Vol.1, Issue: 1
December: 2012
ISSN: 2320-0901
International Journal for Research in Management and Pharmacy (IJRMP)
Research Paper- Pharmacy
PREPARATION AND EVALUATION OF ETHYL
CELLULOSE MICROSPHERES PREPARED
BY EMULSIFICATION - SOLVENT
EVAPORATION METHOD
Balkrushna Patel 1, Vidhi Modi 1, Komal Patel 1, Manisha Patel 1
1
K. J. College Of Pharmacy, Vadasma
ABSTRACT
The study is concerned with the development of ethyl cellulose microspheres by the o/w
emulsification and solvent evaporation method in the presence of tween 80 as an emulsifying
agent. The influence of process parameters such as solvent mixture, composition,
concentration of the emulsifying agent and speed of stirring has been examined. The
microspheres have been analyzed for their size, drug loading capacity and drug release study.
Spherical and smooth surfaced microspheres with desired encapsulation efficiencies were
obtained. Use of acetone in the oil phase drastically reduced the particle size. Slow drug
release from microspheres observed up to 8 h. An optimization procedure was employed to
investigate and identify the key parameters affecting the properties of the microspheres.
Key words: Ethyl Cellulose, Tween 80, Optimization, Emulsifying agent, Ethyl Acetate,
Entrapment Efficacy, Aspirin
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Vol.1, Issue: 1
December: 2012
ISSN: 2320-0901
International Journal for Research in Management and Pharmacy (IJRMP)
INTRODUCTION
Microspheres are one of the multiparticulate drug delivery systems and are prepared to obtain
prolonged (or) controlled drug delivery, to improve bioavailability or stability and to target
drug to specific sites. Microspheres can be defined as solid, approximately spherical particles
ranging from 1 to 1000µm, containing dispersed drug in either solution (or) microcrystalline
form.1, 2 Ethyl cellulose is non-biodegradable, bio-compatible, non-toxic natural polymer and
widely used in oral and topical formulation.3 The microspheres can be produced by several
methods utilizing emulsion system (o/w, w/o, o/w/o and w/o/w). The common emulsion
system used oil-in-water (o/w), with microspheres being produced by the emulsion solvent
evaporation method. This relatively simple method enables the entrapment of a wide range of
hydrophobic drugs.4 The main object of present study was to investigate the possibility of
obtaining sustained release aspirin microsphere by using different concentration of ethyl
cellulose, different composition of solvent mixture, different concentration of emulsifying
agent and different stirring rate. Aspirin used as a model drug for the present investigation.
MATERIALS
Aspirin as a model drug, Ethyl Cellulose as a polymer, Tween80 as an Emulsifying agent,
Acetone and Ethyl Acetate as a solvent were used for present investigation. All the materials
were provided by K. J. College of Pharmacy, Vadasma.
METHODS
Preparation of Microspheres 5, 6, 7
Aspirin microspheres were prepared based on o/w emulsion solvent evaporation technique by
using ethyl cellulose as a polymer. Different formulations were prepared by dissolving the
polymer and the drug in ethyl acetate (oil phase) and acetone as specified in Table 1. This
solution was poured slowly in the 500 ml of distilled water (aqueous phase) containing tween
80 as the emulsifying agent as specified in Table 1 with continuous stirring on propeller
stirrer (Remi, India). The resultant mixture was emulsified at speed mentioned in Table 1 for
4 h. The dispersed drug and polymer solution was immediately transformed into fine
droplets, which subsequently solidified into rigid microspheres due to the solvent
evaporation. The particles were collected by filtration, washed to remove excess oil by
distilled water and dried in hot air oven at 60˚C and characterized.
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Vol.1, Issue: 1
December: 2012
ISSN: 2320-0901
International Journal for Research in Management and Pharmacy (IJRMP)
Physicochemical Characterization of Microsphere 5, 6
Percentage yield
The dried microspheres were weighed and percentage yield of the prepared microspheres was
calculated by using the following formula,
Percentage yield = {The weight of microspheres / (The weight of polymer + drug)}*100
Carr’s index
It was measure by using following formula,
Carr’s Index = {(Vb –Vt) / Vb}* 100
Where, Vb and Vt are the bulk volume and tapped volume respectively.
Angle of Repose
Angle of repose of the microspheres, is the maximum angle possible between the surface of
the pile of microspheres and the horizontal plane, was obtained by fixed funnel method using
the formula;
Angle of Repose ( ) = tan−1 (h/ )
Where, h is height and d is the diameter of the microsphere pile.
Particle Size Analysis
Particle size of the microspheres was determined by optical microscopy. The eye piece
micrometer was calibrated with the help of a stage micrometer. The particle diameters of
more than 50 microspheres were measured randomly. The average particle size was
determined by using Edmondson’s equation.
D=∑
nd / ∑ n
Where, n = Number of microspheres checked; D = Mean of the size range
Drug Entrapment Efficiency 8, 10
Microspheres were crushed using a glass mortar by pestle and equivalent to 5 mg of aspirin
weighed. These microspheres were suspended in 25 ml of phosphate buffer pH 6.8. After 24
h, the solution was filtered; 1 ml of the filtrate was pipette out and diluted to 10 ml and
analyzed for the drug content using UV Visible1spectrophotometer at 265 nm. The drug
entrapment efficiency was calculated using the following formula:
% Drug entrapment efficiency = (Practical Drug content / Theoretical Drug content) X100
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Vol.1, Issue: 1
December: 2012
ISSN: 2320-0901
International Journal for Research in Management and Pharmacy (IJRMP)
In-vitro dissolution study 9, 10, 11
In vitro dissolution test was carried out using USP type I apparatus at 37 ± 0.5 0C in 900 ml
of phosphate buffer solution pH 6.8. Microspheres equivalent to 20 mg aspirin was tied at the
bottom of the paddle using muslin cloth, and rotated at 100 rpm. A sample of 5 ml was
withdrawn at various time intervals like 30, 60, 120, 180, 240, 300, 360 and 420 min and
filtered. Analyze the filtered sample by UV Spectrophotometer at 265 nm and find the
amount of drug release at each interval to calculate cumulative % of drug release after each
time interval.
RESULT AND DISCUSSION
Microsphere was prepared by using ethyl cellulose by employing emulsification solvent
evaporation technique. Aspirin was used as a model drug to check the drug entrapment
efficiency and drug release study. The prepared microsphere was evaluated to check the
effect of key parameter affecting on the properties of microsphere.
For the present work, the composition of each formulation is shown in Table 1. Formulation
F1 and F2 were designed to check the effect of the concentration of ethyl cellulose on the
characteristics of microsphere. Similarly, F1, F3 and F4 were designed to check the effect of
solvent mixture, F1 and F5 were designed to study the effect of stirring rate, F1 and F6 were
designed to study the effect of the concentration of emulsifying agent. The results of physical
characterization of all the formulations are shown in Table 2.
Table 1: Composition of Ethyl Cellulose Microspheres
85
SN
Ingredient
F1
F2
F3
F4
F5
F6
1
Aspirin (g)
3
3
3
3
3
3
2
Ethyl Cellulose (g)
3
6
3
3
3
3
3
Ethyl Acetate (ml)
40
40
30
20
40
40
4
Acetone (ml)
--
--
10
20
--
--
5
Tween (g)
0.4
0.4
0.4
0.4
0.4
0.8
6
Distilled Water (ml)
500
500
500
500
500
500
7
Stirring Rate (rpm)
1000
1000
1000
1000
500
1000
Vol.1, Issue: 1
December: 2012
ISSN: 2320-0901
International Journal for Research in Management and Pharmacy (IJRMP)
Table 2: Physical Evaluation of Ethyl Cellulose Microspheres
SN
Evaluation Parameter
F1
F2
F3
F4
F5
F6
1
CI (%)
14.46
13.94
15.19
16.32
13.11
17.02
2
AOR (ɵ)
21.32
23.15
24.84
24.32
23.52
26.76
3
% Yield
58.11
63.08
58.89
59.67
47.23
60.1
4
Particle Size (µm)
5
Entrapment Efficiency (%)
695.39 730.09 616.27 328.44 989.51 556.96
51.33
58.33
50.13
46.12
57.12
48.13
Percentage Yield
The percentage yield of all formulations was ranging from 47.23 to 63.08 (Table 2). There
was no significant difference observed by solvent mixture and concentration of emulsifying
agent on % yield but concentration of polymer and stirring rate affecting the % yield of
prepared microsphere.
Particle Size and Particle Size Distribution 12, 13, 14
The particle size of aspirin loaded microsphere was analyzed by optical microscopy. All the
batches of microspheres show uniform size distribution. The average particle size of
microspheres was found to be in the range of 328 to 990 µm.
From the results were shown in Table 2 and Figure 1, it was observed that the particle size of
the microspheres increased as the drug: polymer ratio was increased. The increase in size of
the microspheres may be attributed to an increase in viscosity of polymer solution with
increasing concentration, which resulted in the formation of larger emulsion droplets and
finally greater size of microspheres. As the concentration of the emulsifying agent (Span 80)
was increased, the particle size of the microspheres was decreased from. This may be due to
the decrease of interfacial energy between the two droplets and the presence of emulsifying
agent in the cross linking medium, allowing the stabilization of the preformed microspheres
to maintain their size until completion of the cross linking reaction. As the stirring rate was
increased, the particle size of the microspheres was decreased from. This may be due to
formation of small size droplets on higher stirring rate. The concentration of acetone was
significantly affected the size of prepared microsphere. The result in table 2 and figure 1 was
indicated that as the concentration of acetone in comparison to ethyl acetate was increased,
the size of microsphere was decreased.
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Vol.1, Issue: 1
December: 2012
ISSN: 2320-0901
International Journal for Research in Management and Pharmacy (IJRMP)
Figure 1: Effect on Particle size (µm)
1000
800
600
400
200
0
F1
F2
F3
F4
F5
F6
Percentage Drug Entrapment 8, 15
The results were shown in Table 2 and Figure 2 was suggesting that when the drug: polymer
ratio increased, the entrapment efficiency was increased. As the stirring rate was increased,
the entrapment efficiency was decreased. This may be due to formation of small size
microspheres with increased surface area and higher stirring rate was enhanced the diffusion
of drug from such microspheres to aqueous solvent. However the results and figure 2 were
indicated that the change in the concentration of the emulsifying agent and concentration of
acetone was no significant effect in entrapment efficiency of the microspheres.
Figure 2: Effect onEntrapment Efficincy (%)
60
50
40
30
20
10
0
F1
87
F2
F3
F4
F5
F6
Vol.1, Issue: 1
December: 2012
ISSN: 2320-0901
International Journal for Research in Management and Pharmacy (IJRMP)
In Vitro Drug Release Studies 12, 13, 15
The result in Table 3 and Figure 3 indicates that, when drug: polymer ratio was increased, the
in-vitro drug release from microspheres was decreased which may be due to increased path
length for diffusion of drug molecule from microspheres.
Table 3: In Vitro Dissolution Study
SN
Time (min)
1
30
Cumulative % of Drug Release (%CDR)
F1
F2
F3
F4
F5
F6
05.03
4.12
5.81
6.32
4.73
6.17
2
60
13.11
9.36
12.52
14.74
8.34
13.56
3
120
24.19
16.23
24.18
26.48
14.28
24.88
4
180
37.16
25.83
39.37
40.17
24.85
39.77
5
240
46.13
33.12
49.29
51.23
31.51
50.39
6
300
51.42
39.91
55.14
56.89
36.58
56.19
7
360
54.39
43.14
59.32
60.35
41.42
60.45
8
420
56.12
45.11
62.31
62.89
44.18
63.39
9
480
57.81
46.48
63.18
63.48
46.08
64.98
The results were in Table 3 and Figure 4 indicated that, in-vitro drug release from
microspheres was higher from the microsphere prepared at higher stirring rate. Which may be
due to the size of the microspheres prepared at 500 rpm was large and hence effective surface
area was less in comparison to those prepared at 1000 rpm.
From the results were shown in Table 3, Figure 5 and Figure 6 revealed that the concentration
of acetone in solvent mixture and concentration of emulsifying agent was not significantly
affect the drug release of the microspheres.
% CDR --->
Figure 3: Effect of Drug:Polymer ratio on % of drug release
70
60
50
40
30
20
10
0
F1
0
100
200
300
Time (min)
88
400
500
F2
600
Vol.1, Issue: 1
December: 2012
ISSN: 2320-0901
International Journal for Research in Management and Pharmacy (IJRMP)
Fighre 4: Effect of Stirring Rate on Drug Release Profile
70
%CDR --->
60
50
40
30
20
F1
10
F5
0
0
100
200
300
400
500
600
Time (min) --->
Figure 5: Effect of Acetone on Drug Release Profile
70
% CDR --->
60
50
40
30
F1
20
F3
F4
10
0
0
100
200
300
400
500
600
Time (min) --->
Figure 6: Effect of Tween 80 on Drug Release Profile
70
60
% CDR --->
50
40
30
F1
20
F2
10
0
0
100
200
300
Time (min) --->
89
400
500
600
Vol.1, Issue: 1
December: 2012
ISSN: 2320-0901
International Journal for Research in Management and Pharmacy (IJRMP)
CONCLUSIONS
The ethyl cellulose microspheres of aspirin were successfully prepared by emulsification
solvent evaporation technique and confirmed that it is a best method for preparing
microspheres from its size uniformity and spherical shape. Higher percentage of drug loading
was obtained by increasing the concentration of polymer. The particle size of a microsphere
was determined by optical microscopy and all the batches of microspheres show uniform size
distribution. The average particle size was found to be in the range of 328 to 990μm. The in
vitro dissolution studies showed that aspirin microspheres showed better sustained effect over
a period of 8 hours than other formulations. The various parameters such as solvent mixture,
composition, concentration of the emulsifying agent and speed of stirring have found
significant effect on microsphere size, drug loading capacity and drug release study.
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