solid self microemulsification of atorvastatin using hydrophilic carriers a design

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ISSN: 0363-9045 (print), 1520-5762 (electronic)
Drug Dev Ind Pharm, Early Online: 1–10
! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/03639045.2014.938655
RESEARCH ARTICLE
Solid self microemulsification of Atorvastatin using hydrophilic
carriers: a design
R. Nanda Kishore1
, Prasanna Raju Yalavarthi1
, Harini Chowdary Vadlamudi1
, K. R. Vandana1
, Arun Rasheed2
, and
M. Sushma1
1
Pharmaceutics Division, Sree Vidyanikethan College of Pharmacy, A. Rangampet, Tirupati, India and 2
Department of Medicinal Chemistry,
Al-Shifa College of Pharmacy, Poonthavanam, India
Abstract
Context: Atorvastatin has a limited advantage to formulate oral dosage forms.
Objective: To enhance the solubility of Atorvastatin and to design the suitable solid
self-microemulsifying drug delivery systems (S-SMEDDS)
Materials and methods: The clear and transparent self-microemulsifying drug delivery system
(SMEDDS) were formulated using coconut oil and isopropyl myristate as lipid phases; Tween 80
as surfactant; PEG 400 and glycerin as co-surfactant at 2:1, 3:1, 1:2 and 1:3 ratio. The pseudo
ternary phase diagrams were constructed to identify the microemulsion region. The SMEDDS
were evaluated for zeta potential, poly dispersity index, globule size, pH, viscosity and drug
release. The solid SMEDDS were developed by employing adsorption and melt granulation
methods. The S-SMEDDS were evaluated for micromeritics, morphology, solid state property,
reconstitution ability, drug release and stability.
Results: The micro formulations formed with particle size of 25 nm had shown a 3-folds rise in
drug release. The solid SMEDDS had reconstituted to a good microemulsion rapidly in 1–3 min,
with a release of 94.62% at the end of 30 min and behaved as immediate releasing capsules.
Their shelf-life was found to be 1.3 years.
Discussion: The 1:3 ratio SMEDDS had shown more drug release owing to their less particle size.
The solid SMEDDS had shown an increased dissolution profiles than atorvastatin. The solid state
of the drug had changed in formulation inferring their enhanced solubility.
Conclusion: The solid form of atorvastatin liquid SMEDDS had been formulated successfully with
enhanced shelf life and solubility.
Keywords
Adsorption, dialysis tubings, melt granulation,
polydispersity index, shelf-life, zeta
potential
History
Received 25 November 2013
Revised 1 May 2014
Accepted 23 June 2014
Published online 14 July 2014
Introduction
Oral administration is the most versatile approach for majority of
drugs with more reliable advantages for both patients and
formulators. As no route is ideal, oral route also pose few
limitations which a formulator need to look into, one such issue is
solubility of the drug moiety in GI tract. Most of the drugs being
non-polar will face this problem when formulated into solid orals.
Recent past, different potential methods have been proposed to
circumvent the solubility associated problems. One such most
successful method is self-microemulsifying drug delivery system
(SMEDDS)1,2
.
The SMEDDS are preconcentrates of microemulsion, which
forms microemulsion upon contacting water. These SMEDDS
reserve the properties of microemulsion upon formation. These
are isotropic mixtures of lipid and surfactant mixtures; mostly
clear due to presence of only one phase. With SMEDDS, the
solubility of typical drug moieties could be enhanced as they act
as super solvents and thereby the drug candidates get dissolved/
solubilized before entering stomach region. The oil droplet is
encapsulated with amphiphiles that used in formulation and led to
solubilize in aqueous medium, which become an important point
here3–7
.
The SMEDDS on contact with water would form micro
droplets at size range 5100 nm and thus, the method is more
advantageous over other solubility enhancement techniques.
In addition, this technique facilitates permeation via passive
diffusion or through aqueous filled pores due to their micro size.
Enhanced permeation benefits the concentration adequacy in
system. Hence, SMEDDS becomes an option to reduce the dosing
and frequency8
.
Statins are a class of drugs which lowers cholesterol levels by
inhibiting the enzyme HMG-CoA reductase (3-hydroxy-3-methyl-
glutaryl-CoA reductase), which is a rate limiting enzyme in
mevalonate pathway, through which cholesterol is synthesized.
Atorvastatin is an artificial statin, manufactured as a salt of
calcium by Pfizer Inc., to enhance its bioefficacy and stability.
It contains dihydroxyheptanoic acid as the pharmacophore which
acts as pseudo substrate for HMG-CoA, reducing the conversion
of HMG-CoA to mevalonic acid thereby reducing the cholesterol
Address for correspondence: Dr. Prasanna Raju Yalavarthi, Professor,
Pharmaceutics Division, Sree Vidyanikethan College of Pharmacy,
Tirupati 517102, India. Tel: +91 98857 29290. E-mail: kanishka9002@
gmail.com
DrugDevelopmentandIndustrialPharmacyDownloadedfrominformahealthcare.comby106.220.97.66on07/18/14
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synthesis. Fluropheynl group will give tighter interaction with
HMG-CoA moiety than natural statins. With a log p value of 4.2 it
favors lipid solubility, which makes Atorvastatin a bit difficult for
oral administration in turn makes drug suitable to formulate as
SMEDDS. Its oral bioavailability is as low as 12% due to pre-
systemic metabolism in GI mucosa and another important reason
is its poor aqueous solubility. The metabolic products being
active, increasing the solubility solely will increase the amount
of drug in circulation and increasing duration of activity
which can be accomplished by SMEDDS. After 14 h of plasma
half-life, the drug and its active metabolites are eliminated
primarily in bile and a 2% of the administered dose will be
appeared in urine9–15
.
Present study was to establish the solubility of Atorvastatin
calcium (AS) in aqueous systems using self microemulsification
technique. AS containing SMEDDS were developed using
coconut oil and isopropyl myristate as oil phases; Tween 80 as
surfactant; PEG 400 and glycerin as co-surfactants screened from
the solubility studies. The drug release from these formulations
were studied to select the promised liquid formulations and to
convert them into solid form through adsorption and melt
granulation techniques by using fused silica [Aerosil 200Õ
] as
adsorbent and PEG 2000 as granulating agent16,17
.
Materials and methods
Materials
Atorvastatin calcium was a gift sample obtained from M/s.
Unichem Labs, Goa, India. Double refined coconut oil was
purchased from local market. Aerosil 200, glycerin, isopropyl
myristate and methanol were purchased from M/s. Merck
Specialties Ltd., Mumbai, India. Tween 80, PEG 400 and PEG
2000 were obtained from S.D. Fine Chem Ltd., Mumbai, India.
Methods
Solubility studies
The solubility of AS was determined in different oils (coconut oil,
castor oil, palm oil, sesame oil, olive oil, sun flower oil, oleic acid
and isopropyl myristate (IPM)); surfactant and co-surfactant
systems (Tween 80, PEG 2000, PEG 400 and glycerin). Excess
AS was added into 5 ml of each vehicle followed by vortex mixing
for 30 s. Mixtures were equilibrated for 72 h at 27
C on a
controlled shaker. Mixtures were then filtered through a 0.45 lm
nylon filter. The filtrate was suitably diluted with methanol and
drug content was assayed at 246 nm18
.
Pseudo-ternary phase diagram
The pseudo-ternary diagrams were drawn with vehicles that
exhibited higher solubility towards AS, i.e. coconut oil
and isopropylmyristate. The ratios of surfactant (Tween 80):
co-surfactants (PEG 400 and glycerin) were selected at 1:2, 1:3,
2:1 and 3:1 parts by volume. Isotropic systems were developed
with varying ratios of oil to surfactant mixture (Smix) ranging
between 10:0 and 0:10. The isotropic systems were titrated with
distilled water with continuous stirring until solution becomes
turbid as endpoint. The ternary diagrams were plotted to identify
the monophasic microemulsion region19,20
. Table 1 represents the
composition of liquid SMEDDS in the study.
Preparation of drug loaded SMEDDS
The formulatory compositions from the monophasic area of each
phase diagram were selected using respective ratios of oil, and
Smix. To the mixture containing selected composition of oil and
Smix, a weighed quantity of AS was added. The contents were
vortexed until drug was dissolved completely. The obtained
transparent SMEDDS were stored at room temperature for
further use21
.
Selection of SMEDDS
The prepared liquid SMEDD formulations (C1–C8 and I1–I8)
were subjected to drug content analysis and drug release studies.
The liquid SMEDD formulations demonstrating promising drug
release profiles were selected to formulate the solid SMEDDS.
The promised SMEDDS were characterized for globule size, zeta
potential and viscosity.
Evaluation of liquid SMEDDS
Drug content. The drug content present in prepared
formulations was assessed by dissolving 1 ml of the liquid
SMEDD formulation in methanol. After suitable dilutions with
methanol, absorbance was recorded and drug content was
estimated.
In-vitro drug release. The drug release was studied by using
dialysis tubings (cellophane membrane of 0.45 mm pore size). The
dialysis method was carried out by taking the liquid SMEDDS
containing 10 mg equivalent AS in dialysis tubing and were
diluted to 10 ml with 0.1 N HCl. The dialysis tubings were
submerged in 900 ml of 0.1 N HCl. The drug release was assessed
from the both liquid SMEDDS and pure AS by withdrawing the
Table 1. Composition and drug content of the liquid SMEDDS.
Formulation
code % weight of oil Smix ratio (S:CoS) % weight of Smix
% drug content
mean ± S.D. (n ¼ 3)
C1 Coconut oil 14.0 Tween 80 PEG 400 2:1 86.0 96.7 ± 0.55
C2 13.6 3:1 86.4 96.9 ± 0.48
C3 13.8 1:2 86.2 99.82 ± 0.19
C4 16.6 1:3 83.4 99.38 ± 0.60
C5 20.4 Glycerin 2:1 79.6 96.62 ± 0.48
C6 17.2 3:1 82.8 93.78 ± 0.46
C7 15.5 1:2 84.5 96.22 ± 0.60
C8 17.1 1:3 82.9 97.18 ± 0.55
I1 IPM 15.1 PEG 400 2:1 84.9 95.4 ± 0.60
I2 15.8 3:1 84.2 96.92 ± 0.19
I3 15.7 1:2 84.3 93.42 ± 1.14
I4 14.2 1:3 85.7 97.0 ± 0.55
I5 15.8 Glycerin 2:1 84.2 98.4 ± 0.46
I6 13.8 3:1 86.2 94.0 ± 1.07
I7 18.7 1:2 81.2 96.1 ± 0.19
I8 15.9 1:3 84.1 98.86 ± 0.48
2 R. N. Kishore et al. Drug Dev Ind Pharm, Early Online: 1–10
Forpersonaluseonly.

samples at periodical intervals and assayed accordingly at
240 nm22
.
pH and viscosity. A measured volume (10 ml) of SMEDDS
was used to test the hydronium ion concentration of the selected
liquid SMEDDS and it was estimated by glass membrane
electrode (ELICO LI 200, Hyderabad, India). The viscosity of
the SMEDDS was determined using Brookfield Viscometer,
Middleboro, MA (LDLV-E Model) using spindle # 63 at 10 rpm.
Zeta potential and droplet size analysis. Zeta potential of
selected SMEDDS was estimated by Zetasizer HSA 3000
(Malvern Instruments, Malvern, UK, HSA 3000). The selected
liquid formulations were diluted with excess water and then
droplet size was measured.
Design of solid SMEDDS (S-SMEDDS)
The promised liquid SMEDDS were selected to formulate the
S-SMEDDS by employing adsorption and melt granulation
techniques. The compositions of S-SMEDDS are presented in
Table 2.
Method I: Adsorption technique. Solid SMEDDS were prepared
by mixing liquid SMEDDS containing AS with Aerosil 200.
Small amounts of Aerosil 200 were added to the liquid SMEDDS
until a free flowing powder was obtained. The solid mass was
subjected to vacuum drying and screened through # 22 mesh23
.
Method II: Melt granulation. The liquid SMEDDS were
added drop-wise into the molten hydrophilic carrier, PEG
2000 with continuous homogenization. Resulted mixture was
solidified and sifted through sieve # 22 and stored in a vacuum
desiccator16
.
The dried powders obtained from the above methods contain-
ing 10 mg equivalent AS were encapsulated into size ‘‘1’’
capsules. Before encapsulation the flow behavior of powder was
assessed by angle of repose, density and Hausner ratio (HR)17
.
Evaluation of solid SMEDDS
Drug content. The solid SMEDDS filled capsule was allowed to
dissolve in sufficient quantity of methanol for 20 min. The
resulting solution was filtered through 0.45 mm nylon filter and
assayed.
Reconstitution of S-SMEDDS. Each S-SMEDDS filled in
capsule was added to 0.1 N HCl and stirred well at constant
temperature of 37 ºC. The emulsification ability of S-SMEDDS
was observed with time and confirmed visually. Clear emulsion
formation confers with the ‘‘good’’ grade emulsion whereas
turbid appearance refers to poor emulsification ability of
S-SMEDDS22
.
DSC (Differential scanning calorimetry) study. Thermal behav-
ior of AS and selected solid SMEDDS was studied by the
differential scanning calorimetric thermogram analysis (Netzsch
DSC200PC). The samples were placed in aluminum pans, and dry
nitrogen was used as effluent gas. The samples were scanned at a
temperature from 0 to 300
C using aluminum as reference
compound.
Scanning electron microscopy of S-SMEDDS. The surface
morphology of S-SMEDDS was investigated by Scanning elec-
tron microscopy (SEM), operating at 15 kV (Hitachi S-3000N,
Japan).
In-vitro drug release. The in-vitro dissolution study of
S-SMEDDS filled in capsules and pure AS were carried out
using USP type I dissolution test apparatus in 900 ml of 0.1 N HCl
at 37 ± 0.5
C with 50 rpm speed. Samples of 5 ml were
withdrawn at predetermined time intervals and filtered through
0.45 lm nylon filter. The experiment was set for sink condition.
The samples were assayed at 240 nm. The measurements were
done for six independent samples. To investigate the possible
release mechanism of AS from the capsule formulation, the
drug release data were fitted to various kinetic models such as
Zero-order, First-order and Hixson Crowell models23,24
.
Stability testing. The stability studies for S-SMEDDS were
carried out according to the ICH guidelines at different storage
conditions for 90 days. The solid SMEDDS filled in capsules were
stored in stability chamber (Thermolab, India) maintained at
different storage conditions viz. 25
C/60% RH, 45
C/65% RH
and 60
C/75% RH. The capsules were examined for physical
integrity, drug content and also for in-vitro drug release after 15,
30, 60 and 90 days. Shelf-life (t90) of S-SMEDDS was calculated
using the formula t90 ¼ 0.1052/K where K represents first-order
rate constant. The experiment was conducted in triplicate.
Results
Solubility study
Solubility studies were carried out to identify the suitable vehicles
for the formulation of SMEDDS as demonstrated in Figure 1.
With the objective of comparing natural and synthetic oils,
coconut oil and isopropyl myristate were selected as oil phases.
Tween 80 as surfactant and PEG 400 and glycerin as
co-surfactants were selected.
Selection of formulation from ternary diagram
According to compositions given in Table 1, the pseudo-ternary
phase diagrams were established and then clear and stable
microemulsion systems were identified. The coordinates within
the colored regions close to surfactant rich axis was selected by
trial and error process before addition of the drug. The
compositions which form a clear microemulsion were selected
and then drug was mixed.
Characterization of liquid SMEDDS
Drug content
The drug content of AS in SMEDDS was found to be in the range
of 93–99% in both coconut oil and IPM phases. Data infers good
drug-loading and wastage of drug with less significance. The drug
content values were also given in Table 1.
Table 2. The composition of S-SMEDDS (Adsorption and Melt
granulation methods).
Formulation
code
Liquid SMEDDS
equivalent to
10 mg of AS
Aerosil
200 (mg)
PEG
2000 (mg) Talc (mg)
AC4 C4 320 – 20
AC8 C8 320 – 20
MC4 C4 – 300 20
MC8 C8 – 300 20
AI4 I4 320 – 20
AI8 I8 320 – 20
MI4 I4 – 300 20
MI8 I8 – 300 20
DOI: 10.3109/03639045.2014.938655 Solid SMEDDS of Atorvastatin 3
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Figure 1. Solubility of Atorvastatin in various vehicles.
Figure 2. Percent AS release from C1–C8 formulations.
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Drug release
The liquid SMEDDS with 2:1 ratio of Smix, i.e. C1, I1, C5 and I5
formulations have exhibited uniform drug release profiles,
attributing that they contain similar surfactant concentrations.
Whereas C1 and I1 formulations contain PEG 400 as cosurfactant
had shown slightly less drug release compared to that C5 and I5
formulations which contain glycerin as cosurfactant at same
surfactant: co-surfactant (S:CoS) ratios. The same fashion was
found in all liquid SMEDDS. Similarly, the formulations with 3:1
of S:CoS ratio were evidenced with more drug release than that of
2:1 ratio due to increased surfactant concentration, lead appre-
ciable reduction in the interfacial tension. The liquid SMEDDS of
C3, I3, C7 and I7 formulations with 1:2 ratio of S:CoS had shown
less drug release as 85 to 89% when compared to that of surfactant
rich formulations, i.e. C2, I2, C6 and I6. The same mode of
mechanism was observed in C4, I4, C8 and I8 formulations with
1:3 ratio of S:CoS. The affect of higher co-surfactant concentra-
tions was evident with mean globule size of 25 nm. The four
formulations, C4, I4, C8 and I8 had shown the highest drug
release than other liquid SMEDD formulations and a 3-fold rise
than the pure AS which was as low as 33.02%. Based on their
percent drug release and phase behavior, the liquid SMEDDS of
C4, I4, C8 and I8 formulations were selected for further studies.
The drug release patterns of the promised liquid SMEDDS are
shown in Figures 2 and 3; and their phase behavior is depicted in
Figure 4.
Physical properties of optimized SMEDDS
pH and viscosity of optimized formulations. The values of pH
and viscosities were found in same range without much deviation.
The pH values were found nearly neutral, i.e. 7 due to the
presence of non-ionic and neutral excipients in SMEDDS. All the
formulations were having neutral pH, which facilitate them to oral
use. The viscosities of the prepared formulations were found to be
!215 cps, as they were dehydrates and exhibited higher viscosity
values as shown in Table 3.
Droplet size and zeta potential measurement. The data of
droplet size and polydispersity index (PDI) are mentioned in
Table 3. Formulations have a droplet size in between 23 and
28 nm; PDI was less than 1. The liquid SMEDDS contained very
small particle size after dilution with water. By this, it was
attributed that, upon gastric dilution, they can form microemul-
sion with above droplet size. The results of size analysis indicated
that the globules in SMEDDS were uniformly distributed. The
formulation, C8 with 1:3 ratio of S:CoS contain glycerin as
cosurfactant had shown a larger globule size than the other three
formulations (C4, I4 and I8) as it contains large quantities of oil.
Zeta potential of all SMEDDS formulations was found
between À1.2 to À10.7 mV in diluted form as shown in Table 3.
Micromeritics of S-SMEDDS. Powders obtained after the add-
ition of adsorbent and the hydrophilic melt carrier were evaluated
for micromirectic properties. The angle of repose values were
observed between 39 and 42
for powders obtained by adsorption,
whereas melt granules were in range from 41 to 43 as expressed in
Figure 5. The powder from adsorption process had bulk density in
between 0.395–0.444 g/ml and HR was in between 1.12–1.16. The
bulk density of melt granules was found to be in the range of
0.425–0.525 g/ml and HR was found to be in between 1.04–1.19.
The values are summarized in Table 4.
Drug content of S-SMEDDS. The percent drug content of AC4,
AC8, MC4, MC8, AI4, AI8, MI4 and MI8 vary between 84–91.
It was observed that the drug content in melt granulated powder
was less than adsorption process. The C8 of S-SMEDDS
exhibited maximum drug content in both methods. The values
are compared in Figure 5.
Reconstitution property. The time taken to form clear solutions
was noted which determines the solubilization efficiency of
carrier. Table 4 indicates that the formation of microemulsion was
spontaneous and it was in the range of 2–3 min.
Figure 3. Percent AS release from I1–I8 formulations.
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Drug release from S-SMEDDS. As shown in Figure 6, in-vitro
release studies were evident that the AC8 formulation obtained
from C8 of liquid SMEDDDS which was composed with glycerin
as co-surfactant, had highest dissolution profiles (94%) followed
by MI8 with 89% and MC8 with 86% at the end of 30 min. Table 5
explains that the release kinetics of AS from solid SMEDDS
followed variant mechanisms and First-order and Korsemayer–
Peppas kinetic models.
SEM analysis. SEM analysis of S-SMEDDS of AC8 and AI8
were performed. Figure 7 showed that these images showed
particles were loose without much aggregations.
DSC studies. The thermograms of AS, AC8 and AI8 of Figure 8
had shown a negative shift in melting point from 158 to 135
C
showing a change in solid state characteristic, explains the reason
for their enhanced solubility in formulations.
Stability study. The stability testing of S-SMEDDS (AC8 and
AI8) was carried out in triplicate for 90 days at 25
C/60% RH,
45
C/65% RH and 60
C/75% RH. The data presented in Table 6
were evidenced that the solid SMEDDS filled in capsules when
stored at stress conditions had shown some physical variations at
the end of 90 days. A little deformation was observed in some
capsule units kept at 60
C/75% RH condition. The capsules kept
at 45
C/65% RH and 25
C/60% RH conditions were found intact.
There was no significant change observed in the drug content of
formulations kept at 25
C/60% RH and 45
C/65% RH condi-
tions. The difference in the drug release was not significant in the
formulations stored at 25
C/60% RH, 45
C/65% RH and 60
C/
75% RH. Shelf lives (t90) of AC8 and AI8 formulations were
found to be 1.57 and 1.22 years respectively.
Figure 4. Triplots of optimized Liquid SMEDDS formulations.
Table 3. Physicochemical properties of selected liquid SMEDDS.
Formulation
Particle
size (nm)
Polydispersity
Index pH
Viscosity
(cps)
Zeta
potential (mV)
C4 25.43 0.21 7.1 255.20 À3.34
C8 28.14 0.20 7.0 227.03 À1.24
I4 22.92 0.16 7.2 221.12 À10.7
I8 26.28 0.20 7.2 224.15 À4.68
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Discussion
The solubility studies of the AS in various vehicles were intended
for selection of proper vehicles for the formulation of SMEDDS.
The solubility in vehicles followed a fashion relating their HLB.
The vehicles are selected based on their highest solubility towards
AS. The selected oils i.e. coconut oil and IPM has HLB 7 and 11.5
respectively, due to which they showed higher abilities to dissolve
AS in them. The composition of selected vehicles was selected by
drawing a triplot between surfactant mixture, oil and water using
sigma plot 10.0 version. The working formula was prepared by
adding 50 mg of AS to oil and surfactant mixture ratio selected
from the ternary plot and the further characterization were carried
out using these formulae.
The drug content in liquid SMEDDS was assessed by diluting
them with methanol. The data inferred good drug-loading with
low standard deviation indicating the uniformity of drug content.
The data of dissolution were portrayed with variation in drug
release patterns which was due to the efficiency of co-surfactants
used. Glycerin as a co-surfactant had shown greater reduction of
particle sizes as it is a small chain alcohol than PEG 400. Glycerin
being less hydrophilic maintains the hydrocarbon chains of Tween
80 in oil phase between them resulting in effective van Der Waal
attractions, which make the film more strong and stable against
coalescence. Due to long chain length, PEG 400 has a limitation
in reducing interfacial tension to ultra low-level along with Tween
80. The co-surfactant at higher concentrations was able to liquefy
the interfacial film and thereby increase its flexibility to mould
globule to lower size than that of surfactant rich formulations. The
results of size analysis displayed that the globules in liquid
SMEDDS were uniformly distributed. The uniformity among
smaller size globules were the direct results of high co-surfactant
concentrations.
As liquid SMEDDS contain Tween 80 (nonionic surfactant),
was able to reduce the interactions between globules by steric
repulsions rather than electrokinetic approach, and resulted in less
potential development. The negative charge developed was due to
the type of oil/lipid phase used in the SMEDDS. This kind of
electrical approach was of low substantial reason in maintaining
stability of the dispersed system.
The adsorption and melt granulation techniques were
employed to produce the batches of S-SMEDDS and were
screened for their micromeritics. The values of micromeritics in
this study were influential to understand the flow and to select the
size of capsule for encapsulation of S-SMEDDS. With corres-
pondence to tapped volume, powder material containing the dose
equivalent solid SMEDDS about 10 mg was filled into size
1 capsule. The data from the angle of repose and Hausner’s ratio
values indicated the need of an aid for S-SMEDDS flow and in
particular, the powders obtained from melt granulation need bit
more addition of glidant, since the vehicles used were little waxy
in nature.
The rapid release of AS from S-SMEDDS formulations could
be attributed as spontaneous formation of microemulsion. The
S-SMEDDS prepared by adsorption technique had higher drug
release than melt granulation. The principal reason for this
difference relies on how the carrier behaves on contacting water.
In S-SMEDDS prepared by adsorption technique, liquid
SMEDDS adsorbed onto the surface of carrier and rest between
the surface voids till they contacts water. Once it contacts water,
Figure 5 Angle of repose and % Drug content of S-SMEDDS.
Table 4. Micromeritics and reconstitution time (RT) of S-SMEDDS.
Formulation
code
Bulk density
(g/cc)
Tap density
(g/cc) HR RT (min)
AC4 0.42 ± 1.06 0.47 ± 0.22 1.12 2.5
AC8 0.39 ± 0.56 0.45 ± 0.43 1.16 2
AI4 0.43 ± 0.22 0.49 ± 0.48 1.14 3
AI8 0.44 ± 0.17 0.50 ± 0.39 1.14 1.8
MC4 0.52 ± 0.04 0.60 ± 0.36 1.15 2.2
MC8 0.42 ± 1.2 0.44 ± 0.94 1.04 2.3
IC4 0.42 ± 0.63 0.47 ± 0.41 1.11 2
IC8 0.42 ± 0.58 0.50 ± 0.77 1.19 2.1
Values are expressed as mean ± S.D. (n ¼ 6). HR ¼ Hausner ratio.
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Figure 6. Percent AS release from S-SMEDDS.
Figure 7. SEM images of S-SMEDDS.
Table 5. Release kinetics for S-SMEDDS.
Correlation coefficient (r)
Model AC4 AC8 AI4 AI8 MC4 MC8 MI4 MI8
Zero order 0.4223 0.4134 0.5451 0.5221 0.5637 0.6463 0.544 0.38
First order 0.9696 0.9985 0.9969 0.9566 0.937 0.9634 0.9742 0.9493
Higuchi 0.6545 0.6414 0.7441 0.7328 0.7738 0.829 0.7464 0.6167
Peppas 0.9947 0.9903 0.9999 0.9233 0.9966 0.9485 0.9435 0.9003
Hixson Crowell 0.3434 0.2953 0.4564 0.4615 0.4971 0.6396 0.475 0.2943
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liquid SMEDDS forms microemulsion in no time. This was not
evident in melt granulation where the drug was mixed up with a
hydrophilic carrier. The drug release was observed after solubil-
ization of macrogol. Drug release was found to be hindered due to
polymer matrix and physiochemical properties. The globule size
was not affected by methods and carriers used in solid SMEDDS.
The S-SMEDDS had smooth texture and uniform surface obtained
from SEM inferring the proper adsorption of AS onto the carrier.
A negative shift observed in DSC thermogram supports the
enhanced solubility of formulations.
Encapsulated formulations of S-SMEDDS were subjected for
the stability testing at different stress conditions. As gelatin is
hydrophilic, it may get solubilized at higher RH conditions
(60
C/75% RH). Due to the permeation of moisture, capsules lost
the integrity and resulted with a minute loss of drug along with an
insignificant change in capsule weight. Thus prepared
S-SMEDDS formulations offer more stability with increased
shelf-life and become intact over a period of time.
Conclusion
Liquid SMEDDS of AS were composed according to the
solubility of drug in mixtures of oil phase, surfactant and
co-surfactant systems. The formulations with high concentration
of co-surfactant had shown maximum drug release from the
dialysis tubings owing to their less particle size of range 25 nm.
The promised liquid SMEDDS were selected based on their drug
release and pseudo-ternary phase behavior and were formulated as
S-SMEDDS by adsorption and melt granulation techniques.
Adsorption technique was found better than melt granulation in
terms of drug release. The prepared S-SMEDDS has displayed
good reconstitution ability. Upon microemulsification of AS solid
Table 6. Data of stability study.
Test conditions Formulation code 15 days 30 days 60 days 90 days
Physical appearance of S-SMEDDS
25
C/60% RH AC8 Intact Intact Intact Slight elongation
AI8 Intact Intact Intact Slight elongation
45
C/65% RH AC8 Intact Intact Slight elongation Elongated
AI8 Intact Intact Slight elongation Elongated
60
C/75% RH AC8 Intact Slight elongation Elongated Elongated
AI8 Intact Slight elongation Elongated Elongated
Percent drug content in S-SMEDDS
25
C/60% RH AC8 91 ± 0.11 91 ± 0.90 87 ± 0.71 84 ± 0.39
AI8 91 ± 0.20 91 ± 0.19 87 ± 0.16 86 ± 0.64
45
C/65% RH AC8 91 ± 0.13 82 ± 0.22 79 ± 0.54 75 ± 0.88
AI8 91 ± 0.76 81 ± 0.44 76 ± 0.23 75 ± 0.47
60
C/75% RH AC8 91 ± 0.81 77 ± 0.42 69 ± 0.22 64 ± 0.78
AI8 91 ± 0.12 79 ± 0.33 70 ± 0.63 63 ± 0.26
Percent drug release from S-SMEDDS
25
C/60% RH AC8 93.62 ± 0.58 89.02 ± 0.08 91.62 ± 0.28 91.62 ± 0.28
AI8 90.22 ± 0.45 84.22 ± 0.11 89.22 ± 0.42 89.22 ± 0.42
45
C/65% RH AC8 91.62 ± 0.68 85.22 ± 0.78 90.27 ± 0.68 90.27 ± 0.68
AI8 89.22 ± 0.56 92.0 ± 0.12 89.0 ± 0.20 89.0 ± 0.20
60
C/75% RH AC8 87.62 ± 0.80 93.62 ± 0.08 90.24 ± 0.18 88.62 ± 0.68
AI8 88.22 ± 0.31 90.62 ± 0.16 88.21 ± 0.26 85.25 ± 0.21
Values are expressed as mean ± S.D. (n ¼ 3).
Figure 8. DSC thermograms of S-SMEDDS.
Forpersonaluseonly.

formulations, the absorption of AS will be certainly promoted
since alone AS being class II category, has a very poor
bioavailability. The S-SMEDDS filled in capsules which offer
better patient compliance and were intact even at elevated stress
conditions and thus S-SMEDDS possess a shelf-life of 1.3 years
on an average. Overall, S-SMEDD formulations can offer
superiority in circumventing stability associated issues of liquid
SMEDDS, dose accuracy, enhanced absorption and patient
compliance. Thus this technique can be exploited for BCS class
II and IV drug candidates effectively.
Acknowledgements
The authors are thankful to M/s. Unichem Laboratories, Goa, India for
providing gift sample of drug and the management of Sree Vidyanikethan
College of Pharmacy, Tirupati, India for providing the necessary facilities
to carry out the research work.
Declaration of interest
The authors report that the article content has no declarations of interest.
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