Arituclo 3 Seminario Emulsiones

Drug Delivery and Translational Research (2022) 12:1616–1639
https://doi.org/10.1007/s13346-021-01071-9
REVIEW ARTICLE
Lipid‑based emulsion drug delivery systems — a comprehensive

review
Mori Dhaval1 · Poonam Vaghela1 · Kajal Patel1 · Keshvi Sojitra1 · Mohini Patel1 · Sushma Patel1 · Kiran Dudhat2 ·
Sunny Shah1 · Ravi Manek1 · Ramesh Parmar1
Accepted: 20 September 2021 / Published online: 5 October 2021

© Controlled Release Society 2021
Abstract
Lipid-based emulsion system — a subcategory of emulsion technology, has emerged as an enticing option to improve the
solubility of the steadily rising water-insoluble candidates. Along with enhancing solubility, additional advantages such as
improvement in permeability, protection against pre-systemic metabolism, ease of manufacturing, and easy to scale-up have
made lipid-based emulsion technology very popular among academicians and manufacturers. The present article provides
a comprehensive review regarding various critical properties of lipid-based emulsion systems, such as microemulsion,
nanoemulsion, SMEDDS (self microemulsifying drug delivery system), and SNEDDS (self nanoemulsifying drug delivery
system). The present article also explains in detail the similarities and differences between them, the stabilization mecha-
nism, methods of preparation, excipients used to prepare them, and evaluation techniques. Subtle differences between nearly
related terminologies such as microemulsion and nanoemulsion, SMEDDS, and SNEDDS are also explained in detail to
clarify the basic differences. The present article also gives in-depth information regarding the chemical structure of various
lipidic excipients, various possible chemical modifications to modify their inherent properties, and their regulatory status
for rational selection.
Keywords Microemulsion · Nanoemulsion · SMEDDS · SNEDDS · Excipients · Emulsification theory · Method of

manufacturing
Introduction the development phase, has been started to get measured

by using the “kinetic equilibrium method” rather than the
The application of combinational chemistry in the early traditional “thermodynamic equilibrium” method [1]. Basi-
drug discovery phase has made it possible to automati- cally, the difference between the two approaches lies in the
cally synthesize a large number of compounds in a quick fact that the solid compound is introduced into the aqueous
time. Screening of such a large number of compounds has medium for determination of thermodynamic solubility,
challenged analytical scientists to forgo the traditional whereas the pre-dissolved compound is taken as the starting
methods for drug analysis and come up with new rapid and material for assessing kinetic solubility [2]. The thermody-
miniature methods to cope with the discovery phase sci- namic solubility of a compound in a solvent is the maximum
entist. For example, solubility, a key determinant, deciding amount of the most stable crystalline form of the compound
the journey of the compound from the discovery phase to that can remain in solution in a given volume of the solvent
at a given temperature and pressure under equilibrium con-
* Mori Dhaval ditions. Thermodynamic equilibrium will always seek the
[email protected] overall lowest energy state of the system. [3]
Kiran Dudhat The shake flask method, which is considered as the
[email protected] gold standard to measure the equilibrium solubility of
the compound, is time-consuming and tedious, as in this
1
B.K. Mody Government Pharmacy College, Polytechnic method, sufficient time is required to be given in order to
Campus, Near Ajidam, Rajkot, Gujarat, India
establish equilibrium between solute and solvent. (approx-
2
K. V. Virani Institute of Pharmacy and Research Centre, imately 24–48 h) [4]. Contrary to that, kinetic methods
Badhada, Gujarat, India
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Drug Delivery and Translational Research (2022) 12:1616–1639 1617
are based on the ability of an organic solvent (usually • Circumventing the need of drug being ionized form
DMSO) to keep the drug in solubilized form upon com- (required for salt formation) to be eligible for the
ing into contact with aqueous media. The word “kinetic” approach.
represents the constantly changing equilibrium between • Facilitates the permeation of the drug through the gas-
the dissolved solute molecules and the solvent. Tradition- trointestinal mucosa.
ally, it has been used to describe the peak concentration • The flexibility of deciding the final dosage form (tablet,
obtained during a dissolution experiment [4] The kinetic capsule, dry emulsion)
solubility is defined as the concentration of a compound • Easy to scale up,
at the time when an induced precipitate first appears in • The comparatively simple manufacturing process
solution [5]. This methods are quick and do not require (except: ready to used nano-emulsion) [12].
lengthy equilibrium time [6].
The downside of using kinetic methods at the discovery Even though lipid-based drug delivery systems have
stage is that, in many cases, the measured value of kinetics been in play for a long time (since 1960), there are still
solubility is found to be substantially higher than the actual many critical aspects of them that continue to generate
thermodynamic one. [7]. This trend has resulted in the advance- confusion among researchers. Confounding concepts such
ment of compounds with large molecular size and high lipophi- as the differences between microemulsion and nanoemul-
licity in the advanced stages, which is quite evident from the sion systems based on their structure and size are quite
fact that around 40% of currently marketed drugs and up to 75% common as there are not too many reviews or research
of compounds currently under developmental phase are poorly articles available that are exclusively related to them. The
water-soluble (solubility less than 0.1 mg/ml) [8]. Renowned name used to describe different phase diagrams for pre-
formulation scientist Dr. Abu Serajuddin had described this paring pre-concentrates and ready to use micro/nanoemul-
trend very effectively in the following words: “While a value of sion systems is also found to be used quite interchange-
less than 20 μg/mL for the solubility of a NCE (New chemical ably in the literature. The possible chemical modification
entity) was practically unheard of until the 1980s, the situation of natural lipids to improve their applicability to prepare
has changed so much that in the present-day drug candidates the lipid-based system is also not readily available. The
with intrinsic solubility (solubility of the neutral or unionized present review article is aimed at clarifying all of the
form) of less than 1 μg/mL is very common” [9]. Between mentioned points together with other critical aspects of
poor solubility and poor permeability — two critical param- lipid-based drug delivery systems. In the broader view,
eters affecting the bioavailability of the drug, poor solubility the lipid-based emulsion system also includes particu-
is considered to be the preferred limitation as many effective late emulsions (e.g., oil-in-water emulsions such as
approaches are available to rectify it [10]. cubosomes, hexosomes) and other particulate carriers
The prevalent problem of poor solubility has enticed such as solid lipid naoparticles (SLN)/nanostructured
formulation scientists to come up with various formulation lipid carriers (NLC) along with various emulsified sys-
strategies to overcome it. Among all the methods available tems covered in this review article. The “cubosomes” and
to improve the solubility of the drug, such as salt formation, the “hexosomes” are dispersed particles of cubic and hex-
amorphous solid dispersion, and size reduction, the lipid- agonal inverse liquid crystalline phases formed due to dis-
based drug delivery system (microemulsion, nanoemulsion, persion of monoglycerides in water due to their respective
SMEDDS, and SNEDDS) has gained considerable interest nanostructure interiors. The stability of these superstruc-
among researchers and manufacturers [11]. This fact is quite tures is driven by the liquid crystalline phase formation
apparent from the number of research papers published and for cubic and hexagonal based nanostructured emulsions
the number of marketed formulation became available in and by dense (critical) packing of droplets [13–15]. In the
the last 10 years. In broad terms, lipid-based drug delivery case of solid lipid nanoparticles, the biocompatible solid
systems include ready to use microemulsion/nanoemulsion, lipids are used as a matrix material for controlling the rate
self-emulsifying pre-concentrates, and micelle systems that of drug delivery. They typically have photon correlation
are composed of one or more than one type of lipid or lipid- spectroscopy (PCS) diameters between approximately 50
based excipients (oil, surfactants, and co-surfactants). and 1000 nm and can hold both hydrophilic and hydro-
Lipid-based drug delivery systems offer some distinct phobic drugs [16]. It is to be noted that the present review
advantages compared to other formulation strategies such article is restricted to only an emulsified lipid-based
as the following: drug delivery system — microemulsion, nanoemulsion,
SMEDDS, and SNEDDS but does not include lipid-based
• Ability to present the drug in solubilized form, particulate systems (cubosomes, hexosomes solid lipid
• Ability to accommodate large doses, microparticles/nanoparticles).
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1618 Drug Delivery and Translational Research (2022) 12:1616–1639
Microemulsion vs nanoemulsion that under certain experimental conditions and formulation

composition, microemulsions display similar morphologi-
The first confounding point when it comes to lipid-based cal characteristics as nanoemulsions. [19, 20].
drug delivery systems is the distinction between micro-
emulsion and nanoemulsion systems. This misconception Microemulsion
is pretty visible in various published articles in pharma-
ceutical journals during the past 30 years. The origin of Microemulsions are thermodynamically stable, isotropic,
this misconception can be traced back to the first reported a transparent systems consisting of two immiscible liquids
stable transparent spontaneously formed water/oil emul- stabilized by suitable emulsifiers. The literature survey
sion system reported by Schulman et al. in their research points out that the microemulsion had the smallest drop-
paper in 1959. Schulman et al. have reported a spontane- let sizes among all emulsion systems (coarse, micro, and
ously formed water/oil transparent system by using alkali nanoemulsion), which usually ranges from 10 to 200 nm
metal soap as an emulsifier and alcohol as a co-emulsifier in diameter (Fig. 1) [21]. The formation of the microemul-
with an approximate micelle size of 200 Å. The authors sion is a spontaneous forward process that does not require
defined the prepared system as “the dispersed phase con- energy input from the outside. Spontaneous formation of
sists of sub-microscopic micelles” and “swollen soap ionic microemulsion suggests the lower energy status of formed
micelle” system. The micelle size reported by the authors microemulsion compared to separate components [22]. As
in this paper was based on “semi-quantitative” evidence no external energy source is used for the formation of the
rather than direct measurement as it was not possible to microemulsion, a high concentration of surfactant/emul-
directly measure it at that time due to the limitations of sifiers (usually more than 40%) is required to achieve the
instrumental analysis [17]. Since the authors had described desired size globule in a microemulsion formulation [20].
their transparent water/oil system as a “sub-microscopic Additionally, co-surfactants that provide additional flexibil-
level,” the term “microemulsion” was started to be used ity to the surfactant layer surrounding the internal phase are
for describing such systems. Here, the prefix “micro” also often used in the microemulsion system to increase the sta-
indicated the measurement limitations of the analytical bility of formed globules. The high proportion of surfactants
instruments available at that time. Since the publication of and co-surfactants brings the surface tension to an extremely
this paper, the term “microemulsion” started to get popu- low level, thus making the formation of microemulsion a
lar for describing the stable, transparent system consist- spontaneous process — energy favorable process (Gibbs free
ing of two naturally immiscible liquids (oil and water). energy becomes negative).
The confusion started due to the mismatch between the Being at a low energy level compared with separated
actual globule size of the formed system and the limita- phases, microemulsion becomes an energy favored state
tion of the prefix used to describe it. In subsequent years, and therefore thermodynamically stable with a very limited
the advancement in analytical techniques made it possible tendency to get separated over a long time [19]. The micro-
to measure the size of the particles/globules even in the emulsion is also known as “swollen micelle systems” due
nanorange (10–9 m). The trend to use the term “nano” to the presence of enlarges micelles [23]. The formation of
began to gain momentum after the publication of the first the microemulsion and the arrangement of swollen micelles
paper with the term “nanoemulsion” in 1996 as the prefix can be exemplified by taking an example of an oil/water
“nano” tends to be more technically reasonable for defin- microemulsion system prepared by the titration method. For
ing the system with globules size less than 200 nm [18]. example, consider an aqueous phase containing dissolved
The debate again got momentum when it was observed surfactant above its critical micelle concentration (CMC).
Fig. 1 Globule size comparison

for various types of emulsions
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As the concentration of the surfactant exceeds the CMC, microfluidizer, generate immerse disruptive pressure to dis-
the surfactant molecules start to form the micelles by keep- turb both the phases and produce an internal phase with
ing the polar head part towards the water, and the non-polar an acceptable globule size [26]. The low-energy methods
hydrophobic chain inside the core of the micelles. When a include phase inversion temperature, phase inversion com-
relatively low amount of oil is added to this solution, the position, and membrane filtration method [27]. The third
oil molecules start to enter within the hydrophobic internal important difference between the microemulsion and nanoe-
core of the micelles. As a result of this, the micelle starts to mulsion is about the total energy that gets confined in the
grow and the surfactant molecules get assemble surrounding system. The total free energy confined in the nanoemulsion
the oil. These kinds of micelles have a larger diameter than is much higher than the total free energy of separate oil and
conventional micelles, so they are known as the “swollen water systems, making the nanoemulsion a thermodynami-
micelles.” As more oil is added to this system, the micelles cally unstable system [28]. The required kinetic stability to
get saturated and reach a stage where they can no longer the system is provided by creating a large energy barrier
accommodate additional oil in their hydrophobic cavity. between the separate phases and formed nanoemulsion. As
Once the micelles system reaches the saturation point, the the energy barrier between the separate phases and formed
addition of more oil leads to the formation of unstable oil nanoemulsion is greater, the greater the stability of the
globules. At this stage, the system has two distinct phases: formed nanoemulsion. [29]
saturated micelles and unstable oil globules. Saturation con- Vaguely defined boundary lines between microemulsion
centration is defined as the maximum amount of oil that can and nanoemulsion have also created confusion regarding
be incorporated into a unit mass of surfactant under specific “self-emulsifying systems” — SMEDDS and SNEDDS.
environmental conditions (the number of grams of oil solu-
bilized per gram of surfactant). The saturation concentration SMEDDS
depends on the nature of the oil (polarity, proportion), the
type of the surfactants (charged, uncharged, head, and tail According to Pouton’s classification of lipid-based drug deliv-
group), and external conditions such as pH, temperature, ery, Type II and Type III are described as self-emulsifying
and ionic strength. If the total amount of oil present in the systems mean these systems are dispensed in the form of a
system remains below the saturation concentration, the oil semi-solid/liquid system, but upon coming in contact with
molecules get solubilized within the hydrophobic core of the aqueous media, under mild agitation, they immediately form
micelles and form a stable swollen micelle system known a nano-sized emulsion system (Table 1) [32]. Upon coming
as a microemulsion. In the second scenario, where the con- in contact with aqueous media, the Type II system is expected
centration of oil exceeds the saturation concentration level, to form coarse emulsion, whereas the Type III system is
the extra oil (beyond the saturation concentration) appears expected to form microemulsion (less than 200 nm). The Type
as distinct oil droplets [24]. III system that spontaneously converts into microemulsion
(less than 200 nm) is known as “SMEDDS-self microemul-
Nanoemulsion sifying drug delivery systems.” The term SMEDDS appro-
priately justified the word “microemulsion” as it satisfies all
Nanoemulsions are very similar to conventional macro- the criteria required to be classified under such a system. For
emulsions but have very small globule sizes (between 200 example, (1) the formation of the microemulsion is a sponta-
and 400 nm). Nanoemulsions can be oil-in-water (O/W) neous process without the application of energy from outside.
or water-in-oil (W/O) types depending on the proportion (2) The formed globule size is less than 200 nm. (3) The high
of compositions. One of the main differentiating features amount of emulsifiers ensures quick and spontaneous micro-
between microemulsions and nanoemulsions is the accept- emulsification. (4) The formed microemulsion is stable for a
able globule size. [25]. There is no all agreed acceptable very long time.
globule size that defines nanoemulsion but the point that
is well accepted is that the microemulsion has a smaller SNEDDS
globule than nanoemulsion. Another major difference is the
method of preparation for nanoemulsion. The nanoemulsion Another term that is often used interchangeably with
is mostly prepared by energy-driven methods; means energy SMEDDS is SNEDDS (SNEDDS-self nanoemulsifying
is to be supplied from the outside to break the internal phase drug delivery systems). As described in the previous sec-
in acceptable sized globules. tion, nanoemulsion contains ultrafine globules generated due
Based on the amount of energy supplied from exter- to high energy input methods such as high-pressure homog-
nal sources, the methods can be divided into high energy enization, but in most of the research papers where the term
methods and low energy methods. The high energy meth- “SNEDDS” was used, researchers had not use any energy-
ods, like high-pressure homogenizers, ultrasonication, and intensive method for the generation of ultrafine globules. In
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Table 1 Pouton’s classification of lipid-based drug delivery [30, 31]
Type I Type II Type III (A) Type III (B) Type IV
Components Oils without surfactants(e.g. Oils and water insoluble Oils, surfactant, and co-solvent Oil, surfactant, and co-solvent Water soluble surfactant and
triglycerides, diglycerides, surfactant (both water soluble and ( both water soluble and co-solvent ( no-oils)
and monoglycerides insoluble excipients) insoluble excipients)
Dispersion ability No dispersing Emulsion SEDDS SEDDS/SMEDDS formed with SEDDS/SMEDDS formed with Dispersion typically form a
water soluble components water soluble components and micellar solution
low oil content
Advantage Generally recognize as safe Unlike to lose solvent capacity Clear or almost clear dis- Clear dispersion, drug Good solvent capacity for many
state, simple, excellent on dispersion persion, drug dispersion absorption without diges- drugs, dispersion to micellar
capsule compatibility without digestion tion solution
Disadvantage Formulation has poor solvent Turbid O/W dispersion (particle Possible loss of solvent Likely loss of solvent capacity Loss of solvent capacity
capacity unless drug is size 0.25–2 µm) capacity on dispersion, less on dispersion on dispersion may not be
highly lipophilic easily digested digestible
Oil level 100% 40–80% 40–80% < 20% -
% water insoluble surfactant - 20–60 - - 0–20
HLB < 12
% water soluble surfactant - - 20–40 20–50 30–80
HLB > 12
Requirement of enzymatic Required May be May not be necessary May not necessary Not required
digestion
Droplet size after dispersion Coarse 100– 200 nm 100– 200 nm 50–100 nm < 50 nm
fact, most of the research articles have used a high concen- at the boundary of both phases. ΔG(i) is always a positive
tration of emulsifiers (30–40%) to generate ultrafine emul- term as the effective surface area and interfacial tension both
sions [33–36]. Based on the above discussion, it is evident remain greater than zero in normal circumstances; thus, the
that “microemulsion” is a more suitable term rather than the term always opposes the formation of the new dispersion
“nanoemulsion” to describe such systems considering their phase. As the internal phase starts to disperse within the
characteristics. external phase as droplets, the effective surface area between
them increases drastically (ΔA) leading to larger ΔG(i).
ΔS in Eq. (1) indicates the number of the different ways a
A mathematical model describing system can arrange itself, which is always negative because
the formation of the emulsion the number of ways a dispersed internal phase can be
arranged always exceeds the possible arrangement of sepa-
The difference between microemulsion and nanoemulsion at rate phases, and thus, this term always favors the dispersion
the molecular arrangement level can be explained by using phase [38].
the molecular model based on the calculation of the free The interfacial tension that exists at the interface between
energy of the individual components and the finished for- the internal phase and the external phase remains the same
mulation. Consider a system that is in equilibrium between a in both dispersed phases as well as in separate phases. How-
stable dispersion phase and separate individual components ever, the interfacial tension can change depending on the
(oil + emulsifier + water). curvatures of the droplets, which at the optimum curvature
The free energy change associated with forming a new is ultralow — almost tends to zero. As the internal phase
phase — dispersion system — can be explained by the fol- starts to disperse within the external phase, the contribu-
lowing equation. tion of the interfacial free energy term becomes positive
(oppose to the formation of dispersion) because a decrease
ΔG (formation of new phase) = ΔG(i) − TΔSconfiguration (1)
in the globule size increases the effective surface area drasti-
ΔG is the Gibbs free energy for the formation of a new cally. Contrary to that configuration, free energy becomes
phase — change in free energy upon the formation of the progressively negative as a decrease in globule size gives
new phase, ΔG(i) is the interfacial free energy term, T is the internal phase more opportunity to arrange in a myriad
the temperature of the system, and ΔS is the change in the of different ways. Generally, the interfacial free energy term
configuration of enthalpy of the system associated with new is always greater than the configuration enthalpy term, and
phase formation [37]. hence, the overall free energy change becomes positive,
As per Eq. (1), at constant temperature, pressure, and making the formation of the colloidal dispersion system
interfacial chemical potential, ΔG(i) is equal to the multi- thermodynamically unfavorable (Fig. 2) [39].
plication of change in the contact area between the dispersed For making the dispersion of the internal phase within the
phase and the dispersion phase upon the formation of the external phase thermodynamically favorable, the interfacial
new dispersion system and the interfacial tensions that exist tension is required to reduce at an extremely low level. Such
Fig. 2 The difference between

microemulsion and nanoemul-
sion in terms of free energy
confined in the system
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an ultra-low surface tension is achieved when the surfactant start the mass transportation of the component and facilitate
monolayer has the optimum curvature and the particle size the mixing [42–45].
is close to the optimum size [40]. The extremely low inter- Contrary to SMEDDS, ready to use microemulsion is pre-
facial tension at the interface makes interfacial free energy pared by titration method that requires one additional step to
term very low and, therefore, the overall free energy for the the method used to prepare SMEDDS. In this method, oil,
formation of a new phase becomes negative. The negative surfactants, and co-surfactants are pre-mixed, and water is
value for the overall free energy change indicates a ther- added in a drop-wise manner with continuous mixing pro-
modynamically favorable spontaneous reaction. In the case vided by a magnetic stirrer till the transparent microemul-
of the emulsion system, this indicates the spontaneous for- sion is formed. Here, the proportions of all the components
mation of microemulsion upon coming in contact with the — oil, surfactant, co-surfactant, and water — are critical as
aqueous phase under slight agitation — a system known as the change in any one of them can change the character of
microemulsion or SMEDDS. the system. In case of SMEDDS, to graphically represent
In the case of the nanoemulsion system, the energy the proportion of all the components pseudo-ternary phase
required for the formation of ultra-low size globules is diagram is used. The prefixed “pseudo” is added because in
provided by external sources (high-pressure homogenizer, this case, the three-axis represents a four-component system
ultrasonicator, etc.). Once the ultra-fine sized globules are (oil, the mixture of (surfactant + co-surfactant) and water)
formed, the surfactant molecules get arrange around them [46–51].
and lower the interfacial tension at a sufficient level to sta-
bilize them — a system known as the nanoemulsion system. SNEDDS
It is to be noted that the overall free energy confined in the
nanoemulsion is greater than the overall free energy of the As explained in the previous section, a key difference
separated phases, making it thermodynamically unstable. between microemulsion and nanoemulsion is that the prepa-
However, such systems are considered kinetically stable ration of nanoemulsion requires energy-intensive techniques
as the energy barrier between the dispersed phase and the such as high pressure/speed homogenization or microflu-
separate phase is large enough to slow down the separation idization. According to this difference, it is expected that
process. [28, 41]. a SNEDDS preparation also utilizes a similar approach
for preparation but most of the research papers describing
the formulation of SNEDDS have used no such methods.
Method of preparation Contrary to that, the method described in the paper is very
similar to the methods described in the previous section for
Microemulsion/SMEDDS the prepare SMEDDS (a physical mixture of components
followed by mild agitation). A probable reason for this con-
As explained in the previous section, the microemulsions, fusion can be traced back to the vague difference between
being an energetically favored system, spontaneously dis- microemulsion and nanoemulsion. The globule size of the
persed into a globule size of less than 200 nm without need- formed emulsion in SNEDDS formulation is also less than
ing any energy from external sources. The high concentra- 200 nm; thus, the term “nano” found to be more suitable to
tion of emulsifier (surfactant + co-surfactant) used in the explain the formulation characteristics [33–35, 52, 53].
formulation lowers the surface tension to almost zero levels
and hence facilitates the formation of extremely small glob- Nanoemulsion
ules of the internal phase (less than 200 nm). The prepara-
tion of microemulsion and SMEDDS follows a very similar Methods to prepare nanoemulsion can be divided into high
path. In the first phase oil, surfactants, and co-surfactants energy methods and low energy methods based on the
were mixed using a vortex mixture (2–3 min). In the case amount of energy supplies to the system from outside.
of SMEDDS, this premixed is added to fixed quality water
(50 to 100 ml) with mild agitation to facilitate the mixing High‑energy methods
(manually by inversion method or using a magnetic stirrer
or vortex), and the formation of transparent and microemul- The high-energy methods require specialized mechanical
sion is observed. In this method, only the quantity of oil, devices to generate intense forces to disrupt the internal
surfactant, and co-surfactants got varied (water is fixed), so phase and to merge both phases continuously and repeat-
the proportion of each component used in the formulation edly until the desire globule size is achieved. High-pressure
is graphically represented by using a ternary phase diagram homogenizers, high-speed homogenizers, microfluidizers,
— each axis represents one component. In most cases, mild and ultrasonic homogenizers are some of the widely used
energy in the form of gentle agitation is provided in order to equipment to prepare the nanoemulsion. The composition
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of the nanoemulsion and operating parameters of the instru- raises extremely, and at the same time, the static pressure
ments such as homogenization pressure, homogenization drops significantly, resulting in a reduction of the boiling
speed, the number of cycles, and time duration to apply the point of the liquid [58]. The rapid conversion of liquid to
disruptive forces can have a significant influence on key vapor due to the reduced boiling point begins to generate
characteristics of formed nanoemulsion. [54, 55] air bubbles inside the system. The implosion of the air bub-
ble releases the energy that can further reduce the size of
High‑pressure homogenizer A high-pressure homogenizer the internal phase — a process known as “cavitation” [59].
is one of the most widely used continuously operated emul- The critical factors that influence the globule size and its
sifying devices in the industry. High-pressure homogenizers distribution are homogenization pressure and the number
essentially consist of a high-pressure pump, impact ring, and of cycles that pre-mix passes through (Fig. 3a). HPH mostly
homogenization sheet. The pump pushes the crude emul- uses for preparing o/w type nanoemulsion having less than
sion/pre-emulsion towards the available space between the 20% internal phase. One of the critical limitations of HPH is
forcer and homogenization sheet. The homogenizing pres- the generation of heat during the process which can possibly
sure is typically between 50 and 200 MPa [56]. The pre-mix lead to deterioration of the product [19, 60, 61].
exits the space and colloids with the impact ring. The droplet
size of the internal phase gets reduced due to a combina- Ultrasonication Over the years, the ultrasonication method
tion of various mechanisms such as turbulence, shear, and has proven its efficiency and utility for producing kinetically
cavitations. The entry of liquid from the main passage to the stable nanoemulsions. The ultrasonication can be performed
available space between forcer and homogenization sheet by by a bath sonicator or a probe sonicator. Bath sonication has
high-pressure pump suddenly constricts the steams of liquid. a container wall that acts as a barrier of ultrasonic waves
This sudden reduction in the available space for the liquid before reaching the sample, while the sonication probe
creates turbulence in the flow [57]. The turbulence in the produces ultrasonic waves by immersing directly a probe
flow is more at the boundaries compared to the inner part of into the sample. The literature survey indicates that probe
the streams. The creation of uneven surfaces at the boundary ultrasonication has a more effective energy output gener-
of the liquid stream is known as “turbulent eddies” which ated for emulsification than bath ultrasonication. Increas-
starts the process of merging and breaking of droplets. The ing the energy output can lead to smaller droplet sizes of
minute gap between the valve and forcer creates the high nanoemulsions [62]. In the ultrasonication method, a metal
shear requires to reduce the size of premix droplets. When probe, mechanically vibrating at an ultrasonic frequency,
the globules emerge from the space, the dynamic pressure is immersed in the pre-mix system [63]. The formation of
Fig. 3 Schematic diagram
explaining the formation of
nanoemulsion by using a
high-pressure homogenization
method, b the ultrasonication
method, c microfluidization
method, and d membrane filter
method
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nanosized globules proceeds in two phases. (1) The probe is connected to a nitrogen gas inlet attached to a pressure
starts to vibrate at an acoustic frequency which generates gauge. Below this vessel, a beaker containing a continuous
initial waves to begin the disruption of the interface between phase (water + emulsifier + co-emulsifier) is kept with con-
two liquids. As time progresses, continuous generation of stant agitation provided by a magnetic stirrer. As the nitro-
waves starts intermingling of both phases. (2) The frequency gen gas pressure is applied to the oil, it starts to permeate
of the probe increases to the ultrasonic level which along through the uniform pores of the membrane and reaches a
with creating turbulence also starts to generate cavitations continuous phase in form of fine globules.
within the system [64]. Constant generation of ultrasonic
wave initiates the formation of microbubbles [65, 66]. The While the droplets are getting formed, the surfactant
implosion of microbubbles releases the energy to generate molecule, pre-dissolved in the continuous phase, starts to
the extreme level of localized turbulence known as local get adsorbed onto the newly formed oil–water interface and
hot spots (Fig. 3b). Such localized turbulence happening in reduces the interfacial tension to the required extent to form
repeated manner results in merging and disruption of dis- a stable system. The type and concentration of surfactant,
persed phase to form nanosized globules. the in-flow rate of the oily phase, and agitation rate/speed
can have considerable influence on the characteristics of the
High shear mixers Rotor and stator type high shear mix- final product (Fig. 3d).
ers are another widely used instrument for the formation
of nanoemulsion. In this type of high shear mixers, a rotor Low energy methods
rotating at very high speed is fixed on the top, and a stator
available at the bottom provides a stationary surface for size There is a very close similarity between the method used
reduction [67, 68]. The rotation at high speed (ranging from to prepare microemulsion and low energy methods used to
20,000 to 100,000 s−1) dissipates very high localized energy prepare nanoemulsion under certain conditions (the type
between the narrow gap (ranging from 100 to 3000 nm) sta- of emulsifier and agitation requirements). As described in
tor and rotor to reduce the globule size in the nanorange. the previous section, the formation of microemulsion also
The high shear mixers can be of the batch type or continuous requires a limited agitation to initiate the mass transpor-
type depending on the requirement. The generation of heat tation of two phases. Low energy approaches use for the
due to high-speed rotation is one of the critical limitations formation of nanoemulsion depend on changing environ-
of this instrument [69–71]. ment conditions (change in temperature or composition) to
form sub-micron size droplets of internal phase within a
Microfluidization In the microfluidization method, two jets mixed system containing surfactant, oil, and water. When
of crude emulsion from two opposite directions collide with low energy methods are used for emulsification, the type
each other in the interaction chambers. The turbulence gen- of formed emulsion is “micro” or “nano” can be decided
erated due to collision gives rise to cavitations and eddies based on the proportion of surfactant used in the system.
require to reduce the globule size (Fig. 3c) [72]. The nanoe- If the surfactant concentration is high (20 to 40%) then the
mulsion formed using microfludization method was found formed system can be classified as microemulsion and a sys-
to have narrower globule size distribution compared to the tem with a lower surfactant concentration can be classified
globule generated by using HPH [73]. Another advantage of as nanoemulsion.
microfluidizer is that the pre-emulsification stage is not nec-
essary as the entire liquid phase is divided into a number of Phase inversion temperature The phase inversion tem-
small liquid streams by passing through the microchannels. perature method used to prepare nanoemulsion depends on
As there is no moving part in the microfluidizer, it does not changes observed in molecular geometry and solvent affin-
generate any heat which can possibly degrade the product. ity of a non-ionic surfactant (such as Tweens®, Spans®,
and Brijs®) by changing temperature. PIT is a specific
Membrane filtration method Nakashima et al. were the temperature at which the affinity of the surfactant starts
first to use membrane emulsification methods in the late to change towards different phases in such a way that it
1980s to formulate highly uniform-sized kerosene-in-water begins to impact the curvature of the interfaces. The for-
and water-in-kerosene emulsions. They have used Shirasu mation of nanoemulsion by PIT proceeds the following
porous glass — a type of glass membrane to produce nanoe- steps: (1) Below the PIT, an oil/water macroemulsion is
mulsion with a narrow distribution range. Shirasu porous stabilized by non-ionic surfactants. The non-ionic emulsi-
glass (SPG) membranes have uniform pores of the required fiers have an equal affinity for both phases. Below the PIT,
size so they are widely used for the membrane emulsifica- these surfactant molecules that have a more hydrated head
tion process (0.05–50 µm). In this method drug-containing, group means have a high affinity for water compared to the
the oily phase is stored in a pressure-tight vessel which oil phase and therefore make a stable o/w emulsion. (2) As
13
the temperature starts to increase, the head part gradually that the oil phase gets stabilize as nano-size globules within
becomes hydrophobic, causing them to migrate within the the continuous water phase [76–78].
oily phase. (3) When the temperature reaches PIT, a bicon-
tinuous system or lamellar liquid crystalline is formed. At
this temperature, the interfacial tension becomes extremely Excipient components in pharmaceutical
low [14, 74]. (4) Around PIT, two events proceed simul- emulsions
taneously in the system. The ultra-low interfacial tension
promotes the formation of new small droplets and coales- Pharmaceutical excipients are defined by International
cence of the formed droplets which results in droplet growth. Pharmaceutical Excipient Council (IPEC) as “substances
Further increase in the temperature above PIT leads to a other than the active pharmaceutical ingredient (API),
gradual increase in the lipophilicity of the surfactants which which have been appropriately evaluated for safety and
ultimately results in phase inversion of the system (water – are included in drug delivery system to assist within the
internal phase and oil external phase). (5) Rapid cooling of processing of the drug delivery system during its manufac-
such a system — known as “quench cooling” from the PIT ture, assist in product identification or enhance the other
to around room temperature by the addition of water under attribute of the general safety and efficiency of the drug
constant agitation, changes the affinity of the surfactant during storage or use” [79]. The selection of excipients
suddenly and freezes the system with stable nano-sized oil plays a very critical role in the successful formulation of
globules within the water (Fig. 4). One of the major limita- microemulsion and nanoemulsion as stabilization of the
tions of using the PIT method for forming nanoemulsion is internal phase in nano-sized globules heavily depends on
that the formed nanodroplets are very prone to coalescence them. In the case of a self-microemulsifying/nanoemul-
especially when the temperature reaches a near PIT [75]. sifying system, the selection of excipients becomes even
more critical because the dispersion of the internal phase
Phase inversion composition In PIC method is very similar entirely depends on the curvature of the surfactant layer
to the PIT method but here the phase conversion takes place and their ability to make the emulsified process thermo-
due to a change in the proportion of the components rather dynamically favorable (Gibbs free energy negative). The
than a change in temperature. To prepare nanoemulsion by literature survey points out that only a specific combina-
PIC, first, the oil phase is mixed with suitable emulsifiers or tion of lipidic excipients leads to the generation of trans-
a mixture of emulsifiers. After that the continuous phase — parent and uniform nanorange globule size emulsion. The
water — is added to the mixture of oil and surfactant at the following are some of the points which are required to be
predetermined rate. As the proportion of water increases, considered for the selection of excipient.
the system reaches the bicontinuous phase having ultra-low
interfacial tension. Subsequently, the water droplets start to • The objective of the formulation (solubility enhance-
merge with each other and form the continuous phase. At ment, permeability improvement, improving local pen-
the particular point known as the emulsion inversion point, etration)
the curvature of the surfactant starts to change in such a way • Required drug loading capacity
Fig. 4 Schematic diagram
explaining the formation of
nanoemulsion by using the
phase inversion temperature
method
13
• Ease of emulsification: with minimum agitation and attached to glycerin molecule, lipids can be classified as
within a reasonable time monoglyceride (one), diglyceride (two), and triglycerides.
• To have a uniform distribution of globules with accept- Another way to classify the lipid is based on chain length
able size. attached to free fatty acid: short (less than 5 carbons),
medium (6–12 carbons), or long-chain (more than 12 car-
Techniques used for the selection of the excipient bons). The attached carbon chain of free fatty acid can be
saturated or unsaturated in nature. Due to these differences
1. Determination of saturation solubility based on the in chemical nature, there are numerous lipids or lipid-like
shake-flask method excipients used to prepare various formulations, all of
In the Initial phase, lipidic excipients can be screened which are in pharmaceutical jargon called “lipids” [85].
on the basis of their capacity to the solubilized maxi- Naturally, lipids are comprised of mixtures of glycer-
mum amount of drug as the primary aim for preparing ides (monoglyceride, diglyceride, and triglyceride) with
the microemulsion/nanoemulsion system is to improve variable chain length and degrees of unsaturation. The
the solubility of the drug. The excess drug is added to chain length of fatty acid and the degree of unsaturation
a lipidic excipient in a vial or flask to generate the satu- can directly affect the various physicochemical properties
rated solution of the drug. The mixture with excess drug of lipids. The melting point of natural oil increases as the
rotates for 24 to 48 h to establish equilibrium between chain length of free fatty acid increases but contrary to that
drug and lipidic excipient. In the case of semi-solid degree of unsaturation decreases the melting point. The
excipient, the mixture is gently heated to have uniform presence of unsaturated bonds in the free fatty acid chains
mixing of drug and excipient. Upon establishment of of natural lipids makes them vulnerable for oxidative deg-
equilibrium, the mixture is centrifuged to get rid of the radation. To prevent this, they are synthetically hydrogen-
insoluble drug and subsequently the concentration of the ated to decrease the degree of unsaturation. Vegetable oils
soluble drug is measured from the supernatant by using containing natural triglycerides are generally regarded as
a suitable analytical method [80–82]. safe (GRAS) compounds and are widely used for prepar-
ing lipid-based drug delivery systems [86, 87] (Table 2).
2. Ease of emulsification Naturally occurring triglycerides suffer from two major
This test is performed to check the ability of surfactant limitations: (1) inherent variations in composition due to
and co-surfactant to emulsify the oil with acceptable glob- differences in geographical locations and cultivation prac-
ule size and time duration. Usually, the oil, surfactant, and tices and (2) limited solubilization capacity for the drug
co-surfactant having the highest solubility of the drug are molecules. To overcome both of these limitations of natu-
mixed in various ratios. Each mixture is heated generally rally occurring triglycerides, semi-synthetic and synthetic
to facilitate the mixing. The prepared mixture is added to a derivatives of natural lipids are prepared [89].
specific quantity of water (100 to 200 ml) with mild agitation Semi-synthetic lipids are not exclusively made up of the
to check the ability to form the spontaneous emulsion. The monoglycerides, diglycerides, or triglycerides but mostly
time and extent of agitation (in terms of numbers of inver- they are a mixture of them. For example, Maisine® CC,
sion or rpm) require to form spontaneous transparent emul- manufactured by Gattefosse is a mixture of monoglycer-
sion noted. A literature survey indicates that the surfactant ides, mainly containing glyceryl monooleate and glyceryl
and co-surfactant with the highest drug solubilization capac- monolinoleate with varying quantities of diglycerides and
ity might not always lead to form the spontaneous micro- triglycerides. It is manufactured by a glycerolysis (partial)
emulsion. In such cases, other surfactants and co-surfactants of vegetable oils (triacylglycerols of linoleic acid mainly).
with promising solubility for the drug are tried [83, 84]. Semi-synthetic and synthetic lipids are prepared in vari-
ous ways such as (1) by changing the fatty acid chain —
Excipients are used to prepare a lipid‑based drug the number of carbon or degree of unsaturation, (2) by
delivery system changing the numbers of fatty acid chains that are attached
to the glycerol backbone, and (3) by attaching the new
Lipids chemical group to the fatty acid chain which can provide
new functionality. Transesterification, interesterification,
Lipids are triglycerides of long chain fatty acids, their direct esterification, and polyglycolysis are some of the
derivatives, and related substances. The lipids can be liq- chemical reactions that are used to prepare semi-synthetic
uid (oils) or solid (wax) depending on the carbon chain lipids from natural lipids (Table 3). [90]
length present in the structure. Structurally lipids are com- Although semi-synthetic and synthetic glycerides are
posed of long-chained fatty acids attached to a glycerin considered to be more uniform in functional properties
molecule. Depending on the numbers of fatty acid chains than natural triglycerides, they still display variability in
13
Table 2 Composition of various natural oil used in lipid-based drug delivery system [88]
No of carbonNumbers of Almond Arachis oil Castor oil Coconut oil Maize oil Olive oil vir- Repeseed oil Sesame oil Soya bean Sunflower Wheat germ
double bond oil, virgin refined virgin refined refined gin refined refined refined oil refined oil refined oil refined
refined virgin
Caproil 6 0 <1.5
Caprylic 8 0 5–11
Capric 10 0 4–9
Lauric 12 0 40–50 <0.1
Myristic 14 0 <1 <0.4 15–20 <0.6 <0.1 <0.1 <0.2
Plamitic 16 0 4–9 7–16 <2 7–12 8.6–16.5 7.5–20 2.5–6 7.9–10.2 9–13 4–9 14–19
Plamitooleic 16:1 1 <0.2 <3.6 <0.2 <0.3
Margaric 17:0 0 <0.2
Stearic 18:0 0 <3 1.3–6.5 <2.5 1.5–5 <3.3 0.5–5 <3 4.8–61 3–5 1–7 <2
9,10 Dihy- 18:0 0 0.3–0
drostearic 7
Ricinooleic 18:1 1 85–92
Oleic 18:1 1 62–86 3.5–7.2 2.5–6 4–10 20–42.3 56–85 50–67 35.9–42.3 17–30 14–40 12–23
Linolenic 18:2 2 20–31 13–43 2.5–7 1–3 39.4–63.6 3.5–20 16–30 41.5–47.9 48–58 48–14 52–59
Linolenic α 18:3 3 <0.4 <0.6 <1 <0.2 0.3–1.3 <1.2 6–14 <0.4 5–18 3–10
Arachidic 20:0 0 <0.0.2 1–3 <0.2 <0.2 <0.7 <0.6 <1
Eicosenoic 20:1 1 <3 0.5–2.1 <1 <0.2 <0.5 <0.4 <5 <0.3 <1 <2
Behenic 22:0 0 <2 1–5 <1.5 <0.3 <0.3 <1
Erucic 22:1 1 <0.1 <0.5 <2
Lignoceric 24:0 0 0.5–3 <0.2 <0.3
Nervonic 24:1 1
Any other <1
13
1627
Table 3 Composition of various lipidic excipients with the approved route of administration [91–93]
1628
Excipient name Definition/description Form Melting HLB Functionality Application route

point (°C)
13
Apifil® PEG-8 beeswax Pellets 59–70 9 Emulsifier Topical
Capryol™ 90 Propylene glycol monocaprylate (Type II, Liquid / 5 Bioavailability enhancement, Oral/topical/veterinary
monoesters > 90%) NF solubilizer
Capryol™ PGMC propylene glycol monocaprylate (Type Liquid / 6 Bioavailability enhancement, Oral OTC
I, monoesters > 55%) NF solubilizer
Compritol® 888 ATO Glycerol dibehenate EP/glyceryl dibehenate Powder 65–77 1 Lubricant, API protection, Oral/ocular
NF/glyceryl behenate Ch.P sustained release
Compritol® 888 Pellets Glycerol dibehenate EP/glyceryl dibehenate Pellets 65–77 1 Lubricant, API protection, Topical/rectal/vaginal
NF/glyceryl behenate Ch.P sustained release, thickener
Compritol® HD 5 ATO Behenoyl polyoxyl-8 glycerides NF Powder 60–67 5 Lubricant Oral OTC
Emulcire™ 61 WL 2659 Mixture of cetyl alcohol EP/NF and ethoxylated Pellets 46.5–50.5 10 Emulsifier Topical
Pellets fatty alcohols (Ceteth-20, Steareth-20) EP/NF
Geleol™ Mono and Diglyc- Glycerol monostearate 40–55 (Type I) EP/ Pellets 54–64 3 API protection, sustained Oral/topical/rectal/vaginal
erides NF mono and diglycerides NF release, thickener, test
masking
Geloil™ SC Mixture of refined soybean oil EP/NF, glyceryl Viscous gel / 5 API protection, vehicle for Dietary supplements
distearate EP/NF, and polyglyceryl-3 dioleate capsules
NF
Gelot™ 64 Mixture of glycerol monostearate EP/NF and Pellets 55.5–62.5 10 Emulsifier Topical
PEG-75 stearate (Type I) NF
Gelucire® 43/01 Hard fat NF/EP/JPE Pellets 42–46 1 API protection, thickener, Oral
Gelucire® 44/14 Lauroyl macrogol-32 glycerides EP/Lauroyl Block 42.5–47.5 11 Bioavailability enhancement Oral/nasal
polyoxyl-32 glycerides NF
Gelucire® 48/16 PEG-32 stearate (Type I) NF/EP pending Pellets 46–50 12 Bioavailability enhancement Topical
Gelucire® 50/13 Stearoyl macrogol-32 glycerides EP/stearoyl Pellets 46–51 11 Bioavailability enhancement Oral
Labrafac™ Lipophile WL Triglycerides medium-chain EP/medium-chain Liquid / 1 Bioavailability enhancement, Oral/topical/vaginal/inject-
1349 triglycerides NF/medium-chain fatty acid vehicle for capsules, oily able/ophtalmic/sublingual/
triglyceride JPE vehicle veterinary
Labrafac™ PG Propylene glycol dicaprylocaprate EP propyl- Liquid / 1 oily vehicle Oral
ene glycol dicaprylate/dicaprate NF
Labrafil® M 1944 CS Oleoyl macrogol-6 glycerides EP/Oleoyl poly- Liquid / 9 Bioavailability enhancement, Oral/topical/rectal/vaginal/
oxyl-6 glycerides NF solubilizer nasal/veterinary
Labrafil® M 2125 CS Linoleoyl macrogol-6 glycerides EP/linoleoyl Liquid / 9 Bioavailability enhancement Oral/topical/rectal/vaginal/
polyoxyl-6 glycerides NF inhalation
Labrafil® M 2130 CS Lauroyl macrogol-6 glycerides EP/lauroyl Liquid / 9 Solubilizer Topical/rectal/vaginal
Labrasol® Caprylocaproyl macrogol-8 glycerides EP Liquid / 12 Solubilizer Topical/transdermal
Caprylocaproyl polyoxyl-8 glycerides NF
Table 3 (continued)
point (°C)
Labrasol® ALF Caprylocaproyl macrogol-8 glycerides EP Liquid / 12 Bioavailability enhancement Oral

caprylocaproyl polyoxyl-8 glycerides NF
Lauroglycol™ 90 Propylene glycol monolaurate (Type II, Liquid / 3 Bioavailability enhancement, Oral/topical/nasal
monoesters > 90%) EP/NF solubilizer
Lauroglycol™ FCC FCC propylene glycol monolaurate (Type I, Lliquid / 5 Solubilizer Oral/topical
monoesters > 45%) EP/NF
Maisine® CC Glycerol monolinoleate EP/Glyceryl Liquid / 1 Bioavailability enhancement Oral
monolinoleate NF
Monosteol™ Propylene glycol monopalmitostearate EP Pellets 33–40 4 Thickener Topical
Ovucire® range Mixture of hard fat EP/NF/JPE with additives Pellets 32–34 / Vehicle Vaginal
Peceol™ Glycerol monooleates (Type 40) EP/glyceryl Liquid / 1 Bioavailability enhancement, Oral/topical/transdermal/
monooleate (Type 40) NF oily vehicle dietary supplements
Plurol® Diisostearique Diisostearique Triglycerol diisostearate EP/ Liquid / 4.5 Emulsifier Topical
polyglyceryl-3 diisostearate NF
Plurol® Oleique CC 497 Polyglyceryl-3 dioleate NF Liquid / 3 Bioavailability enhancement, Oral/vaginal

solubilizer
Precirol® ATO 5 Glycerol distearate (Type I) EP/glyceryl distea- Powder 2 Sustained release, lubricant, Oral
rate NF test masking
Sedefos™ 75 Mixture of triceteareth-4 phosphate and Pellets 47–52 10 Emulsifier Topical
ethylene glycol stearate EP/NF/JPE (and)
diethylene glycol stearate EP/NF/JPE
Suppocire® range Hard fat EP/NF/JPE/Ch.P Pellets 33–45 / Vehicle Rectal/vaginal
Tefose® 1500 Mixture of PEG-6 stearate (Type I) NF/EP Block 40.4–44.4 10 Emulsifier Topical/rectal
pending and PEG-32 stearate (Type I) NF/EP
pending
Tefose® 63 Mixture of PEG-6 stearate (Type I) NF/EP Block 46–53 9.5 Emulsifier Topical/rectal/vaginal
pending and ethylene glycol palmitostearate
EP/NF/JPE (and) PEG-32 stearate (Type I)
NF/EP pending
Transcutol® HP Highly purified diethylene glycol monoethyl Liquid / 4 Bioavailability enhancement, Oral/auricular/injectable
ether EP/NF solvent
Transcutol® P Highly purified diethylene glycol monoethyl Liquid / 4.2 Solvent, solubilizer Topical/transdermal/vaginal
ether EP/NF
Transcutol® V—Veterinary Highly purified diethylene glycol monoethyl Liquid / Not applicable Solvent, solubilizer, bioavail- Topical/transdermal /injectable
ether EP/NF ability enhancement
Captex® 300 EP/NF Medium chain triglyceride (EP, NF) capric Clear colorless Bioavailability enhancer, Oral/topical/parenterals
(C10) 25–35% liquid solubilizer, emollient
Caprylic (C8) ≈ 70%
Triglyceride (100%)
13
1629
1630

point (°C)
13
Captex® 300 Low C6 EP/ Medium chain triglyceride (EP/NF/JPE), Clear colorless Bioavailability enhancer, Oral/topical/parenterals
NF/JPE Capric (C10) 25–35% liquid lubricant, viscosity modifier
Caprylic (C8) ≈ 70%,
Triglyceride (100%)
Captex® 355 EP/NF Medium chain triglyceride (EP, NF), Clear colorless Moisturizer, lubricant, Oral/topical/parenterals
Capric (C10) 35–45% liquid modifier
Caprylic (C8) ≈ 55%,
Triglyceride (100%)
Capmul® MCM EP/NF Glyceryl monocaprylocaprate Type I (EP) Colorless or Emulsifier/co-emulsifier, Oral/topical/parenterals
Glyceryl monocaprylocaprate Type I (NF), slightly yellow plasticizer, vehicle
Capric (C10) 10–50% liquid or soft
Caprylic (C8) 50–90%, mass
Monoglyceride (45–75%) Diglyceride
(20–50%) Triglyceride (< 10%)
Capmul® MCM C8 EP Glycerol monocaprylate Type I, Colorless or Bioavailability enhancer, Oral/topical
Caprylic (C8) ≥ 90%, slightly yellow emulsifier/co-emulsifier
Monoglyceride (45–75%) Diglyceride liquid or soft
(20–50%) Triglyceride (< 10%) mass
Capmul® GMO-50 EP/NF Glycerol mono-oleates (EP) Amber liquid or Penetration Enhancers, solu- Oral/topical
Glyceryl monooleate (NF), semi-solid bilizers emulsifiers
Oleic (C18:1) ≥ 60%
Linoleic (C18:2) ≤ 35%,
Monoglyceride (55–65%) Diglyceride
(15–35%) Triglyceride (2–10%)
Capmul® 808G EP/NF Glycerol monocaprylate Type II (EP, NF), Colorless or Emulsifier/co-emulsifier Oral/topical
Caprylic (C8) ≥ 90%, slightly yellow
Monoglyceride (≥ 80%) Diglyceride (≤ 20%) solid
Triglyceride (≤ 5%)
Capmul® PG-2L EP/NF Propylene glycol dilaurate (EP, NF), Lauric Colorless or Emulsifier/co-emulsifier Oral/topical
(C12) ≥ 95%, slightly yellow
Propylene glycol diesters (≥ 70%) Propylene liquid
glycol (≤ 30%)
Capmul® PG-8 NF Propylene glycol Monocaprylate Type II, Colorless liquid Emulsifier/co-emulsifier, Oral/topical
Caprylic (C8) ≥ 90%,
Propylene glycol Monoesters (≥ 90%)
Capmul® PG-8–70 NF Propylene glycol Monocaprylate Type I, Colorless or Emulsifier/co-emulsifier, Oral/topical
caprylic (C8) ≥ 90%, slightly yellow
Propylene glycol Monoesters (55–80) Propylene liquid
glycol diesters (20–45)
point (°C)
Capmul® PG-12 EP/NF Propylene glycol monolaurate Type II, lauric Colorless or Emulsifier/co-emulsifier Oral/topical
(C12) ≥ 95% slightly yellow
Propylene glycol monoesters (≥ 90) liquid
Acconon® MC8-2 EP/NF Caprylocaproyl Macrogolglycerides (EP) Clear colorless Bioavailability enhancer, Oral/topical
caprylocaproyl polyoxyglycerides (NF), liquid stabilizer
Capric (C10) 30–40%
Caprylic (C8) 60–70%
Acconon® C-44 EP/NF Lauroyl macrogolglycerides (EP) lauroyl Pale yellow solid Bioavailability enhancer, Oral/topical
polyoxyglycerides (NF), stabilizer
Lauric (C12) 40–50%
Acconon® C-50 EP/NF Stearoyl macrogolglycerides (EP) stearoyl Pale yellow solid Bioavailability enhancer, Oral/topical
polyoxyglycerides (NF), Palmitic (C16) stabilizer
40–50%
Stearic (C18) 48–58%
Acconon® AKG-6 EP/NF Oleoyl macrogolglycerides (EP) stearoyl poly- Light amber Bioavailability enhancer, Oral/topical
oxyglycerides (NF), liquid stabilizer

Oleic acid (C18:1) 58–80%
Linoleic acid (C18:2) 15–35%
Sterotex® NF Hydrogenated vegetable oil Type I (NF), Fine white 63 °C Encapsulation, dry binding, Oral
hydrogenated vegetable Oil (BP) powder controlled release, process-
ing aids
Sterotex® HM NF Hydrogenated vegetable oil Type I (NF), Fine white 69 °C Encapsulation, dry binding, Oral
hydrogenated vegetable oil (BP) powder controlled release, pro-
cessing aids
Sterotex® K NF Hydrogenated vegetable oil Type I (NF) Fine white 83 °C Encapsulation, dry binding, Oral
powder controlled release, pro-
cessing aids
13
1631
the relative position of fatty acid chain attached to glyc- the internal phase in the form of nano-sized globules within
erol molecule along with the degree of esterification and the external phase. However, charged emulsifiers (cationic,
hydrogenation. This variability is attributed to the varia- anionic, and or zwitterions) also provide extra stabilization
tion in natural raw materials and the randomness of the by providing steric hindrances between charged molecules.
chemical reaction by which they are prepared. The range Compared to all other types of excipients, non-ionic sur-
of variability in the composition of semi-synthetic deriva- factants are generally considered safer and more suitable for
tives and synthetic derivatives often depends on the quality oral drug delivery [100, 101]. Water-insoluble surfactant,
of starting material and consistency in the manufacturing having an HLB value between 8 and 12, is insufficiently
process. [94, 95]. hydrophilic to dissolve in water and form micelles but still is
Another way of preparing semi-synthetic derivatives is sufficiently hydrophilic to form a stable emulsion. Compared
by the addition of PEG (polyethelene glycol) molecules in to that, the formation of self microemulsion/nanoemulsion
the fatty acid chain (fatty acid ester of PEG). The terminal requires surfactants with a higher HLB value (12 or greater)
primary hydroxyl groups present in PEG can create the ether above their “critical micelle concentration” [102, 103].
bridges with natural lipids (such as castor oil) to form semi-
synthetic polyethylene glycol derivative of glyceride and fatty Co‑surfactants
acid. PEG-40 hydrogenated castor oil is hydrogenated castor
oil with an average of 40 mol ethylene oxide. In the case Co-surfactants provide required flexibility and elasticity to
of PEG-60 hydrogenated castor oil, average moles of ethyl- the surfactant film so it can modify in accordance with the
ene oxide are 60. In polyglyceryl fatty acid esters, glycerol curvature of the interface and thus helps in the stabilization
molecules having one or more fatty acid chains are joined of the internal phase especially in the case of microemulsi-
together by ether linkages. For example, in polyglyceryl-3 fication system (SMEDDS or conventional microemulsion)
dioleate, three glycerol molecules are joined and esterified [104, 105]. The presence of co-surfactant also reduces the
with two molecules of oleic acid [96, 97]. concentration of surfactants requires to generate sponta-
The HLB (hydrophilic-lipophilic balance) value of semi- neous self-emulsification, thus prevents the possible GI
synthetic and synthetic derivatives ranges from 3 (very lipo- mucosal irritation and systemic toxicity caused by them.
philic) to 16–17 (highly hydrophilic). HLB is the balance Commonly used co-surfactants are polyols such as PEG
of the size and strength of the hydrophilic and lipophilic 400, PG, n-butanol, isopropyl alcohol, and transcutol [106].
moieties of a surfactant molecule [98]. They are extensively Medium-chain length alcohols also increase the mobility of
used as a lipid, emulsifier, and co-emulsifier for the formula- the hydrocarbon tail and also allow greater penetration of
tion of various lipid-based drug delivery systems especially a greater amount of oil into this region. Furthermore, the
“self” microemulsifying /nanoemulsifying systems. They are presence of alcohol possibly also influences the solubility
also used as plasticizers to facilitate the extrusion process of the drug in the aqueous and oily phases by affecting the
(lowers the Tg of polymer) while preparing amorphous solid partition process [107].
dispersion by hot-melt extrusion technique.
Surfactants Evaluation
Along with suitable oils, the surfactants/emulsifiers play a Appearance and color

very critical role in the formation of stable microemulsion
or nanoemulsion system. Surfactants are amphiphilic com- Ready to use microemulsion is generally transparent but the
pounds containing the polar head and non-polar long chain nanoemulsion has a slight bluish appearance. In the case of
groups (usually made of carbohydrate) that get adsorb at the SMEDDS, the appearance of spontaneously formed micro-
interface of two immiscible liquids (usually water and oil). emulsion plays a very critical part in the selection of suitable
By getting adsorb at the interface, surfactant reduces the excipients. Here the fixed weight of SMEDDS is added to
interfacial tension between two immiscible liquids by replac- a fixed quantity of dissolution medium under slight agita-
ing the cohesive forces between the like molecules (oil-oil/ tion provided by either vortex or magnetic stirrer. A suitable
water-water) with adhesive forces between unlike molecules SMEDDS spontaneously forms transparent to the slightly
(surfactant-oil/surfactant-water) [99]. bluish emulsion upon coming in contact with dissolution
Surfactants can be classified as cationic, anionic, neutral, media, indicating the ability of SMEDDS formulation to
or zwitterions compounds based on the charges they carry keep the drug in the solubilized form [108]. Contrary to
on the polar head group. The reduction of the interfacial ten- that if the formed solution appeared to be hazy and opaque,
sion is the main mechanism by which surfactants stabilize it indicates precipitation of the drug upon coming in contact
13
with the dissolution medium. The nanoemulsion can be microemulsion and nanoemulsion system, stress conditions
transparent, turbid, or opaque depending on its composi- possibly accelerate the coalesce of the globules which ulti-
tions and method of preparation [109]. mately lead to phase separation. The formulations are sub-
jected to different stress conditions such as heating–cooling
cycle, centrifugation, and freeze–thaw cycle tests, and peri-
Globule size odically various physicochemical parameters such as glob-
ule size, particle size distribution, zeta potential, the poly-
The mean globule size of the formulation is a critical morphic form of the drug, and stability of the API in the
parameter that affects many pivotal properties such as formulation are checked. This test also gives an idea about
appearance, stability, dissolution profile, and bioavail- the possible degradation pathway that a particular system
ability. The accepted limit of the globule size in the case likely to follow (e.g., oxidation, hydration) during the stress
of the microemulsion is less than 200 nm, whereas in the conditions.
case of nanoemulsion, it is less than 500 nm. These limits
are not stringently defined by any regulatory authorities. • Heating cooling cycle: The formulations are shifted
The globule size is usually measured by using a particle repeatedly between refrigerator temperature 4 °C and
size analyzer which measures fluctuation in the intensity 45 °C after keeping them for at least 48 h [114].
of the scattering of light due to Brownian motion of the • Centrifugation: The formulations were centrifuged and
globules [110]. checked for phase separation.
• Freeze–thaw cycle: The formulation is shifted
Ease of emulsification between −21 and + 25 °C repeatedly, and key parameters
of the formulation were reassessed [115].
This test is relevant for self-emulsifying drug delivery sys-
tem. This indicates the time and intensity of agitation requires Viscosity measurement
to emulsify the product. The suitable SMEDDS formulation
immediately forms clear and transparent dispersion with no The rheology of lipid-based drug delivery systems possi-
sign of drug precipitation. To measure it, the fixed quantity bly varies from low viscosity fluids to semi-solid gel-like
SMEDDS formulation is added to the suitable dissolution materials depending on their composition of the formula-
media under mild agitation conditions. Subsequently, time tion. Brookfield type rotary viscometer is commonly used
and extended agitation required for the formation of the trans- to measure the viscosity of lipid-based formulations. For
parent microemulsion is observed [111, 112]. the self-emulsifying system, it is important to measure
the viscosity of pre-concentrates as well as formed micro-
Surface charge (zeta potential) emulsion/nanoemulsion. The viscosity of pre-concentrate
gives an idea about the ease of processing — filling in the
The electric charges exist on the surface of globules due capsule or solidification process requires to convert into a
to the adsorption of surfactant molecules play a very criti- suitable dosage form.
cal role in stabilizing the system. Globules with high sur-
face charges repulse each other and thus resist coalesce The drug release study
of the globules and ultimately phase separation [113].
The zeta potential is defined as the potential difference In the lipid-based drug delivery system, as the drug is
between the shear plane and the electroneutral region. already solubilized in the oily vehicle, estimation of the
Zeta potential decides the degree of repulsion between total effective surface area generated by the nano-sized
similarly charged globules. Zeta potential is measured by globules has a more significant effect on the drug release
the electrophoresis technique which measures the veloc- compared to the ability of aqueous media to solubilized
ity of particles when they are placed between two elec- the drug [116]. Digestion of the lipid and subsequent
trodes with specific voltage differences. The ZP value of micellization are considered to be primary factors affect-
beyond ± 60 mV suggests the excellent stability of the ing the transport of drugs through intestinal epithelia.
system. The efficiency of both of these processes (digestion of
the lipid and subsequent micellization) dictates the total
Thermodynamic stability effective surface area generated by the emulsified for-
mulation. In the case of ready to use microemulsion and
The ability of the formulation to maintain the physical nanoemulsion, the globule size and its distribution are
and chemical integrity under stress conditions is evalu- more reflective of the in vivo performance rather than the
ated by exposing it to extreme conditions. In the case of dissolution test [117].
13
Bio-relevant media are generally considered more suit- of supersaturation, as the concentration of the dissolved
able compared to conventional media in order to improve drug breaches the saturation level, it leads to aggregation
the in vivo prediction power of the used in vitro dissolu- of the dissolved molecules and which ultimately results in
tion test. In case self-emulsifying systems, depending on the precipitation of the dissolved drug [127, 128]. The precipi-
final dosage form (capsule/tablet), generally, USP Type I or tation of the dissolved drugs decreases the concertation of
Type II apparatus are used to evaluate the in–vitro dissolu- a molecularly dispersed drug in the dissolution medium.
tion properties of the final formulation. The reduction in the amount of molecularly dispersed
drugs impairs the absorption process as the absorption of
most of the drug is directly proportional to the concerta-
Recent advances and marketed product tion gradient of the molecularly dispersed drug across the
GI lumen [129].
Though the lipid-based systems especially SMEDSS/ Supersaturation is a phenomenon where the concentra-
SNEDDS offer a significant improvement in solubil- tion of the dissolved drugs is maintained above its satu-
ity and dissolution properties compared to a pure drug, ration level, without any precipitation. The maintenance
these formulations also suffer from some of the critical of the supersaturation above the saturation increases the
inherent limitations that restrict its applicability on a amount of the molecularly dissolved drugs in the dis-
pan-industry scale. Some of the critical concerns are as solution media and thus creates a significantly high con-
follows: (1) SMEDDS/SNEDDS being semi-solid/liquid centration gradient across the GI membrane. Such a high
are difficult to fill in the gelatin capsules. (2) There is concentration gradient improves the absorption of the
always the risk of getting leached out from the capsules drug by promoting the movement of molecules across the
due to the hydrophilic nature of excipients. (3) The pos- membrane according to Fick’s first law [130]. Amorphous
sible interaction between the composition of SMEDDS, solid dispersion where the drug molecules are entrapped
especially surfactant and co-surfactants and capsule in a high energetic amorphous state or molecularly dis-
shell, can also possibly results in softening of capsule persed state within a polymer matrix system is one of
shells. [118, 119] the very widely used approaches for improving the dis-
All of the above-mentioned concerns, mainly due to solution properties of poorly soluble drugs works on the
the semi-solid/liquid nature of the lipid-based system, mechanism of maintaining the supersaturation of the
have given birth to a trend of converting these semi-solid/ dissolved drug. [131] In supersaturated SMEDDS, the
liquid formulations into solid ones — a system known as prepared SMEDDS are adsorbed on long-chained poly-
Solid SMEDDS (S-SMEDDS). S-SMEDDS is prepared mers that prevent the precipitation of the dissolved drug
by adsorbing the semi-solid/liquid SMEDSS on suitable molecules by inhibiting the nucleation and subsequent
carriers which are having excellent internal surface areas crystallization in the dissolution medium [132]. The poly-
such as neusiline US2, MCC (Microcrystalline Cellulose), mer molecules get adsorbs on the surface of the growing
and Fujicalin, maltodextrin. Adsorption of the SMEDDS nuclei and due to their long-chain structure prevent the
on solid carriers results in the improvement of critical pro- further aggregation of nuclei by providing the steric hin-
cessing characteristics such as flowability, compressibility, drances [133]. Prevention of nucleation and subsequent
and compatibility. The adoption on the solid carrier also crystallization maintains the concentration of the dis-
provides steric hindrance against coalesce of the semisolid solved drug above the saturation level — a phenomenon
material and improves the overall stability of the system known as kinetic stabilization of drug supersaturation
[120–126]. [134]. The maintenance of the dissolved drug concerta-
Another newly developed modification that has gar- tion above the saturation level improves the absorption
nered much traction among researchers is a system known of the drug across the membrane and thus the bioavail-
as supersaturating-SMEDDS. As discussed in the previ- ability. [135, 136] PVP, Soluplus, HPMC, poloxamer 407,
ous section, SMEDDS/SNEDDS formulation instantly poloxamer 188 and copovidone are the example of some
converts into ultrafine globules upon coming in contact polymers that have been used to prepare supersaturating
with gastric fluid, under the influence of mild agitation SMEDDS [137].
provided by the movement of the GI tract. The formation The lipid-based drug delivery system has not been just
of ultrafine globules offers an extremely high surface area confined to academic research that is quite evident from the
for the dissolved drug to release in the dissolution media. considerable numbers of marketed formulations available.
The sudden release of such a high amount of drug that The history of commercializing lipid-based formulation goes
inherently has very limited solubility in the dissolution back to 1940 but the real increase in the number of marketed
media leads to an increase in the concentration of the drug products for lipid-based delivery systems was only observed
above its saturation level. According to Mayer’s theory after 1990. Years between 1990 and 2009 accounted for the
13
Table 4 Marketed lipid-based formulations [139–141]

Drug Product name Company Therapeutic area Dosage form
Amprenavir Agenerase® Glaxo SmithKline HIV antiviral Soft gelatin capsules

Calcitrol Rocaltrol® Roche Calcium regulator Soft Gelatin capsule
Clofazimine Lamprene® Geigy Leprosy Soft Gelatin capsule
Cyclosporin A/III Gengraf® Abott Immuno-suppressant Soft gelatin capsules
Cyclosporine Sandimmune® oral Novartis Immunosuppressant Soft Gelatin capsule
Cyclosporine Neoral® Novartis Immunosuppressant Soft Gelatin capsule
Cyclosporine A Restasis® Allergan Immunomodulation Ophthalmic emulsion
Dexamethazone Palmitate Limethason® Green Cross Carticosteroid Intravenous injection
Diazepam Diazemuls® Braun Melsungen Sedation Intravenous injection
diclofenac diethylammonium voltarol® GlaxoSmithKline Pain relief gel Topical gel
Doxercalciferol Hectoral® Bone care Calcium regulator Soft gelatin capsules
Dronabionol Marinol® Roxane Anoxeria Soft gelatin capsules
Dutasteride Avodart® GSK Benign Prostatic Hyperplasia Soft gelatin capsules
(BPH)
Efavirenz Sustiva® Bristol-Meyers HIV antiviral Hard gelatin capsules
Etomidate Etomidate Lipuro- 2® B. BRAUN – ALMANYA Anesthesia Intravenous injection
Finofibrate Fenogal® Genus Anti hyperlipproteinomic Hard gelatin capsules
Isotretionoin Accutane® Roche Acne Soft gelatin capsules
Miconazole nitrate miconaz-H® Medical union Pharmaceutical Anti-fungal Topical gel
Paricalcitol Zemplar® Abbott Calcium regulator Soft gelatin capsules
Progesterone Prometrium® Solvay Endometrial hyperplasia Soft gelatin capsules
Propofol Diprivan® AstraZeneca Anesthesia Intravenous injection
Ritonavir Norvir® Abbott AIDS Soft gelatin capsules
Ritonavir/lopinavir Kaletra® Abbott AIDS Soft gelatin capsules
Saquinavir Fortovase® Roche AIDS Soft gelatin capsules
Tipranavir Aptivus® Boehringer Ingelheim AIDS Soft gelatin capsules
Tritionoin Vesanoid® Roche Acne Soft gelatin capsules
Valproic acid Depakene® Abbott Epilepsy Soft gelatin capsules
Vitamins A, D, E, and K Vitalipid N® Kabi Nutrition Intravenous injection
commercialization of nearly 63% of all lipid-based products. phase drug candidates. The availability of wide ranges
Overview of the published literature and online databases of excipients, relative eases of scaling, and along with
of the approved product suggested the commercialization improving the solubility, ability to address permeability,
of around 67 lipid-based formulations in the USA and EU and pre-systemic metabolic liabilities have given lipid-
market currently. Among all the formulated dosage form based emulsion system a unique edge compared to other
containing lipid-based systems, more than 50% product is in solubility improvement methods. Though the lipid-based
the form of a soft gelatin capsule [138]. Along with the abil- drug delivery system is been well explored by academia
ity to improve solubility, ease of manufacturing compared and industry, there are some critical areas of formulations
to other methods, easy to scale up and availability of a wide and manufacturing that still offer considerable challenges.
range of excipients for the formulation have attracted manu- Selection of the excipients which can have sufficient solu-
facturers to come up with a verity of marketed formulations. bility to accommodate the required amount of drug along
A list of marketed formulation available in the market based with required emulsification ability is still a challenge. In
on a lipid-based drug delivery system is given in Table 4. most of the research papers, the excipients were selected
based on their ability to the solubilized maximum amount
of drug but as it was observed in many articles that the
Conclusion excipients with the maximum solubility might not have
the required emulsification ability. The emulsification of
Lipid-based emulsion system provides an attractive option oil is quite a complex process that is governed by many
for enhancing the solubility and dissolution properties of factors such as interfacial tension, the combination of
poorly soluble already marketed /still in the discovery adhesive and cohesive forces, and comparative affinity
13
of the molecules for the oil phase and aqueous phase, maintenance of an amorphous state in solid dispersion with
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Arituclo 3 Seminario Emulsiones

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Drug Delivery and Translational Research (2022) 12:1616–1639

Lipid‑based emulsion drug delivery systems — a comprehensive

Accepted: 20 September 2021 / Published online: 5 October 2021

Keywords Microemulsion · Nanoemulsion · SMEDDS · SNEDDS · Excipients · Emulsification theory · Method of

Introduction the development phase, has been started to get measured

Microemulsion vs nanoemulsion that under certain experimental conditions and formulation

Fig. 1 Globule size comparison

Fig. 2 The difference between

Excipient name Definition/description Form Melting HLB Functionality Application route

Labrasol® ALF Caprylocaproyl macrogol-8 glycerides EP Liquid / 12 Bioavailability enhancement Oral

Plurol® Oleique CC 497 Polyglyceryl-3 dioleate NF Liquid / 3 Bioavailability enhancement, Oral/vaginal

Excipient name Definition/description Form Melting HLB Functionality Application route

oxyglycerides (NF), liquid stabilizer

Along with suitable oils, the surfactants/emulsifiers play a Appearance and color

Table 4 Marketed lipid-based formulations [139–141]

Amprenavir Agenerase® Glaxo SmithKline HIV antiviral Soft gelatin capsules

You might also like

Arituclo 3 Seminario Emulsiones

Uploaded by

Copyright:

Available Formats

Arituclo 3 Seminario Emulsiones

Uploaded by

Document Information

Copyright

Available Formats

Share this document

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Arituclo 3 Seminario Emulsiones

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Drug Delivery and Translational Research (2022) 12:1616–1639

Lipid‑based emulsion drug delivery systems — a comprehensive

Accepted: 20 September 2021 / Published online: 5 October 2021

Keywords Microemulsion · Nanoemulsion · SMEDDS · SNEDDS · Excipients · Emulsification theory · Method of

Introduction the development phase, has been started to get measured

Microemulsion vs nanoemulsion that under certain experimental conditions and formulation

Fig. 1 Globule size comparison

Fig. 2 The difference between

Excipient name Definition/description Form Melting HLB Functionality Application route

Labrasol® ALF Caprylocaproyl macrogol-8 glycerides EP Liquid / 12 Bioavailability enhancement Oral

Plurol® Oleique CC 497 Polyglyceryl-3 dioleate NF Liquid / 3 Bioavailability enhancement, Oral/vaginal

Excipient name Definition/description Form Melting HLB Functionality Application route

oxyglycerides (NF), liquid stabilizer

Along with suitable oils, the surfactants/emulsifiers play a Appearance and color

Table 4 Marketed lipid-based formulations [139–141]

Amprenavir Agenerase® Glaxo SmithKline HIV antiviral Soft gelatin capsules

You might also like

Fig. 1 Globule size comparison

Fig. 2 The difference between

Table 4 Marketed lipid-based formulations [139–141]