Formulation and Evaluation of Solid Self Micro Emulsifying Drug Delivery System using Aerosil 200 as Solid Carrier

Abstract

Improvement of bio-availability of poorly water soluble drugs presents one of the furthermost challenge in drug formulations. One of the most admired and commercially viable formulation approach for this challenge is solid self micro emulsifying drug delivery system (S-SMEDDS). There are many techniques to convert liquid SMEDDS to solid, but an adsorption technique is simple and economic. Hence aim of present study was to develop S-SMEDDS of poorly water soluble drug Telmisartan (TEL) using Aerosil 200 as solid carrier. Liquid SMEDDS was prepared using Acrysol EL 135, Tween 80 and PEG 400 as oil, surfactant and co-surfactant and was converted to S-SMEDDS by adsorbing it on Aerosil 200. Prepared S-SMEDDS was evaluated for flow properties, drug content, reconstitution properties, DSC, SEM, in-vitro drug release and ex-vivo intestinal permeability study. Results showed that prepared S-SMEDDS have good flow property with 99.45 ± 0.02% drug content. Dilution study by visual observation showed that there was spontaneous micro emulsification and no sign of phase separation. Droplet size was found to be 0.34 μm with polydispersity index of 0.25. DSC thermogram showed that crystallization of TEL was inhibited. SEM photograph showed smooth surface of S-SMEDDS with less aggregation. Drug releases from S- SMEDDS were found to be significantly higher as compared with that of plain TEL. Ex-vivo intestinal permeability study revealed that diffusion of drug was significantly higher from S-SMEDDS than that of suspension of plain TEL. Study concluded that S-SMEDDS can effectively formulated by adsorption technique with enhanced dissolution rate and concomitant-ly bioavailability.

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Bhagwat and D’Souza, International Current Pharmaceutical Journal 2012, 1(12): 414-419
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Formulation and evaluation of solid self micro emulsifying drug
delivery system using aerosil 200 as solid carrier
*Durgacharan Arun Bhagwat, John Intru D’Souza
JJT University, Jhunjhunu, Rajasthan, India
Dept. of Pharmaceutics, Tatyasaheb Kore College of Pharmacy, Warananagar, Kolhapur, Maharashtra, India-416113
INTRODUCTION
Poor bioavailability is a trouble, frequently faced in
the drug development process. Enhancement of
bioavailability of poorly water soluble drugs becomes
farthest challenge for pharmaceutical scientist. Most
of new drug candidates reveal low solubility in
water, which leads to poor oral bioavailability, high
intra- and inter-subject variability and lack of dose
proportionality. Various approaches should use to
improve the dissolution rate of the drug. Among
them, Self micro emulsifying drug delivery systems
(SMEDDS) have shown great pledge for enhancing
bioavailability of poorly soluble compounds. Con-
ventional SMEDDS are usually prepared in a liquid
dosage form that can be administered in soft gelatin
capsules, which have some disadvantages particular-
ly in the manufacturing process and incompatibility
problems with the shells of soft gelatin. Solid
SMEDDS have recently been described and they
surmount the disadvantages of liquid SMEDDS as
well as exhibited more commercial potential and
patient acceptability (Akhter et al., 2012; Bhagwat et
al., 2012; Agarwal et al., 2009).
Many techniques are offered to convert convention-
al liquid SMEDDS to solid such as adsorptions to
solid carriers, spray drying, spray cooling, melt
extrusion, nanoparticles technology, supercritical
fluid based methods, etc. But among these the
adsorption technique is simple and just involves
addition of liquid formulation onto carriers by
mixing in a blender. The resulting powder may then
ORIGINAL RESEARCH ARTICLE OPEN ACCESS
International Current
Pharmaceutical Journal
ABSTRACT
Improvement of bio-availability of poorly water soluble drugs presents one of the furthermost challenge in drug
formulations. One of the most admired and commercially viable formulation approach for this challenge is solid self
micro emulsifying drug delivery system (S-SMEDDS). There are many techniques to convert liquid SMEDDS to
solid, but an adsorption technique is simple and economic. Hence aim of present study was to develop S-SMEDDS of
poorly water soluble drug Telmisartan (TEL) using Aerosil 200 as solid carrier. Liquid SMEDDS was prepared using
Acrysol EL 135, Tween 80 and PEG 400 as oil, surfactant and co-surfactant and was converted to S-SMEDDS by
adsorbing it on Aerosil 200. Prepared S-SMEDDS was evaluated for flow properties, drug content, reconstitution
properties, DSC, SEM, in-vitro drug release and ex-vivo intestinal permeability study. Results showed that prepared
S-SMEDDS have good flow property with 99.45 ± 0.02% drug content. Dilution study by visual observation showed
that there was spontaneous micro emulsification and no sign of phase separation. Droplet size was found to be 0.34
µm with polydispersity index of 0.25. DSC thermogram showed that crystallization of TEL was inhibited. SEM
photograph showed smooth surface of S-SMEDDS with less aggregation. Drug releases from S- SMEDDS were found
to be significantly higher as compared with that of plain TEL. Ex-vivo intestinal permeability study revealed that
diffusion of drug was significantly higher from S-SMEDDS than that of suspension of plain TEL. Study concluded
that S-SMEDDS can effectively formulated by adsorption technique with enhanced dissolution rate and concomitant-
ly bioavailability.
Key Words: Telmisartan, S-SMEDDS, adsorption technique, reconstitution properties, dissolution rate, ex-vivo
intestinal permeability.
*Corresponding Author:
Durgacharan Arun Bhagwat, Research Scholar
JJT University, Jhunjhunu, Rajasthan
Dept. of Pharmaceutics, Tatyasaheb Kore College of Pharmacy
Warananagar, Kolhapur, Maharashtra, India 416113
E-mail: durgapharma@gmail.com
Contact No.: +919561350999
INTRODUCTION

415
be filled directly into capsules or, alternatively,
mixed with suitable excipients before compression
into tablets. A significant benefit of the adsorption
technique is good content uniformity. The SMEDDS
can be adsorbed at high levels up to 70% w/w on to
suitable carrier (Katteboina et al., 2009).
TEL is Angiotensin II Receptor Antagonist, which is
used in the prevention and treatment of Hyperten-
sion. TEL belongs to class II drug in BCS
classification. One of the foremost problems with
this drug is its low solubility in biological fluids,
which results into poor bioavailability after oral
administration. The solubility of TEL in aqueous
medium is very low i.e. 0.078 mg/ml in water.
Absolute bioavailability of the TEL is 42-58% and
biological half-life is 24 hours that results into poor
bioavailability after oral administration. Thus
increasing aqueous solubility and dissolution of TEL
is of therapeutic meaning (Kausalya et al., 2011;
Bhagwat et al., 2012).
Hence present study aimed towards development of
S-SMEDDS of TEL by adsorption technique using
Aerosil 200 as solid carrier for enhanced bioavaila-
bility.
MATERIALS AND METHODS
Telmisartan was obtained as a gift sample from
Glochem Industries Ltd. Vishakhapatnam, AP,
India. Acrysol EL 135 was gifted by Corel Pharma
Chem, Gujarat, India. PEG 400, Tween 80 and
Aerosil 200 were obtained from S. D. Fine Chem.,
Mumbai. All other chemicals were of reagent grade.
Preparation of Liquid SMEDDS
Authors have already developed and evaluated
liquid SMEDDS of TEL successfully by determining
solubility of TEL in various oils, surfactants and co-
surfactants and by constructing pseudo ternary
phase diagram to identify micro emulsion region.
From that satisfactory composition was selected to
prepare liquid SMEDDS.
In brief TEL (20 mg/10gm) was placed in glass vial.
To this Acrysol EL 135 (10 % w/w) added and
warmed on water bath. To this oily mixture Tween
80 (30 % w/w) and PEG 400 (40 % w/w) was added.
Then the components were mixed by gentle stirring
and vortex mixing at 37°C until TEL was completely
dissolved. Then the mixture was sealed in glass vial
and stored at room temperature until used (Tang et
al., 2008; Bhagwat et al., 2012).
Preparation of S-SMEDDS
S-SMEDDS was prepared by mixing liquid
SMEDDS containing TEL with Aerosil 200 in 1:1
proportion. In brief liquid SMEDDS was added
drop wise over Aerosil 200 contained in broad
porcelain dish. After each addition, mixture was
homogenized using glass rod to ensure uniform
distribution of formulation. Resultant damp mass
was passed through sieve no. 120 and dried at
ambient temperature and stored until further use
(Bandivadekar et al., 2011).
Evaluation of S-SMEDDS
Flow properties of S-SMEDDS
Angle of repose
The angle of repose of S-SMEDDS was determined
by funnel method. Accurately weighed sample were
taken in a funnel. Height of the funnel was adjusted
in such a way that the tip of the funnel just touches
the apex of the heap of S-SMEDDS powder. The
powder were allowed to flow through funnel freely
onto the surface. The diameter of the powder cone
was measured and angle of repose calculated using
the following equation (More et al., 2004):
tan =

Bulk density
Both loose bulk density (LBD) and tapped bulk
density (TBD) were determined. A quantity of 2 g of
S-SMEDDS was introduced into a 10 ml measuring
cylinder. Initial volume was observed, the cylinder
was allowed to fall under its own weight onto a
hard surface from a height of 2.5 cm at 2 second
intervals. The tapping was continued until no
further change in volume was noted. LBD and TBD
were calculated using the following formulae (More
et al., 2004):
LBD
=   
  
TBD
=   
   
Compressibility Index
The compressibility of the granules was determined
by Carr’s Compressibility Index.
Carr's compressibility index (%)
=

  

 × 100
MATERIALS AND METHODS

416
Hausner ratio
A similar index like compressibility index has been
defined by Hausner. Hausner ratio can be calculated
by formula:
Hausner ratio
= 

Drug content determination
TEL content in S-SMEDDS was estimated using the
UV method. S-SMEDDS was dissolved in sufficient
quantity of methanol. The solution was sonicated for
10 mins for extraction of the drug in methanol and
filtered. The absorbance of filtrate was read at 296 nm
on UV- Visible Spectrophotometer (Patel et al., 2010).
Reconstitution properties of S-SMEDDS
Dilution study by visual observation
Dilution study was done to study the effect of
dilution on S-SMEDDS, because dilution may better
mimic the condition of stomach after oral adminis-
tration. In this method, S-SMEDDS (100 mg) was
introduced into 100 mL of double distilled water in
a glass beaker that was maintained at 37ºC and the
contents mixed gently using a magnetic stirrer. The
tendency to emulsify spontaneously and progress of
emulsion droplets were observed with respect to
time. The emulsification ability of S-SMEDDS was
judged qualitatively “good” when clear microemul-
sion formed and “bad” when there was turbid or
milky white emulsion formed after stopping of
stirring (Nekkanti et al., 2010).
Droplet size determination
10 mg of S-SMEDDS formulation was diluted with
10 mL double distilled water in a beaker with
constant stirring on a magnetic stirrer. The average
Droplet size and polydispersity index of micro-
emulsion from S-SMEDDS was assessed by lesser
light scattering technique using Mastersizer 2000
Ver. 5.22 Serial Number: 34027-08 Malvern Instru-
ments Ltd. Malvern, UK.
Differential scanning calorimetry (DSC)
Thermograms of pure drug, Aerosil 200 and S-
SMEDDS were obtained using Differential Scanning
Calorimetry instrument equipped with an intracoo-
ler (TA Instruments, SDT-2960, USA). Indium
standard was used to calibrate the DSC temperature
and enthalpy scale. The powder samples was
hermetically kept in the aluminium pan and heated
at constant rate 10/min, over a temperature range
of 35 to 350. Inert atmosphere was maintained
by purging nitrogen at the flow rate of 100 mL/min.
Scanning electron microscopy (SEM) of S-SMEDDS
Surface topography of the S-SMEDDS was investi-
gated by SEM, operating at 20 kV. The sample was
fixed on SEM stub and then coated with thin layer
of platinum (JEOL, - 6360, JEOL Japan).
In-vitro drug release study
The in-vitro dissolution study of S-SMEDDS and
plain drug were carried out using USP- type-II
dissolution test apparatus (Veego, VDA-8DR ) in pH
1.2 and pH 7.5 buffer solutions at 37±0.5°C with 50
rpm rotating speed. Samples of 5 mL were with-
drawn at regular time interval of 5, 10, 15, 30, 60 and
120 min and filtered using 0.45µm filter. An equal
volume of respective dissolution medium was
added to maintain the volume constant. Drug
content from sample was analyzed using UV-
spectrophotometer (Shimadzu-1800, Japan) at 296
nm. All measurements were done in triplicate from
three independent samples (Patel et al., 2010).
Ex-vivo intestinal permeability study
All experiments and protocols described in this
study were approved by the Institutional Animal
Ethics Committee (Ref. No. IAEC/TKCP/2012/09)
and all experiments were conducted as per the
norms of the Committee for the Purpose of Control
and Supervision of Experiments on Animals
(CPCSEA). Male Wister rat (250-300g) was sacrificed
by CO2 inhalation method. Intestine was isolated
and cleaned properly. Reconstituted solution of S-
SMEDDS and plain drug suspension was filled into
the intestine which was tied at both the end. The
tissue was placed in an organ bath with continuous
aeration at 37°C. The receptor compartment (organ
tube) was filled with phosphate-buffered saline pH
Table 1. Micromeritic properties and drug content of S-
SMEDDS.
Properties of S-SMEDDS
Results
Angle of Repose (degree)*
27.63 ± 0.04
LBD (g/ml)*
0.54 ± 0.12
TBD (g/ml)*
0.65±0.47
Carr’s Index (%)*
16.92± 0.31
Hausner Ratio*
1.20± 0.06
Drug content (%)*
99.45 ± 0.02
*Values expressed as Mean ± SD (n=3)

417
7.4 with 1% sodium lauryl sulphate. At predeter-
mined time intervals, samples were withdrawn
from the receptor compartment. Fresh buffer was
used to replenish the receptor compartment. The
samples were analyzed spectrophotometrically at
296 nm for the content of TEL. The percent diffusion
was calculated using PCP-Disso v2.08 software and
plotted against time (Thakkar et al., 2011).
RESULTS AND DISCUSSION
Evaluation of S-SMEDDS
Flow properties of S-SMEDDS
Various micromeritic properties of S-SMEDDS of
TEL are shown in Table 1. Results showed that S-
SMEDDS has good flow properties.
Reconstitution properties of S-SMEDDS
Dilution study by visual observation
A visual test was carried out to assess self emulsifi-
cation of S-SMEDDS in 100 mL double distilled
water at 37°C under gentle agitation. S-SMEDDS
showed spontaneous micro emulsification and there
was no sign of phase separation or phase inversion
of micro emulsion after storage of 2 h.
Droplet size determination
Mean droplet size of reconstituted S-SMEDDS was
found to be 0.34 µm with polydispersity index 0.25
(Figure 1). S-SMEDDS showed polydispersity index
less than 1, indicating uniform distribution of
droplets throughout formulation.
Differential scanning calorimetry (DSC)
Figure 2 shows DSC curves of TEL, Aerosil 200 and
S-SMEDDS. TEL shows sharp endothermic peak at
near about 267.56°C. The S-SMEDDS exhibit
retained small endothermic peak for TEL and it may
be due to solubilization of TEL in SMEDDS.
SEM of S-SMEDDS
Figure 3 showed that S-SMEDDS appeared as smooth
surfaced S-SMEDDS particles, indicating that the
liquid SMEDDS is adsorbed or coated inside the pores
of Aerosil 200 with a lesser amount of aggregation.
In-vitro drug release study
Cumulative % drug release of TEL in pH 1.2 and 7.5
was found to be 96.55± 2.56 and 97.82± 2.52 respec-
tively and that of plain TEL was found to be 29.35±
1.36 and 31.47± 2.06 respectively (Figure 4). This
showed that drug releases from S- SMEDDS was
found to be significantly higher as compared to
plain TEL. From results it was also found that
dissolution of TEL is pH independent.
Figure 1. Mean droplet size of reconstituted S-SMEDDS.
Figure 3. SEM of S-SMEDDS.
Figure 2. DSC curves of A) TEL B) Aerosil 200 C) S-SMEDDS.
RESULTS AND DISCUSSION

418
Ex-vivo intestinal permeability study
The results of the ex-vivo intestinal permeability
study are shown in Figure 5. After 6 h of diffusion
70.38 % of the drug was diffused from S-SMEDDS,
while from plain drug suspension the diffusion was
found to be 36.73%. Thus, the amount of the drug
diffused through the biological membrane has more
when it is given in the form of S-SMEDDS. The
enhancement in diffusion is due to formation of
micro emulsion droplets (mean droplet size 0.34
µm) in micrometer range and improved permeation
of the TEL because of the presence of surfactant,
which reduces the interfacial tension of formulation
(Thakkar et al., 2011).
CONCLUSION
Study concluded that, S-SMEDDS of TEL prepared
using Aerosil 200 by adsorption process showed good
flow properties and drug content. After reconstitution
it formed micro emulsion with micrometric range. In-
vitro drug release and Ex-vivo intestinal permeability
was much higher than that of plain TEL. Hence
adsorption process using Aerosil 200 as solid carrier
may efficiently formulate S-SMEDDS which enhance
dissolution rate and intestinal permeability and
concomitantly bioavailability.
ACKNOWLEDGEMENT
We gratefully thank to Hon. Shri. G. D. Patil,
Secretary, Shree Warana Vibhag Shikshan Mandal,
Warananagar, Kolhapur, MS India, for constant
inspiration and making available the necessary
facilities and Corel Pharma Chem, Gujarat, India for
providing gift sample of Acrysol EL 135.
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0
20
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60
80
100
120
020 40 60 80 100
Cumulative % drug release
Time (min)
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TEL S-SMEDDS in pH 7.5
Plain TEL in pH 1.2
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Figure 5. Ex-vivo intestinal permeability study of S-
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0
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060 120 180 240 300 360
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CONCLUSION
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