The solvent
employed has significant influence on Propranolol hydrochloride release from
the microcapsules in both the sizes studied. Solvents may influence the porous
structure of the microcapsule in two ways, (i) by their high volatility and
hence rapid desolation of the coating material to highly porous structure or
(ii) by solvent interaction with polymer chains to influence polymer -polymer
cohesion. In the present study, the first factor may be considered important
since the less volatile solvent acetone: water (92.5%:7.5% v/v) produced low
permeable microcapsules when compared to other volatile solvents. Large sized
spherical microcapsules of ethyl cellulose containing Propranolol hydrochloride
as core could be prepared by an emulsion solvent evaporation method. Drug
release from the microcapsules can be controlled by the size of the microcapsules
and the solvent employed in the preparation of microcapsules. Acetone : water
(92.5% : 7.5% v/v) was found to be a promising solvent for preparing ethyl
cellulose microcapsules for controlled release as slow, controlled and complete
release of Propranolol hydrochloride over a period of 12h was observed with
these microcapsules.
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