Study of Formulation, Characteristics, and Evaluation of Self
Nanoemulsifying Drug Delivery System (SNEDDS) for Atorvastatin Calcium
Nurfianti Silvia1*, Taofik Rusdiana1,2, Dolih Gozali1,2, Patihul Husni1,2
1Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor 45363, Indonesia
2Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy,
Universitas Padjadjaran, Jatinangor 45363, Indonesia
Submitted: 10/11/2023, Revised: 28/12/2023, Accepted: 15/01/2024, Published: 24/01/2025
ABSTRACT
A Self-Nanoemulsifying Drug Delivery System (SNEDDS) is a formulation
approach used in the pharmaceutical and biotechnology industries to improve the
solubility and bioavailability of poorly water-soluble drugs. Atorvastatin calcium
has limited water solubility, which can affect its bioavailability when administered
orally. Its solubility can be enhanced by various formulation techniques, such as
the use of self-nanoemulsifying drug delivery systems (SNEDDS). The purpose of
this study is to determine the formulation and characterization of SNEDDS and
determine how it affects the bioavailability of atorvastatin calcium. The data were
collected from published journals. The carrier components required in the
formulation of atorvastatin calcium with SNEDDS formulation include oils (oleic
acid, peceol, capyrol 90, and capmul CMC), surfactants (tween 80, tween 20,
labrasol, cremophor RH 40) and co-surfactants (brij 30, propylene glycol,
transcutol-P, PEG 400, transcutol HP). Characterization of atorvastatin calcium
with SNEDDS formulation showed droplet size 21.6-162.2 nm; zeta potential -
1.32 - 24.6±6.47 mV; and polydensity index 0.164 - 0.297. SNEDDS formulation
increased the percentage of drug release and increased the bioavailability of
atorvastatin calcium.
Keywords: self-nanoemulsifying drug delivery system, SNEDDS, atorvastatin
calcium, formulation, characteristics, dissolution, bioavailability
Vol. 5, Issue 2, 2023 (449-457)
http://journal.unpad.ac.id/IdJP
*Corresponding author,
e-mail: nurfianti17001@mail.unpad.ac.id (N. Silvia )
https://doi.org/10.24198/idjp.v5i2.50996
© 2023 N. Silvia et al
450
1. Introduction
The first-choice medication for
reducing low density lipoprotein (LDL)
cholesterol in the blood is a statin. LDL
cholesterol is thought to be the primary
cause of many cardiovascular disease (1).
When it comes to treating
hypercholesterolemia and atherosclerosis,
atorvastatin calcium (AT) is one of the
most effective statins on the market (2).
Atorvastatin calcium is a medication that
belongs to a class of drugs known as
statins. It is commonly prescribed to
lower cholesterol levels in the blood,
particularly low-density lipoprotein
(LDL) cholesterol, often referred to as
"bad" cholesterol. Atorvastatin is known
by its brand name Lipitor, among others
(3).
Atorvastatin belongs to
Biopharmaceutical Classification System
(BCS) class II where the nature of the
active substance has low solubility and
high permeability. Due to the low
solubility of atorvastatin in water (0.1
mg/mL), the oral bioavailability of
atorvastatin is low (12%) (4). Poor
bioavailability may lead to the
administration of higher doses to achieve
therapeutic goals which may risk liver
abnormalities, rhabdomyolysis, arthralgia
and renal failure (5).
In recent years, there has been
increased interest on lipid-based drug
delivery systems, that comprise natural or
synthetic lipids as a potential method of
enhancing the oral bioavailability of
lipophilic, weakly water soluble
therapeutic candidates (6). Self-
nanoemulsifying drug delivery systems
(SNEDDS) is one method that has been
proven to improve the solubility and
bioavailability of drugs that are not very
soluble in water (7). According to
Makadia et al. (2013), SNEDDS is an
isotropic blend of oils, cosurfactants, and
surfactants that may spontaneously
generate nanoemulsions when in contact
with stomach fluids under modest
agitation (8).
A Self-Nanoemulsifying Drug
Delivery System (SNEDDS) is a
formulation approach used in the
pharmaceutical and biotechnology
industries to improve the solubility and
bioavailability of poorly water-soluble
drugs. This technology is particularly
important because many drugs with
valuable therapeutic properties often have
low aqueous solubility, which can limit
their effectiveness when administered
orally (9). SNEDDS represent an
innovative strategy for enhancing the
bioavailability of poorly water-soluble
drugs. By improving solubility,
dissolution, and controlled release,
SNEDDS can make a significant
difference in the effectiveness of these
drugs, ultimately improving patient
outcomes (10).
The purpose of this review is to
explain how how to formulate and
characterize SNEDDS for atorvastatin
calcium and show some studies that have
been conducted by researchers using the
SNEDDS method to increase the
bioavailability of atorvastatin calcium.
2. Methodology
The references used are primary
and secondary reference sources, namely
research journals and books related to the
theme of the literature review. In the
results of the literature review, the
references used are primary reference
sources in the form of research journals
published in the last 10 years (2013 -
2023). Research journals were obtained
from the PubMed journal database with
the keywords “atorvastatin calcium”,
“atorvastatin”, “formulation”,
“characteristics”, “self-nanoemulsifying
N. Silvia et al / Indo J Pharm 5 (2023) 449-457
451
Drug Delivery System" and "drug delivery system". The search results obtained from
PubMed and GoogleSchoolar database totaled 132 journals. From these search results, the
final journals selected for review amounted to 8 journals.
N. Silvia et al / Indo J Pharm 5 (2023) 449-457
Figure 1. Flowchart of methodology
2.1. Physicochemical properties of
atorvastatin calcium
The physicochemical properties of a
drug like atorvastatin calcium are
important factors to consider when
formulating, manufacturing, and
analyzing the drug. These properties
provide insights into the drug's behavior
and characteristics. Here are some of the
key physicochemical properties of
atorvastatin calcium:
1. Chemical Structure:
Figure 2. Chemical structure of atorvastatin calcium (11)
2. Molecular Formula: The
molecular formula of atorvastatin
calcium is C66H68CaF2N4O10,
indicating the number and types
of atoms in the compound (11).
3. Molecular Weight: The molecular
weight of atorvastatin calcium is
approximately 1155.36 g/mol
(11).
4. Physical State: Atorvastatin
calcium is typically a white to
off-white crystalline powder, and
it is sparingly soluble in water
(11).
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N. Silvia et al / Indo J Pharm 5 (2023) 449-457
5. Solubility: Atorvastatin calcium
has limited water solubility,
which can affect its
bioavailability when administered
orally (12).
6. pKa (Acid-Base Dissociation
Constant): Atorvastatin calcium
has a pKa of approximately
4.46, which is indicative of its
ionization behavior at different
pH levels. Understanding the
pKa can be important for drug
formulation and
pharmacokinetics (5).
7. Melting Point: Atorvastatin
calcium has a melting point
around 151-157°C (303-
315°F) (13).
8. Log P (Partition Coefficient): The
partition coefficient, or Log P, is a
measure of a compound’s
lipophilicity (its tendency to
partition into a lipid phase) (14).
Atorvastatin calcium has a Log P
value of approximately 5.4,
indicating its lipophilic nature
(15).
9. Stability: Atorvastatin calcium
should be stored in a cool, dry
place and protected from light
to maintain its stability. It can be
sensitive to degradation under
certain conditions, so proper
storage is essential (11).
10. Spectral Properties: Atorvastatin
calcium can be characterized by
various spectroscopic
methods, including infrared (IR)
spectroscopy, ultraviolet-visible
(UV-Vis) spectroscopy, and
nuclear magnetic resonance
(NMR) spectroscopy (16).
11. Crystalline Forms: Atorvastatin
calcium may exist in different
crystalline forms, which can
impact its solubility, dissolution
rate, and stability. Polymorphs of
the compound can be a focus
of study during drug development
(17).
These physicochemical properties play a
crucial role in the design and
development of pharmaceutical
formulations, including tablets, capsules,
or other dosage forms. They can
influence factors such as drug solubility,
dissolution behavior, and bioavailability.
Understanding these properties is
essential for optimizing drug delivery
systems and ensuring the efficacy and
safety of medications like atorvastatin
calcium.
3. Result and Discussion
Tabel 3.1 Study parameters of atorvastatin calcium formulation SNEDDS
Carrier
% Disolution
Bioavailability
(AUC or %
absorption)
Droplet
Size
(nm)
Potential Zeta
(mV)
Index
Polidipersit
as
Sourc
e
A1 A2 B1 B2
Oleat acid 20%
Tween 80 60%
Brij 30 20%
56.86 94.12 45.34%
86.67%
162.2 -24.6±6.47 0.297 (18)
Olear acid
Tween 80
Propilen glikol
NA 86.53
30249.74
84612.1
773.5 -24.1 NA (19)
453
N. Silvia et al / Indo J Pharm 5 (2023) 449-457
Keterangan: A1 = pure atorvastatin calsium/market product; A2 = SNEDDS atorvastatin
kalsium; B1 = AUC% or absorption pure atorvastatin calcium/market product; B2 =
AUC% or absorption SNEDDS, NA = not available
Peceol
Labrasol
PEG 400
Significantl
y increased
(A1<A2)
Significantl
y increased
(A2>A1)
NA NA 36.22
nm -1.32 0.164 (21)
Capyrol 90 10%
Tween 80
42.71%
Transcutol HP
Significantl
y increased
(A1<A2)
Significantl
y increased
(A2>A1)
59.04 ±
1.07
209.56
± 2.28 97nm -9.56 0.238 (22)
Capmul CMC
Cremophor RH
40
Transcutol-P
57.6±1.0 99.7±0.3 NA NA 79.85 -23.75 0.250 (23)
Capmul CMC
Tween 20
Significantl
y increased
(A1<A2)
Significantl
y increased
(A2>A1)
NA NA 21.10 ±
4.11 −14.7 ± 2.22 0.293 ±
0.001 (24)
3.2. Formulation SNEDDS
The percent dissolution of
atorvastatin calcium with a self-
nanoemulsifying delivery system after 60
minutes was 94.12%. The carrier
components used were oleic acid as oil,
tween 80 as surfactant, and brij 30 as co-
surfactant. Oil serves as the main carrier
of the active substance in SNEDDS
formulations, the oil component plays an
important role in determining the size of
the emulsion formed and the capacity of
the active substance that
can be carried(18).
Surfactants reduce the droplet size of
the emulsion and keep the active
substance in the absorption site for a long
time, preventing precipitation in the
gastrointestinal tract. The co-surfactant in
SNEDDS formulation helps the surfactant
to lower the surface tension of water and
oil, increase the dissolution of the active
substance, and improve the dispersibility
and absorption of the active substance.
The percentage release of atorvastatin
calcium with self-nanoemulsifying
delivery system in Venkatesh and
Mallesh's 2013 study was higher than the
market product which resulted in a
percent dissolution of 56.86%. This is due
to the low viscosity and high surfactant
concentration of tween 80. Tween 80 also
showed the most optimal solubility in
other studies (19, 22). This could be due
to the high HLB value of tween 80 (HLB
= 15), which increases the efficiency of
nanoemulsion formation.
Proper component selection is an
important first step to create a stable
SNEDDS
Oleat acid 10%
Tween 20 45%
Transcutol-P
45%
63.797 96.971 NA NA 21.6 -17.78 0.315 (20)
454
N. Silvia et al / Indo J Pharm 5 (2023) 449-457
formulation. To prevent drug precipitation
during the shelf life of the formulation
and subsequent dilution in
gastrointenstinal fluids, the drug must
have adequate solubility in the
nanoemulsion components. The carrier
component was selected based on the
ability of the carrier to dissolve
atorvastatin calcium and form
nanoemulsion spontaneously.
3.3. Characteristics SNEDDS
Droplet size in the studies studied had a
size in the range of 21.6-162.2 nm,
indicating that all atorvastatin calcium
formulations in the SNEDDS studies
studied were able to increase the release
speed of atorvastatin and reduce surface
tension. this is in line with the research of
Mohsin et al., (2016) a decrease in droplet
size will reduce surface tension and the
smaller the droplet size, the greater the
surface area so that it is expected that the
drug can be absorbed in the digestive
system quickly and increase its
biaovailability (25).
In addition to droplet size, zeta potential
and polydispersity index values are also
important characteristics for evaluating
SNEDDS formulations. A high zeta
potential, which is above 30 mV or less
than 30 mV, indicates that the formulation
is stable enough to prevent agglomeration
of preparation particles caused by
repulsive forces. Higher zeta potential
values increase repulsion and emulsion
stability due to the reduction of particle
aggregation, flocculation, coalescence,
and coagulation (26). The presence of
free fatty acids in negatively charged
preparations and preparations, indicated
by negative zeta potential values.
The zeta potential values in the study
were in the range of -1.32 - 24.6±6.47
mV, indicating that the formulation of
atorvastatin calcium with SNEDDS is
stable.
The polydispersion index value indicates
that the particle size of SNEDDS from
temulawak preparation is well distributed
or homogeneous. The polydispersity
index value in the study reviewed had a
value range of 0.164 - 0.297, this value is
in accordance with the desired ideal value
of <0.5 which indicates a monodisperse
formula and identifies the formula has
good particle or globule size uniformity
(27).
Other research for SNEDDS formulation
studies on oral antihyperlipidemia agents
showed that atorvastatin had a
polydispersity index value of 0.241 using
a combination of two surfactants (Tween
80 and Cremophor RH 40) (22). A lower,
or almost zero, polydispersity index value
indicates that the droplet size distribution
is more homogeneous and better. The
particle size distribution in an ideal
SNEDDS formula sample can be used to
determine the polydispersity index.
3.4. SNEDDS for improving
bioavailability
From several studies reviewed, all
formulations of atorvastatin calcium
using the SNEDDS method showed an
increase in percent dissolved when
compared to pure atorvastatin
calcium/market products. The increase in
percent dissolved is predicted to increase
the bioavailability of atorvastatin
calcium, supported by data on the
increase in bioavailability in three studies
(18, 19, 22).
4. Conclusion
The carrier components required in
the formulation of atorvastatin calcium
with SNEDDS formulation include oils
(oleic acid, peceol, capyrol 90, and
capmul CMC),
455
N. Silvia et al / Indo J Pharm 5 (2023) 449-457
surfactants (tween 80, tween 20, labrasol,
cremophor RH 40) and co-surfactants
(brij 30, propylene glycol, transcutol-P,
PEG 400, transcutol HP).
Characterization of atorvastatin calcium
with SNEDDS formulation showed
droplet size 21.6-162.2 nm; zeta potential
-1.32 - 24.6±6.47 mV; and polydensity
index 0.164 - 0.297. SNEDDS
formulation increased the percentage of
drug release and increased the
bioavailability of atorvastatin calcium.
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