Bulletin of Pharmaceutical Research 2018;8(2):156

An Official Publication of Association of Pharmacy Professionals

ISSN: 2249-6041 (Print); ISSN: 2249-9245 (Online)

DOI: 10.21276/bpr.2018.8.2.1

RESEARCH PAPER

D-OPTIMAL MIXTURE DESIGN FOR OPTIMIZATION OF

SELF MICRO-EMULSIFYING DRUG DELIVERY SYSTEM OF
SIMVASTATIN: CHARACTERIZATION AND IN VITRO
EVALUATION
Kalpana G. Patel*, Apeksha T. Patel, Jenee R. Christian, Asha S. Patel, Purvi A. Shah and
Mukesh C. Gohel
Department of Quality Assurance; Department of Pharmaceutical Chemistry; Department of Pharmaceutics,
Anand Pharmacy College, Anand, Gujarat 388001, India

*E-mail: kalpanapatel.pharma@gmail.com
Tel.: +91 9825587547.

Received: Jun 20, 2018 / Revised: Jul 22, 2018 / Accepted: Jul 23, 2018

The objective of present research work was to develop self-micro emulsifying drug delivery system to
improve the in vitro dissolution of a Biopharmaceutical Classification System Class II lipid lowering agent,
simvastatin. Solubility study was performed to identify the potent oil, surfactant and co-surfactant showing
highest solubility of simvastatin. The ternary phase diagrams were constructed for selected components to
identify the area of microemulsion formation. D-optimal mixture design was applied for optimization using
three formulation variables namely, oleic acid, Tween 80 and Cremophore EL. The liquid self-micro
emulsifying drug delivery systems (SMEDDS) were evaluated for droplet size, self-emulsification time,
percent transmittance and drug solubility. The optimized batch showed self-emulsification time and
solubility. The optimized liquid formulation was solidified using Aerosil 200 to prepare solid SMEDDS. Solid
SMEDDS showed good flow property and uniform drug content. Solid state characterization was performed
by differential scanning calorimetry, X-ray diffraction study and scanning electron microscopy. The zeta
potential and globule size was -3.66mV and 755.3 nm, respectively. The rate and extent of drug dissolution
from solid SMEDDS was significantly higher than tablet formulation. The optimized formulation was found
to be stable. These results demonstrate the potential of SMEDDS as a means of improving solubility and
dissolution.
Key words: Simvastatin, SMEDDS, D-Optimal design, Solubility, Dissolution.

INTRODUCTION and antithrombotic effect that influences their

The statins are 3-hydroxy-3-methylglutaryl- therapeutic application (Słupski et al 2017).
coenzyme (HMG-CoA) reductase inhibitors, the Simvastatin is lipophilic and being
most potent and most widely used cholesterol Biopharmaceutical Classification System II (BCS
lowering drugs. They inhibit the conversion of II) drug exhibits poor water solubility which
HMG-CoA to mevalonic acid, leading to reduced results in low bioavailability, intra and inter
biosynthesis of cholesterol. They have various subject variation and lack of dose
pleiotropic properties; improvement of the proportionality. The recommended oral
endothelial function, stabilization of administration of solid dosage forms of
atheromatous plaque, an increase of nitric oxide simvastatin for primary hypercholesterolemia
(NO) synthesis, as well as the anti-inflammatory results in low bioavailability attributed to its low
1 
Patel et al Bull. Pharm. Res. 2018;8(2)

solubility, pre-systemic clearance in the cell membrane and tight junctions of the
gastrointestinal (GI) mucosa, and extensive first- intestinal epithelium increasing the permeability
pass metabolism in the liver (Yeom et al 2016). of the intestinal barrier (Djekic et al 2017).
Hence, it poses a challenge in developing an Moreover, the lipoidal part of SMEDDS
optimum oral solid dosage form with enhanced encourages the intestinal lymphatic uptake of
bioavailability. drugs which further helps in avoiding the pre-
Many techniques have been used to overcome or systemic biotransformation of drug molecules
modify solubility and permeability issues (Qureshi et al 2015; Li et al 2017; Kalepu et al
including micronization, complexation, solid 2013). This feature makes SMEDDS a meaningful
dispersion, cyclodextrin nanoparticles, co- choice for oral delivery of lipophilic and low
precipitation (Janković et al 2016; Dahiya, 2017; bioavailable simvastatin. Recently, numerous
Patel et al 2015; Prusty, 2014; Pabreja and Dua, SMEDDS products such as Sandimmun Neoral®,
2011; Sachan and Pushkar, 2011; Pathak et al Norvir®, and Fortovase® have been widely
2008; Dahiya et al 2008; 2015; Dahiya and commercialized (Yeom et al 2016).
Pathak, 2006; 2007). Lipid based drug delivery is Further, a systematic and structured
an alternative and rational formulation strategy optimization study was employed to design the
by selection of appropriate lipid vehicles. self-emulsifying drug delivery system of
Moreover, many lipid excipients with acceptable Simvastatin by using the Design of Experiments
regulatory and safety limits have been available. (DoE). With the application of DoE, drug
The availability of lipid excipient with acceptable products with high and reproducible quality can
regulatory and safety profiles coupled with their be anticipated. Among all experimental designs,
ability to improve solubility and permeability D-optimal mixture design is particularly suited
have gained much importance. An appropriate for micro-emulsion systems as microemulsions
selection of lipid vehicle, formulation strategies essentially consist of three components, namely
and rational drug delivery system can lead to oil, surfactant and co-surfactant phase.
successful drug delivery system. Lipid based Moreover, D-optimal designs are model
formulation approaches, particularly self-micro independent and hence a straight way of
emulsifying drug delivery system (SMEDDS) is optimization based on a set of criterion chosen
well established as a promising strategy for and the suitable model that can fit can be
improvement of oral delivery of hydrophobic attained. This in turn, allow a systematic
drug substances associated with limited manipulation of critical process parameters to
solubility and low oral bioavailability (Silva et al achieve better product and process
2015; Janković et al 2016). understanding with the identification of the
According to the Lipid Formulation Classification optimal values of the critical process parameters
System (LFCS), SMEDDS are type III B self- that would yield a product with the required
dispersing systems comprising a drug substance properties and characteristics (Zhang and Mao,
in a mixture of lipids (< 20%), hydrophilic 2017; Kumar and Shishu, 2015).
surfactants (20-50%) and co-solvents (20-50%) Hence, the purpose of this study was to
(Djekic et al 2017). SMEDDS optimized to form systematically investigate the influence of the
oil-in-water micro-emulsion based formulation type and concentration of the oil, surfactants and
is a blend of oils and surfactants in suitable co-surfactant on the drug loading capacity,
proportion that rapidly forms an oil in water dispersibility in aqueous media, and in vitro
micro-emulsion with moderate gastric motility potential for drug absorption enhancement of
when exposed to the aqueous media present in the SMEDDSs for oral delivery of simvastatin.
the gastrointestinal tract. It typically produces a Solidification was done by using suitable
transparent micro-emulsion having reduced adsorbent so as to get advantage of unit dosage
globule size and high thermodynamic stability. form and improved physical stability.
Rapid emulsion formation helps to keep the drug
in a dissolved form, however, small droplet size МATERIALS AND METHODS
offers a considerably larger interfacial surface Materials
area which further accelerate the absorption Simvastatin was gifted by Zydus Cadila Pvt. Ltd.,
rate of drug with limited solubility and the Ahmedabad, India. Cremophore EL and
extent of drug absorption by different Cremophore RH 40 were gifted by BASF,
mechanism related with the micro-emulsion Mumbai. Tween 80, Tween 20, PEG 200 and PEG
carrier itself, thereby causing disturbance of the 400 were purchased from S D Fine Chemicals,
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Patel et al Bull. Pharm. Res. 2018;8(2)

Mumbai. Isopropyl myristate, isopropyl a mixture of surfactant and co-surfactant at fixed

palmitate and oleic acid were purchased from weight ratios. For each Smix ratio, a separate
Chemdyes Corporation, Rajkot. All other phase diagram was constructed. Only
chemicals and reagents were of pharmaceutical microemulison points are plotted (shaded area),
grades. so that there is no overcrowding of the phases in
the diagram, as for the formulation development
Solubility studies viewpoint, only the microemulsion formation
The solubility of simvastatin in various oils, area is of interest (Dokania and Joshi, 2015;
surfactants and co- surfactant were determined Andey et al 2016).
by adding excess amount of drug in each vial
containing 2 ml of vehicle. The prepared Optimization of SMEDDS using D-Optimal
mixtures were then mixed using a vortex mixer mixture design
to facilitate solubilization. Mixtures were shaken Development of SMEDDS involves rational
on shaker bath at 30°C for 48 h. After reaching selection of excipients, like oil, surfactant, co-
equilibrium, the mixtures were centrifuged at surfactant. One of the current requirements in
3000 rpm for 10 min, then 0.1 ml supernatant dossier for ANDA submission is the development
was taken and the drug content was quantified of product considering the concepts of quality by
using UV visible spectrophotometer at 237.59 design (QbD). Hence, thorough understanding of
nm after dilution with methanol (Padia et al influence of excipients on the performance of
2015). product is essential. D-optimal mixture design
provides an efficient means of optimizing the
Pseudo ternary phase study process as well as determining the optimal
Pseudoternary phase diagrams were formulation of a specific mixture of oil,
constructed using water titration method in surfactant, co-surfactant in self micro
order to obtain the concentration range of emulsifying drug delivery system. To explore
components for identifying the region of simvastatin apparent solubility, a mixture (D-
microemulsion. Surfactant (Tween 80) and co- optimal) experimental design was set up within
surfactant (Cremophore EL) were mixed in six the restricted domain.
different volume ratios [1:1(A), 1:2(B), 1:3(C), In this study, the restricted experimental region
2:1(D), 3:1(E) and 4:1(F)] to prepare six was selected on the basis of results obtained
different Smix. These Smix ratios were chosen to from ternary phase diagram. The experimental
reflect the increasing concentration of co- study was designed based on a three component
surfactant with respect to surfactant and system: the oil X1 (oleic acid), the surfactant X2
increasing concentration of surfactant with (tween 80) and the co-surfactant X3
respect to co-surfactant for detailed study of the (Cremophore EL). Based on the previous results
phase diagram in the microemulsion formation. obtained from phase diagram and preliminary
Pseudo ternary phase diagrams were screening, the range of X1 was selected as 1-
constructed using the aqueous titration method 10%, X2 was selected as 10-29% and X3 was
from 1:9 to 9:1 ratio of oil to Smix. Slow titration selected as 5-15%. Values of independent
with the aqueous phase was performed for each variables were introduced into the Design-
combination of oil and Smix separately. The Expert version 7 software and batch matrix was
amount of aqueous phase added was varied to derived. Sixteen batches were prepared within
produce a water concentration in the range of the restricted domain, which allowed fitting of a
5% and 95% of total volume at around 5% reduced cubic model, a check for lack-of-fit and
interval. After each 5% addition of the aqueous an estimate for experimental error. The
phase to the oil: Smix mixture, visual observation experiments were carried out randomly to
was made and recorded. Through visual minimize systematic errors and experimental
observations, the categories assigned were results were analyzed with Design Expert 7.0.
either transparent and easily flowable, oil/ The self- emulsification time (Y1) and solubility
water microemulsion or milky/cloudy emulsion. (Y2) were chosen as the responses (Patil et al
The physical state of the microemulsion was 2016; Chatterjee et al 2016).
marked on pseudo three component phase
diagram constructed using PROSIM software Preparation of liquid SMEDDS
with one axis representing aqueous phase, the A series of SMEDDS were prepared by mixing
other representing oil and the third representing accurately measured amount of oleic acid,
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Patel et al Bull. Pharm. Res. 2018;8(2)

Tween 80 and Cremophore EL into glass vials. Adsorption on solid carrier is easy and reliable
The components were mixed well by gentle method to convert liquid SMEDDS into solid
stirring at 37°C in water bath. Then, weighed product (S-SMEDDS). Colloidal silicon dioxide
amount of simvastatin (20 mg per 0.5 ml) was (Aerosil 200) shows high adsorption capacity
added and the systems were stirred and so it was used. The liquid SMEDDS (0.5 ml)
continuously until simvastatin was completely was added dropwise over solid absorbent in a
dissolved. The mixtures were stored at room broad petri dish. After each addition, the mixture
temperature. was homogenized using glass rod to ensure
uniform distribution of the components. The
Characterization of liquid SMEDDS resultant S-SMEDDS were passed through 500
Self-emulsification time, solubility study, percent mesh to get uniform free flowing aggregates. The
transmittance determination, droplet size aggregates were stored over anhydrous calcium
analysis and zeta potential were determined for chloride in desiccator until further evaluation.
characterization of liquid SMEDDS. The
efficiency of self-emulsification of oral micro Evaluation of solid SMEDDS of simvastatin
emulsion was assessed using a standard USP DSC, XRD and SEM studies
dissolution apparatus. One millilitre of each Differential scanning calorimetry (DSC) thermo
formulation was added to 500 ml of water at scans of the pure simvastatin and respective S-
37±0.5°C. A standard stainless steel dissolution SMEDDS were recorded using thermal analyzer.
paddle rotating at 50 rpm provided gentle The samples were heated from 50 to 180°C at a
agitation. Time required to form emulsion was rate of 10°C/min in an open pan using alumina
assessed visually (Čerpnjak et al 2015; Chavan et as a reference material.
al 2015). X-ray diffraction pattern of drug alone and
For solubility study, drug was added to 2 ml of formulation were recorded using X-ray
liquid SMEDDS till super saturation. The diffractometer. D8 advance of Bruker AXS
resultant solution was kept in orbital shaker for instrument, with Vertical Theta-Theta
48 h. Each vial was centrifuged at 3000 rpm for Goniometer with -1100 < 2θ < 1680 goniometer
10 min. The supernatant was diluted with control was used. New short ceramic Copper X-
methanol. The concentration of drug was ray tube with fine long focus was used. Two
quantified by measuring the absorbance at exchangeable detectors of scattered X-rays: NaI
specific wave length (238.73 nm) using UV– scintillator type detector with low background
visible spectrophotometer. The content of drug (0.4 cps) and high dynamic range (up to 2 × 106)
was calculated from the standard calibration and Braun position-sensitive detector were
curve (Jannin et al 2015). Percent transmission employed.
measurement can be used to reflect clarity and Scanning Electron Microscopy was performed
micron size of globules. The percent for morphological study, sample was fixed on an
transmittance of the system was measured at aluminium stub with conductive double sided
650 nm using UV-visible spectrophotometer by adhesive tape and coated with gold/palladium in
using distilled water as blank (Zhang and Mao, an argon atmosphere (50 Pa) at 50 mA for 50 s
2017). For droplet size analysis and zeta and micrograph was taken at an appropriate
potential measurements, one ml of liquid magnification for detailed visualization of the
SMEDDS of simvastatin was dissolved in 500 ml surface using a Nova nano SEM 450 (FEI Ltd.,
of distilled water. The droplet size of the USA). The samples were scanned at a voltage of
emulsions was determined by using a zetasizer 5kV.
that is able to measure sizes between 10 and
5000 nm. Light scattering was monitored at 25°C Drug content studies
at a 90° angle, after external standardization Drug content was determined by accurately
with spherical polystyrene beads. The weighing powder equivalent to 10 mg drug
micromeritic size range of the globules is dissolved in 10 ml methanol. It was stirred for
retained even after 500 times dilution with 15 min and filtered. Appropriate dilutions were
water proves the system’s compatibility with prepared subsequently and were analyzed by
excess water (Zhang and Mao, 2017). UV-VIS spectrophotometer (UV-1600, Shimadzu,
Japan) at 238.73 nm. Flow property was
Preparation of solid SMEDDS of simvastatin evaluated in terms of Carr’s index,

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Patel et al Bull. Pharm. Res. 2018;8(2)

compressibility index, Hausner’s ratio and angle surfactants were compatible with the drug at
of repose. room temperature. Amongst the oils tested, the
maximum solubility of simvastatin was found in
In-vitro drug release study the oleic acid.
The in-vitro dissolution study of S-SMEDDS and The reason behind this result is that other oils
marketed drug product were carried out using are less polar than oleic acid. The hydrophilic
USP-Type II dissolution test apparatus in 900 ml lipophilic balance (HLB) value has been proven
0.1 M hydrochloric acid at 37±0.5°C with 100 to be very useful in choosing the best type of
rpm rotating speed. Samples were withdrawn at surfactant for immediate formation of O/W
10, 20, 30, 40, 50 and 60 min time interval and droplets and/or rapid spreading of the
filtered through whatman filter paper. An equal formulation in the aqueous environment. An
volume of dissolution medium was replenished important criterion for selection of the
after every sampling to maintain constant surfactant is that the required HLB value to form
volume. Samples were analyzed using a double O/W micro-emulsion is greater than 10. A
beam UV spectrophotometer at 238.73 nm. The proper surfactant HLB value is a key factor for
cumulative percentage drug released was the formation of emulsion with small droplets.
calculated and graph was plotted against time. Among surfactants tested, Tween 80 could
solubilize highest amount of simvastatin.
RESULTS AND DISCUSSION Therefore, Tween 80 was selected as the
Solubility study surfactant for SMEDDS formulation. Among co-
In this study, different oils, surfactants and co- surfactants tested, Cremophore EL showed
surfactants were explored for determining highest drug solubility. Therefore, cremophore
solubility of simvastatin. For each excipient, EL was selected as the co-surfactant for SMEDDS
λmax of the drug in methanol, i.e. 237.59 nm was formulation. The average solubility of
found to be retained. This information indicates simvastatin in various oils, surfactant and co-
that each of these oils, surfactant and co- surfactant is as depicted in Figure 1.

Figure 1. Solubility of simvastatin in various components, oil,

surfactant and co-surfactant

Pseudo ternary phase diagram diagram mixture. Only certain combinations of

The concentration of mixture components were oil, surfactant and co-surfactant produced fine
recorded in order to complete the microemulsion upon dilution with water. The
pseudoternary phase diagrams, and then the area bound by the points in the phase diagram
contents of oil, blend of surfactant and co- displays the concentration range of SME mixture
surfactant (Smix) and water at appropriate components that resulted in a clear
weight ratios were selected based on the results microemulsion out of all the trial concentrations.
of ternary phase diagrams. All the combinations under test formed a
An o/w microemulsion region was found microemulsion in certain concentrations, but the
towards the water-rich apex of the phase combination with wider SME region is
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Patel et al Bull. Pharm. Res. 2018;8(2)

considered to be a better combination in terms study, ratio 2:1 was found to have wider SME
of self-micro emulsification efficiency. In this region (Figure 2).

A(1:1) B(1:2)

C(1:3) D(2:1)

. E(3:1) F(4:1)
Fig. 2. Pseudo-ternary phase diagram formed by olive oil, Tween 80 and Cremophore EL surfactant blend
and water; (A) 1:1; (B) 1:2; (C) 1:3; (D) 2:1; (E) 3:1; (F) 4:1

Optimization of SMEDDS using D-optimal of 16 experiments for three factors (amount of

mixture design oleic acid, Tween 80 and Cremophore EL). The
From pseudo ternary phase diagram study and experimental runs with independent variables
preliminary experiments, the ranges of A (oleic and the observed responses for the 16 SMEDDS
acid in %), B (Tween 80 in %) and C formulations are shown in Table 1. The model
(cremophore EL in %) were selected as 1-10%, incorporating main effect and interaction effects
10-29% and 5-15% respectively. D-optimal was selected based on the estimation of several
mixture design was selected for the statistical parameters, such as the multiple
optimization. The mixture design includes a total correlation coefficient (r2), adjusted multiple

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Patel et al Bull. Pharm. Res. 2018;8(2)

correlation coefficient (adjusted r2) and the provided by the Design-Expert software (7.0)
predicted residual sum of squares (PRESS), version.

Table 1. D-optimal mixture design with responses

Oleic acid Tween 80 Cremophore EL Solubility of Self emulsification
Run
(%) (%) (%) simvastatin (mg/ml) time (sec)
1 4.763 24.794 5.441 72.862 108
2 1.000 28.99 5.007 66.055 31
3 1.321 18.678 15.00 71.640 16
4 5.270 14.729 15.00 76.876 92
5 9.992 10.007 15.00 105.846 166
6 10.00 19.214 5.785 117.539 73
7 1.321 18.678 15.00 71.815 15
8 1.000 23.693 10.306 77.748 11
9 9.992 10.007 15.00 105.846 102
10 4.550 18.094 12.355 74.432 83
11 1.000 28.993 5.007 66.055 20
12 5.544 20.453 9.001 78.621 70
13 10.00 19.214 5.785 117.714 100
14 8.154 12.893 13.952 93.63 93
15 1.000 23.693 10.306 77.574 33
16 8.631 15.134 11.234 95.898 105

The statistical parameters of ANOVA analysis for signal to noise ratio. Adequacy of precision
each response is listed in the Table 2. The compares the range of predicted values of the
difference observed in the predicted and design points to the average prediction error.
adjusted r2 is less depicting their close Ratios greater than 4 indicate adequate model
agreement. Adequate precision measures the discrimination.

Table 2. Statistical parameters by ANOVA analysis for models and responses

Adjusted Predicted Adequate
Response Std. Dev. Mean % CV PRESS r2 p value
r2 r2 Precision
Solubility 0.17 85.63 0.190 7.99 1 0.991 0.992 391.660 <0.0001
Self emulsification
25.2 69.88 3.607 13.02 0.92 0.985 0.947 8.990 0.0002
time

The polynomial equation in terms of coded graphs of RSM are generated by plotting the
factors can be used to make predictions about response model against three of the factors, in
the response for given levels of each factor. By which the interaction between the variables and
default, the high levels of the factors are coded as their mutual dependence is clearly observed as
+1 and the low levels of the factors are coded as - depicted in Figure 3a-b. A, B and C respectively
1. The model was cubic for response solubility represents percentage of oleic acid, Tween 80
and linear for self-emulsification time. The coded and Cremophore EL. The Figure 3a shows that
equation is useful for identifying the relative solubility of simvastatin increases with increase
impact of the factors by comparing the factor in amount of oil up to certain extent and
coefficients; for response solubility, -20.25*A+ decreases with increase in amount of surfactant
1.008*B-1.99*C+1.87*A*B+1.59*A*C+0.28*B*C- and co- surfactant. The Figure 3b depicts linear
0.09*A*B*C+0.04*A*B*(AB)-0.005*A*C*(A-C)+0. relationship between factor A, B and C. It can be
0024*B*C*(B-C) and for self-emulsification time, observed from the plot that self emulsification
+10.12*A+0.24*B+1.18*C. The model F value for time increases with increase in amount of oil and
both the responses further indicates that the decreases with increase in amount of surfactant
model is significant. The three-dimensional and co-surfactant.
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Patel et al Bull. Pharm. Res. 2018;8(2)

125 170

Self emulsification time

109 130

Solubility
93 90

77 50

61 10

A (20) A (20)
B (10) B (10)
C (24) C (24)

C (5) C (5)
A (1) A (1)

B (29) B (29)

(a) (b)
Fig. 3. 3-D response surface plot for (a) solubility and (b) self emulsification time
The design offered many solutions to prepare an composition. Therefore, to validate the
optimized batch, but the solutions were reduced optimized model, the formulation composition 1
by setting constraints for the response self and 2 were prepared. Observed value of an
emulsification time (less than 25s). The Design optimized solution 2 was quite closer to the
expert 7.0 suggested 5 solutions with predicted value, resulting in less % error (Table
desirability 1 and among these two were 3). Hence, optimized formula (1:28.993:6.199)
selected for optimization of formulation was selected for preparation of SMEDDS.

Table 3. Verification study: a comparison of predicted and experimentally observed

responses of all components
Oil (%): Surfactant (%): % Prediction
Response Predicted Observed
Co-surfactant (%) error
Solubility (mg/ml) 66.03 65 2.96
Solution 1 : 1:27.801:5.007
Self emulsification time (sec) 23.94 24.65 1.55
Solubility (mg/ml) 70.43 71.23 1.135
Solution 2 : 1:28.993:6.199
Self emulsification time (sec) 24.06 23.78 1.16

Evaluation of optimized SMEDDS physical stability (Figure 4).

In order to assess the optical clarity, UV-visible
spectrophotometer was used to measure the Evaluation of solid SMEDDS of simvastatin
amount of light of given wavelength transmitted The physical state of the drug present in solid
by the SMEDDS. The % transmittance of SMEDDS was confirmed from DSC studies. The
optimized batch was found to be 99.1%. Droplet DSC curves of simvastatin and S-SMEDDS
size is considered to be a decisive factor in self formulations are shown in Figure 5 and pure
emulsification performance because it is related simvastatin showed sharp endothermic peak at
with the rate and extent of drug release and temperature 138 °C, corresponding to its
absorption. melting point and indicating its crystalline
Non-ionic surfactants can effectively stabilize the nature showing melting occurred at that
oil-water interface and hence are more efficient. temperature. However, result shows the
Furthermore, the decrease in the droplet size disappearance of endothermic peak of the drug
reflects the formation of a better closed packed in the S-SMEDDS and supports the presence of
film of the surfactant at the oil-water interface, simvastatin in an amorphous form in S-SMEDDS.
thereby stabilizing the oil droplets. The droplet X-ray diffraction pattern of simvastatin and solid
size of optimized SMEDDS was determined after SMEDDS was recorded using X-ray
dilution of 500 times in water. The mean droplet diffractometer, XRD study was used to measure
size was found to be 755.3 nm. Zeta potential of the crystallinity of the solid SMEDDS. The peak
the optimized batch was found to be -3.66 mV. position (angle of diffraction) is an identification
The low value of zeta potential indicate better tool of a crystal structure, whereas the number

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Patel et al Bull. Pharm. Res. 2018;8(2)

of peak measures sample crystallinity in a solid SMEDDS are presented in Figures 6a-b
diffraction. The XRD pattern of simvastatin and respectively.

(a)

(b)
Fig. 4. SMEDDS: (a) zeta potential and (b) globule size

(a)

(b)
Fig. 5. DSC thermogram of (a) pure simvastatin and (b) solid SMEDDS of simvastatin
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Patel et al Bull. Pharm. Res. 2018;8(2)

The XRD pattern of simvastatin indicated the reflected the crystallinity of drug and above
presence of major peaks at 8.32°, 10.88°, 17.17°, peaks were noticeably reduced in case of S-
18.6°, 21.38°, 22.16°, 23.9°, 24.66°, 31.6° and SMEDDS indicating the conversion of crystalline
32.06°. The diffraction pattern of pure drug state to an amorphous state.

(a)

(b)
Fig. 6. X-ray diffraction pattern of (a) pure simvastatin and (b) solid SMEDDS of simvastatin

Fig. 7. SEM image of solid SMEDDS

The morphology of the optimized S-SMEDDS volume (4.133 ± 0.152), tapped volume (3.7 ±
showed spherical particles without aggregation 0.173), angle of repose (29.367 ± 0.416), bulk
by scanning electron microscopy (Figure 7). density (0.484 ± 0.017), tapped density (0.541 ±
The mean percent drug content of S-SMEDDS 0.025), compressibility index (10.499 ± 1.509)
was found to be 96.931±0.236%. S-SMEDDS and hausner’s ratio (1.118 ± 0.018). Dissolution
exhibited good flow property in terms of bulk profile of optimized batch of S-SMEDDS revealed
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Patel et al Bull. Pharm. Res. 2018;8(2)

83.833% drug release within 20 min, whereas S-SMEDDS had better dissolution profile
tablet showed 42.391% drug release after 20 compared to marketed tablet, as shown in the
min. So, it can be concluded that the optimized Figure 8.

Fig. 8. Cumulative drug release profiles for S- SMEDDS and tablet formulation

CONCLUSION to marketed tablet indicates the potential of

Solid SMEDDS is one of the recent approaches SMEDDS. In nutshell, solid SMEDDS formulation
for formulation of unit dosage form for drugs is capable to enhance solubility and dissolution
with low aqueous solubility. Selection of oil and of poorly water soluble drugs like simvastatin
surfactant, co surfactant blend is crucial and which may result in improved therapeutic
vary from drug to drug based on solubility study performance.
and hence optimization using experimental
design allowed evaluating the selected factors CONFLICT OF INTEREST
simultaneously, including interactions between There is no conflict of interest.
factors, by means of a rational approach in order
to reach the optimum conditions. ACKNOWLEDGEMENT
The optimized batch showed good results in The authors are grateful to GUJCOST for
terms of self-emulsification time (<25 s) and providing financial grant for the present
solubility (>70 mg/ml). The optimized solid investigation. The authors would also like to
SMEDDS formulation of simvastatin showed express thanks to Zydus Cadilla for providing
significant increase in dissolution rate compared gratis sample of simvastatin.

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