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Formulation and Characterization of SNEDDS of Dayak Onion Extract with
Comparative Variation of Surfactants, Co-Surfactants, and Palm Oil
Rahmi Annisa*, Alif Firman Firdausy, Ihda Mahila Alawiyah, Farianda Reformasiska
Department of Pharmacy, Faculty of Health and Medicine, Maulana Malik Ibrahim State Islamic
University of Malang, Malang, Indonesia
Email: [email protected]
Abstract
Self-Nanoemulsifying Drug Delivery System (SNEDDS) is a thermodynamically stable drug
administration unit with the capacity to increase the solubility of active pharmaceutical ingredients (API)
and bioavailability. In addition, dayak onion extract is an active ingredient developed to increase the
effectiveness of therapy. The aims to formulate, characterize, and investigate stability. Moreover, the
HLB approach was used to formulate SNEDDS from dayak onion extract, with a component ratio of palm
oil, a combination of surfactants (hydrophilic Tween 80, Tween 20) and lipophilic (Span 20 and
Transcutol) and PEG 400 as co-surfactants. A total of sixty formulas were used, with an HLB range of
11-15 and a ratio of 1:8:1, 1:7:2, and 2:7:1, followed by evaluating product characteristics. Furthermore,
two formulas were selected, including F13 (HLB 13) and F34 (HLB 14), at ratios 1:8:1 and 1:7:2. The
results showed particle size ranging from 10-200 nm, percent transmittance of <90%, while the viscosity
and pH values were stable at various dilutions. The evaluation for thermodynamics indicates an unstable
preparation. Therefore the SNEDDS formula of dayak onion extract using long-chain triglycerides (palm
oil) was ineffective.
Keywords: SNEDDS, self-nano emulsification, characteristic test, palm oil, HLB, dayak onion
(Eleutherine palmifolia).
Introduction
The development of formulation technology has attracted many researchers as an effort to
produce new drugs with ideal properties by considering molecular ion balance, hydrophilic-
lipophilic equilibrium, biopharmaceutical processes, metabolism and biodegradation, drug-
receptor affinity, physiological considerations, and the biocompatibility of the system as the
main factors influencing the development of formulation technology. Commonly done in
research is about nanotechnology (Martien et al., 2012). Nanoemulsion is a thermodynamically
stable preparation, transparent dispersion of oil and water stabilized by the interfacial film of
surfactant and co-surfactant molecules and has a droplet size of less than 100 nm (Shafiq-un-nabi
et al., 2007).
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Self-Nanoemulsifiying Drug Delivery System (SNEEDS) is one of the developments of
nanoemulsion delivery systems that can penetrate cell tissue by considering the physicochemical
properties of the active ingredients and additives in the formulation so that they affect the
resulting nanoemulsion preparations, such as droplet size, size distribution, and emulsification
time. (Date et al., 2010). The components of SNEEDS are influenced by the oil phase,
surfactant, and co-surfactant (Huda et al., 2016).
The oil component in this preparation is the primary carrier of the active substance. It is a
determinant of the droplet size of the emulsion formed. The oil used is palm oil
(Elaeisguineensis Jacq). Palm oil is a food oil with dominant long-chain fatty acids, which are
essential to reduce unsaturation, prevent oxidative degradation, and affect drug solubility in
water (Marpaung, 2014).
The next component, namely surfactants, reduces the size of droplets or emulsion droplets
and stabilizes the active substance at the absorption site. There is no deposition in the
gastrointestinal tract. The surfactants used were Transcutol, Span 20, Tween 80, and Tween 20.
Co-surfactants function to assist surfactants in finding the surface tension of water and oil,
increasing dissolution, and improving active substances' absorption (Marpaung, 2014). The co-
surfactant used is PEG with stable properties, easily soluble in warm water, non-toxic.
The number of comparisons between oil, surfactant, and co-surfactant in this study used
three ratios of variation between the three constituent components, namely 1:8:1, 1:7:2, 2:7:1. It
is also influenced by the HLB value to get the most stable SNEDDS. SNEDDS with HLB
between 11-15 is a stable vulnerability in the manufacture of SNEDDS systems (Winartiet al.,
2016).
The natural extract preparations that have been developed produce therapeutic
effectiveness with large enough doses, low solubility, and less than optimal oral bioavailability.
SNEDDS is used to increase the absorption and bioavailability of drugs in the body, especially
for low solubility in water (Nasr et al., 2016). The utilization of natural materials in this research
uses dayak onion extract with naphthoquinone secondary metabolite compounds that have
bioactivity as anticancer. The purpose of this research is expected to be an innovation for the
development of drug delivery systems with extracts of natural ingredients using various
concentrations of surfactants-co-surfactants with the oil used to improve the bioavailability of
active substances in the body.
Materials and Methods
Materials
The materials used in this study were dayak onion extract, palm oil, Tween 80 (Merck,
Germany), Transcutol (Gattefose, France), Tween 20, Span 20, PEG 400 (Bratachem,
Indonesia), Ethanol, HCl, NaOH, KH2PO4 pro analysis (Merck, Germany).
Methods
Optimization of the SNEDDS Formulation Design Using the HLB Method
SNEDDS components consist of palm oil, surfactants (Tween 80, Tween 20, Span 20, and
Transcutol), and co-surfactants (PEG 400). The ratio of the formula to 1:8:1, 1:7:2, 2:7:1. Two
hydrophilic surfactants (Tween 80, Tween 20) were mixed with two lipophilic surfactants (Span
20 and Transcutol) to form 4 binary combinations of surfactants with an HLB range of 11-15
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(Table 1). The HLB mix of each surfactant mixture is calculated by the following equation
(Winartiet al., 2016):
HLBmix = fAHLBA + fBHLBB
HLBA dan HLBB : surfactant value of A dan B
fA : weight fraction of surfactant A
fB : weight fraction of surfactant B
Tabel 1. Formula based on HLB and Component Ratio
Formula HLB Mix Surfaktan (% b/b) Component
mix Tween 80/ Tween 80/ Tween 20/ Tween 20/ Ratio
ratio Span 20 Transcutol Span 20 Transcutol
F1 11 30,00/50,00 - - -
F2 12 42,50/37,50 - - -
F3 13 55,00/25,00 - - -
F4 14 67,50/12,50 - - -
F5 15 80,00/0,00 - - -
F6 11 - 50,37/29,63 - -
F7 12 - 57,77/22,23 - -
F8 13 - 65,20/14,80 - -
F9 14 - 72,60/7,10 - -
F10 15 - 80,00/0,00 - - 1:8:1
F11 11 - - 23,70/56,30 -
F12 12 - - 33,58/46,42 -
F13 13 - - 43,46/36,54 -
F14 14 - - 53,30/26,70 -
F15 15 - - 63,21/16,79 -
F16 11 - - - 43,52/36,48
F17 12 - - - 49,92/30,80
F18 13 - - - 56,32/23,68
F19 14 - - - 62,72/17,80
F20 15 - - - 69,12/10,88
F21 11 26,25/43,75 - - -
F22 12 37,2/32,80 - - -
F23 13 48,13/21,87 - - -
F24 14 59,1/10,90 - - -
F25 15 70,00/0,00 - - -
F26 11 - 44,07/25,93 - -
F27 12 - 50,56/19,44 - - 1:7:2
F28 13 - 57,04/12,96 - -
F29 14 - 63,52/6,48 - -
F30 15 - 70,00/0,00 - -
F31 11 - - 20,74/49,26 -
F32 12 - - 29,40/40,60 -
F33 13 - - 38,02/31,98 -
F34 14 - - 46,67/23,33 -
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F35 15 - - 55,31/14,69 -
F36 11 - - - 38,08/31,92
F37 12 - - - 43,68/26,32
F38 13 - - - 49,28/20,72
F39 14 - - - 54,88/15,12
F40 15 - - - 60,48/9,52
F41 11 26,25/43,75 - - -
F42 12 37,20/32,8 - - -
F43 13 48,13/21,87 - - -
F44 14 59,10/10,90 - - -
F45 15 70,00/0,00 - - -
F46 11 - 44,07/25,93 - -
F47 12 - 50,56/19,44 - -
F48 13 - 57,04/12,96 - -
F49 14 - 63,52/6,48 - -
F50 15 - 70,00/0,00 - -
2:7:1
F51 11 - - 20,74/49,26 -
F52 12 - - 29,40/40,60 -
F53 13 - - 38,02/31,98 -
F54 14 - - 46,67/23,33 -
F55 15 - - 55,31/14,69 -
F56 11 - - - 38,08/31,92
F57 12 - - - 43,68/26,32
F58 13 - - - 49,28/20,72
F59 14 - - - 54,88/15,12
F60 15 - - - 60,48/9,52
SNEDDS Preparation
The preparation of SNEDDS, namely hydrophilic and lipophilic surfactants, was stirred at
300 rpm for 10 minutes. Co-surfactant PEG 400 was added and stirred for 10 minutes, finally
added oil little by little and stirred for 10 minutes. SNEDDS were stored for 24 hours and
observed for phase separation. The most stable preparation with the lowest surfactant
composition, the highest oil component, and the highest HLB was chosen as the SNEDDS
formula for dayak onion extract (Winarti et al., 2016).
Preparation of SNEDDS Bawang Dayak Extract
The design of the optimized SNEDDS formula consisting of oil, surfactant, and co-
surfactant added 50 mg of dayak onion extract, then mixed until homogeneous with a magnetic
stirrer LAB MS-H (Heidolph, Germany) for 10 minutes and stored at 25oC for further
characterization.
SNEDDS Characteristic Test of dayak onion extract.
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1. Transmittan Percent Test
Measurement of percent (%) transmittance of SNEDDS was carried out using a UV-Vis
1800 spectrophotometer (Shimadzu, Germany). Measurement by taking 100 L of each formula
then diluted with distilled water to 100 mL. The mixture was homogenized with a magnetic
stirrer at 200 rpm. SNEDDS was measured at a wavelength of 650 nm to determine the percent
transmittance (Nasr et al., 2016).
2. Emulsification Time Test
The SNEDDS formula was evaluated visually to determine the emulsification time using a
magnetic stirrer. A total of 100 L of SNEDDS was dropped into a beaker containing 100 mL of
simulated gastric fluid (SGF) without enzymes pH 1.2 ± 0.05 and simulated intestinal fluid (SIF)
at pH 6.8 ± 0.05 without enzyme (Ren et al., 2009), temperature 37oC with stirring 200 rpm. The
time for emulsification was determined as the SNEDDS time to form a homogeneous mixture
after mixing (Basaliusetal., 2010).
3. Particle Size Measurement
SNEDDSparticles were measured using the Microtrac Nanotrac wave II Particle Size
Analyzer (PSA). Take 100 L of SNEDDS, then put it into a cuvette. The cuvette used must be
free of foam and grease. The cuvette that has been filled with the sample is inserted into the
sample holder. The tool is turned on, and the particle size menu is selected.
4. pH measurement
The pH measurement of each formula was carried out using a calibrated digital pH meter
pH-700. Take 5 mL of SNEDDS, the electrode is inserted into the SNEDDS, and the number
indicated by the pH meter is recorded (Annisaet al., 2016).
5. Viscosity Measurement
Viscosity measurements were carried out to see the viscosity of SNEDDS produced due to
the influence of the addition of other ingredients such as surfactants and the power of
manufacturing techniques. Viscosity measure meant using a Brookfield cone and plate
viscosimeter. A stationary plate forms the bottom of the movable sample cup and is filled with
0.5 mL-2.0 mL SNEDDS. The system is accurate within ± 1.0% of the fulls clearance.
Reproducibility ± 0.2%. The tool works in a temperature range of 0-100oC (Zhao et al., 2015).
6. Dilution with Various Media
The stability of the dayak onion extract in nanoemulsion after dilution with water, SGF,
and SIF was examined by monitoring the concentration of whole dayak onion extract during
incubation at room temperature. SNEDDS were added to 100 mL of distilled water, artificial
intestinal fluid (SIF), and artificial gastric fluid (SGF). The mixture was then homogenized with
a vortex for 2 minutes (Ren et al., 2009) (Astutiet al., 2018).
7. ThermodynamicStability
Heating-cooling Cycle
The test was carried out by taking 2 mL of SNEDDS diluted with 10 ml of aquadest and
stored at 4°C and 45°C for 48 hours. The temperature was exchanged for each preparation.
Physical damage to the SNEDDS preparation was observed (Winartiet al., 2016).
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Freeze-Thaw Cycle
The test was carried out by taking 2mL of SNEDDS, diluting with 10ml of aquadest, and
stored at -20°C and 25°C for 48 hours. The temperature was exchanged for each preparation.
Physical damage to the SNEDDS preparation was observed (Winartiet al., 2016).
Centrifugation
Thermodynamic testing of 10 mL SNEDDS was carried out using a Hettich Rotofix 32
centrifuge at 3500 rpm for 30 minutes. Then the SNEDDS were stored at -20ºC and the others at
25ºC. Stability observations were carried out after 24 hours of storage (Winartiet al., 2016).
Result and Discussion
Optimization of the composition of the SNEDDS material was carried out by mixing the
ratio of surfactants (Tween 80, Tween 20, Span 20, and Transcutol) and co-surfactants
(Transcutol) with palm oil as a carrier oil with an HLB range of 11-15 which is a stable HLB in
SNEDDS (Syukri et al., 2019). Palm oil is an extended chain oil group that has the advantage of
increasing drug transport through lymphatics, thereby reducing first-pass metabolism, but its
ability to emulsify compared to medium-chain triglycerides, diglycerides, or fatty acid esters
(Sapraet al., 2012). The use of HLB ranges from 11-15 because this value shows O/W droplets,
and the higher the HLB value, the more hydrophilic nanoemulsion preparations are obtained.
Furthermore, the ratios of 1:8:1, 1:7:2, and 2:7:1 to determine the stable formulation of
SNEDDS. The comparison between the amount of surfactant by mixing hydrophilic and
hydrophobic surfactants to form nanoemulsions with better characteristics and affect the surface
tension of the preparation (Debnath et al., 2011).
The composition of the ingredients was mixed until homogeneous and not observed for 24
hours to determine the formula for the HLB value and a stable ratio indicated by the absence of
phase separation. Preparations with a clear physical appearance and no phase separation will be
selected next to be tested for physical characteristics of SNEDDS preparations. The resulting
formula is 60 formulas using three ratio ratios of SNEDDS components. A formula with a clear
appearance and no phase separation indicated a stable preparation in the formation of SNEDDS.
From the optimization obtained 15 formulas namely F1, F2, F3, F4, F5, F10, F11, F12, F13, F21,
F22, F31, F32, F33 and F34. The formula consists of surfactants tween 80 and span 20 with a
ratio of surfactant oil and co-surfactant 1:8:1 (F1, F2, F3, F4, F5), surfactant tween 80, and
transcutol 1:8:1 (F10). ), surfactant tween 20 and span 20 ratio 1:8:1 (F11, F12, F13), surfactant
tween 80 and span 20 ratio 1:7:2 (F21, F22), surfactant tween 20 and span 20 ratio 1:7 :2 (F31,
F32, F33, F34). Of the 15 formulas, the ratios are 1:8:1 and 1:7:2, which can produce stable
compositions when diluted, with good droplet sizes and meet the stability test requirements
(Syukriet al., 2019).
The 15 formulas were then tested for %transmittance to determine the level of clarity of
the preparation using UV-VIS Instruments at a wavelength of 650nm. F13 and F34 were
obtained at HLB 13 and 14, respectively, with a ratio of 1:8:1 and 1:7:2, which had
%transmittance values >90% (Wirnartiet al., 2018). Furthermore, both formulas were tested for
emulsification time with dilution in SIF and SGF liquids. Both formed homogeneity with a value
of <2 minutes (Winartiet al., 2016). Then proceed to the particle size test on the preparation by
diluting SGF and SIF. The range of values obtained is between 10-200 nm (Syukriet al., 2016).
The preparation was carried out by mixing the composition of the SNEDDS material with
a predetermined ratio in a stable formula, then homogenized and observed for 24 hours at room
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temperature. In this case, the formula that is made is a formula that is stable at the time of
optimization of SNEDDS without dayak onion extract, namely F13 and F34.
The selection of this formula will then be tested for the physical characteristics of the
SNEDDS preparation by adding dayak onion extract to improve the bioavailability of the active
substance in the body.
1. Transmittance Percent Test
The data from the percent transmittance test are in Table 2. This result shows a value that
is far from the range, namely >90% (Sahumena, 2014). This result contradicts the research,
which stated that the emulsion with transparent and clear preparation conditions had a
transmittance value close to aquadest. It could be concluded that the emulsion droplet size value
was 10-200 nm (Syukriet al., 2016). SNEDDS, which has a low transmittance value, shows a
larger particle size. A macroemulsion is formed to look cloudy because its solubility with water
is very low (Syukriet al., 2018).
The lack of clarity of SNEDDS, which can be indicated, is that the oil globules are not
dispersed with the active ingredients and other components in a homogeneous and nano-sized
manner (Nurdianti and Rahmiyanti, 2016). It can also be indicated that dayak onion extract,
which has lipophilic properties, also affects the instability of the oil because of the amount of oil
in the preparation increases. Increasing the amount of oil in the preparation can reduce the
stability of the preparation if it is not accompanied by an increase in the amount of surfactant,
which functions as a decrease in surface tension and can produce smaller globules (Nurdianti and
Rahmiyanti, 2016). Both formulas are still being continued for other characteristic tests.
Tabel 2. Results of Transmittance Percent
Formula HLB Average ± SD
F13 13 49,90 ± 0,81
F34 14 53,85 ± 5,41
2. Particle Size Test
Droplet size characterization was carried out to determine the nanoemulsion droplet size.
This particle size affects a larger interfacial surface area for drug absorption. The size of the
nanoemulsion has a droplet size of less than 200 nm (Syukri et al., 2019). The droplet size can be
known through the appearance of the preparation. The more cloudy the preparation is, the more
likely it is to have a large droplet size (Winarti et al., 2016).
Table 3 in F13 shows that the particle size value when diluted follows the parameter value
range, which is 10-200nm. However, at F34, the particle size value is below the parameter range
or smaller than the parameter. The Polydispersity Index (PDI) value is also obtained in Table 4 if
the value <1 indicates the uniformity of particle size is well-formed and uniform.
The size of the dispersed phase dramatically affects the appearance of the emulsion to be
transparent or cloudy, and this is due to the size of the oil droplets dispersed in water. Suppose
light passes through an emulsion system with very small droplet sizes. In that case, the light
beam will be transmitted so that the color of the solution looks transparent and the resulting
transmittance is more excellent (Sahumena, 2014).
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Tabel 3. Result of Particle Size Test
Formula HLB Average ± SD (SGF (nm)) Average ± SD (SIF (nm))
F13 13 93,13 ± 4,36 106,43 ± 17,64
F34 14 1,14 ± 0,16 50,17 ± 15,52
Tabel 4. Results of the Polydispesity Index (PDI)
Formula HLB Average ± SD (SGF) Average ± SD (SIF)
F13 13 0,10 ± 0,00 0,27 ± 0,21
F34 14 0,11 ± 0,05 0,15 ± 0,06
3. Emulsion Time Test
The data from the emulsification time test in Table 5 aims to determine the SNEDDS
preparation formed when peristalsis occurs in the gastrointestinal tract by diluting it with
simulated intestinal and gastric fluids. In formulas F13 and F34, homogeneous preparations were
included when diluted and stirred for >2 minutes. The best results are shown if the practice
shows an emulsion time >2 minutes (Wirnarti et al., 2018).
Tabel 5. Result of Emulsification Time
Formula HLB Average ± SD (SGF) Average ± SD (SIF)
F13 13 20,24 ± 0,04 27,60 ± 1,10
F34 14 17,38 ± 0,94 19,43 ± 0,80
4. pH test
Table 6 states that the pH test results of SNEDDS preparations can penetrate well at pH 6-
9, which is the pH of the intestine (Zhao et al., 2015). The formula with a pH of 6-8
nanoemulsion W/A will produce a large negative charge and prevent droplets from approaching
each other and aggregating to form a stable nanoemulsion preparation (Komaiko and
McClements, 2015).
Tabel 6. Result of pH test
Formula HLB Average ± SD
F13 13 9,0±0,1
F34 14 8,3±0,46
5. Viscosity Test
The purpose of the viscosity test is to determine the level of available viscosity of
SNEDDS due to the influence of other materials such as surfactants and preparation techniques.
The results of the viscosity test are listed in Table 7. The formulas F13 and F34 showed an
increase in the viscosity of the formula with an increase in the proportion of surfactant in the
formulation to achieve an optimal formulation ranging from 7.0 ± 0.1 to 42.0 ± 0.2 centipoises
(Syukriet al., 2019).
Tabel 7. Result of Viscosity Test
Formula HLB Average ± SD
F13 13 30,49 ± 1,71
F34 14 28,26 ± 11,47
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6. Dilution Test with Various Media
The fluid used is a simulated fluid with pH in the gastrointestinal tract, namely the stomach
and intestines and distilled water. The pH values in the intestines ranged from 6-9, and the pH in
the stomach was 1.2. The results in Table 8 are stable preparations and provide values according
to the pH parameters in each gastrointestinal tract. The physiological environment has a pH
range varying from pH 1.2 (pH in the stomach) to 7.4 and greater (pH of blood and intestines)
(Syukri et al., 2019). The pH value of the resulting nanoemulsion is safe to use as a drug base
because it follows the pH of the small intestine (7-7.24) as the main organ of drug absorption
(Jusnita et al., 2019).
Tabel 8. Result of Dilution Test with Various Media
Average Average Average
Formula HLB
± SD (SGF) ± SD (SIF) ± SD (Aquadest)
13 1,23 7,4 8,67
F13
± 0,12 ±1,09 ± 0,15
7. Thermodynamic Stability Test
This test was carried out with three cycles with one cycle at a temperature of -20̊ and 25̊ C
with a storage time of 48 hours per cycle. The results showed that in the preparations F13 and
F34, there was a separation of the clear phase and the cloudy phase on the upper surface of the
preparation.
A freeze-thaw test was carried out with three cycles at -20̊ and 25̊ C, with a storage time of
48 hours for each process. The effect of this temperature is to observe the instability of
preparations such as cracking, creaming. The results on F13 and F34 preparations were unstable
due to physical changes in the practices and cracking in each trial.
Centrifugation test on SNEDDS F13 and F34 preparations to determine the presence of
deposits after screening at a certain speed and time, namely at a speed of 3500 rpm for 30
minutes (Syukriet al., 2018). The results that appear after screening are preparations that occur
separation of the clear yellowish phase and the dark red phase. The practice was then placed at a
temperature of -20̊ C and 25̊ C and allowed to stand for 24 hours. The results were observed and
showed that both formulas froze and indicated that the preparation was unstable.
The instability of the preparation is due to the surfactant being unable to reduce the
interfacial free energy and providing a mechanical barrier for coalescence to occur, resulting in a
less spontaneous thermodynamic dispersion (Pratiwi, 2018).
Conclusion
The SNEDDS formula using the ratio of palm oil, surfactant, and co-surfactant used in this
study was able to form SNEDDS, but after the addition of the active ingredient dayak onion
extract as the active ingredient showed less stable results on the stability of the physical
preparation of SNEDDS with marked cracking and creaming in practice. When testing the
characteristics of the SNEDDS preparation.
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