AAPS PharmSciTech (2019) 20: 323

DOI: 10.1208/s12249-019-1550-5

Review Article

A Rundown Through Various Methods Used in the Formulation of Solid

Self-Emulsifying Drug Delivery Systems (S-SEDDS)

Sharel Rency D. Almeida1 and Vamshi Krishna Tippavajhala1,2

Received 11 April 2019; accepted 26 September 2019; published online 25 October 2019

Abstract. The most common route of the drug administration is oral route despite the fact
that most drugs have low oral aqueous solubility and bioavailability especially for BCS class
II and class IV drugs. Many methods have been developed in recent years to overcome the
poor solubility and oral bioavailability which includes self-emulsifying drug delivery systems
(SEDDS) as one of the approaches. Not only for hydrophobic drugs, but also for hydrophilic
compounds with low permeability, bioavailability can be enhanced by self nanoemulsifying
drug delivery systems. Recently, a lot of focus and attention has been put in the conversion of
liquid SEDDS (L-SEDDS) to solid SEDDS (S-SEDDS) to overcome the limitations of liquid
formulations related to their physical and chemical stability, portability, accurate dosing, and
limited choices of dosage forms. This article aims to review the formulation components used
in SEDDS, various approaches used in the conversion of L-SEDDS to S-SEDDS, their
applications, merits, and demerits.
KEY WORDS: solid self-emulsifying drug delivery systems; solubility enhancement; bioavailability
enhancement; lipid-based formulations.

INTRODUCTION aqueous medium of gastrointestinal tract, the agitation for

self-emulsification being provided by the peristaltic move-
A significant percentage (up to 70%) of chemical ment in vivo (1,3–5). The hydrophobic drug in the oil phase
substances considered in drug development has poor aqueous will be exposed to the large interfacial area across which
solubility problem that will affect gastrointestinal absorption diffusion occurs. The oil and surfactant in each formulation
(1). Formulation of a suitable delivery system for a drug with are the major factors to decide the mechanism, rate, and
low water solubility is thought-provoking. The main Biophar- degree of absorption of the drug from the emulsion (6).
maceutical Classification System (BCS) Classes with low In comparison to conventional dosage forms like cap-
solubility are class II (low solubility and high permeability) sules or tablets, the SEDDS generates micro emulsion in
and class IV (low solubility and low permeability) (2). The gastrointestinal fluids with drug dissolved in very fine
lipid-based formulation approaches for oral drug delivery emulsion droplets that come in contact with gastrointestinal
systems have several benefits such as enhanced permeability, tract for quicker absorption (4). The joint action of specific
reduced pre-systemic metabolism, and increased drug appar- excipients with lower levels of free energy results in
ent solubility resulting in enhanced oral bioavailability of m i c r o e m u l s i o n i m p u l s i v e l y ( 7 ) . T h e dr o p l e t s of
these poorly water soluble drugs (3). A renowned alternative microemulsion formed in the GIT are exposed to a larger
approach for delivery of the low water-soluble drug is by surface area that help in rapid drug release of the dissolved
formulating as a lipid formulation particularly the self- drug from the micelles. They also play significant role in the
emulsifying drug delivery systems (SEDDS) which deal with transportation of the drug across the unstirred water layer to
low aqueous solubility and poor oral bioavailability (1). the gastrointestinal membrane during an absorption process.
SEDDS are thermodynamically stable formulations that Along with dissolution enhancement of the drug by SEDDS,
are comprised of an isotropic mixture of co-surfactants, the bioavailability is improved by lymphatic transport
surfactants, and oils that result in an o/w emulsion with avoiding the hepatic first-pass effect (4,7). The small globule
submicron size on slight stirring when introduced into size together with surface activity allows more efficient
aqueous media. These mixtures self-emulsify quickly in transport through intestinal membrane ensuing rapid onset
of action. SEDDS are the systems with droplet size between
1
Department of Pharmaceutics, Manipal College of Pharmaceutical 100 and 300 nm (8) upon emulsification but generally with a
Sciences, Manipal Academy of Higher Education, Manipal, Karna- droplet size below 250 nm (9). Upon dispersion in water,
taka, India. SEDDS yield crude, milky emulsions. As per Anette
2
To whom correspondence should be addressed. (e–mail: Müllertza et.al, the jargon around SMEDDS is uncertain.
[email protected])

1530-9932/19/0800-0001/0 # 2019 American Association of Pharmaceutical Scientists

323 Page 2 of 14 AAPS PharmSciTech (2019) 20: 323

The reason for the confusion is due to the formation of a Type III formulations are commonly mentioned as self-
dispersed emulsion with nanometer range for both SMEDDS micro emulsifying drug delivery system (SMEDDS); these are
and SNEDDS (10). The liquid formulation of SMEDDS has demarcated by the addition of surfactants HLB > 12, i.e.,
more than a few limitations which include stability issues hydrophilic surfactant and cosurfactant, for example, poly-
during the process of manufacturing and portability issues ethylene glycol, ethanol, and propylene glycol. Type III
during transport (4). The liquid SEDDS has limitations of systems can be separated into (a) type IIIA and (b) type
chemical instability, drug precipitation, portability issues, and IIIB; the type IIIB systems are more hydrophilic where the
limited choices of dosage forms associated with the liquid cosolvents and hydrophilic surfactants content upsurges and
SEDDS (11). The solid form of SMEDDS (S-SMEDDS) is the lipid amount declines (19). Type IIIA systems are
anticipated to be a more appropriate formulation owing to formulations with small amounts of water-soluble surfactants.
better patient compliance, improvement of physical and These formulations form fine submicron dispersion as they
chemical stability on storage, and dosing accuracy. Since solid have a potential to disperse quickly resulting in transparent
systems are prone to cause a reduced amount of irritation to dispersion (14). The SEDDS and SMEDDS are commonly
GIT, safety can also be improved (3). distinguished based on optical clarity and the particle size of
resultant dispersion. SMEDDS (with a greater number of
hydrophilic co-surfactants and surfactants) give tiny droplets
LIPID-BASED CLASSIFICATION SYSTEM with particle size ranging below 100 nm with slightly
opalescent or optically clear dispersion while SEDDS provide
Colin W. Pouton et al. described lipid-based classification an opaque dispersion with a particle size above 100 nm.
system (LBCS) of formulations that can be categorized into four Several water-soluble surfactants can be used to formulate
types on the basis of constituents in the formulation and the type III systems like Cremophors and PEGylated mixed
dilution and digestion effects on their capability to stop precipi- glycerides (Gelucires and Labrasol) (19).
tation of the drug. Type I formulations contain digestible oils, type Type IV systems were added to LBCS in 2006. Type IV
II formulations are self-emulsifying drug delivery systems that systems are oil-free formulations and they represent the
contain water-insoluble ingredients, type III systems are hydrophilic formulations, essentially only surfactants or
SMEDDS or SEDDS which can be further classified as type mixtures of surfactants and cosolvents (13,14). In type IV
IIIA containing surfactants that are water-soluble and type IIIB formulation, the blending process of cosolvent and surfactant
with cosolvents or a larger amount of water-soluble components, will offer a benefit of more solvent capacity on dilution (as a
and the type IVare oil preparations which predominantly include micellar solution) than when cosolvent is used alone. The
hydrophilic surfactants in addition to cosolvents as compiled in cosolvent also facilitates the surfactant dispersion which likely
Table I (12–14). reduces the variability and the irritancy produced by the
The type I formulation includes a drug in mixed surfactant’s high concentrations. Type IV system is beneficial
glycerides and/or triglycerides or in stabilized o/w emulsion for the drugs that are not lipophilic in nature; nevertheless, it
with a lesser amount of emulsifiers like 1.2% (w/v) lecithin is necessary to note that these systems may not be well-
(15) and 1% (w/v) polysorbate 60 (16). Usually, these tolerated on chronic use of the drug (13). The capsule
formulations show low aqueous solubility initially and to formation of amprenavir HIV protease inhibitor (Agenerase,
produce more amphiphilic lipid digestion products, they GSK) is an example of type IV formulation (20).
require the co-lipase/pancreatic lipase in GIT for digestion
and for promoting the transfer of the drug to the colloidal
phase. Therefore, the type I formulation defines the drug that FORMULATION OF SEDDS
is potent or highly lipophilic which allows incorporation of
required dose due to its adequate solubility in oil (17). Type I The formulation of SEDDS includes a primary step to
systems are limited to their ability to self-disperse in water as investigate the solubility of the drug in various excipients like in
this system lacks surfactants. Mixed glycerides, such as mono/ oil, surfactant, and cosurfactant and to identify the specific
diglyceride blends (Imwitor 988, Capmul MCM) are often combination of above excipients to possess self-emulsifying
used in type I formulations and have been used alone (with property (21). Miscibility of excipients is necessary to produce a
drug) in capsule products (14). stable and clear liquid formulation. Usually, the water-insoluble
Type II systems consist of oils as well as water-insoluble surfactants are miscible with medium chain triglycerides and long-
surfactants (HLB < 12) which on introduction to aqueous chain triglycerides oils so that type II systems can be formulated
media self-emulsify to form an oil-in-water emulsion with just these two components. The chemical diversity of lipid
(14,17). When the surfactant concentration exceeds 25% excipients can lead to immiscibility on long-term storage; hence,
w/w, it leads to the formation of self-emulsifying systems, long-term physical stability tests should be carried out during
30–40% being the optimum surfactant range. Above 50% of development. The formulation of SEDDS can be briefly
the surfactant range, the emulsification is slower because of explained in the steps given in Fig. 1.
formation of liquid viscous crystalline phase at the o/w
interface. The SEDDS formulation will depend on the
dispersed lamellar layer crystalline phase formed at lower Selection of Excipients
water contents of about 5–10%, which further helps in the
water penetration initiating interfacial disruption. Typical Only certain pharmaceutical excipients can self-emulsify.
formulations are mixtures of medium chain triglyceride The different variables affecting such property are surfactant
(MCT) oil and polysorbate 85 (18) or mixtures of MCT oil concentration, type of surfactant-oil pair, the ratio used, and
and Tagat TO (14). the temperature at which self-emulsification takes place (22).
 AAPS PharmSciTech (2019) 20: 323

Table I. Pouton’s Lipid Formulation Classification System

Types Type I Type II Type III A Type III B Type IV

Water-soluble surfactant (%) (HLB less than 12) – 20 to 60 – – 0 to 20

Water-soluble surfactant (%) (HLB greater than 12) – – 20 to 40 20 to 50 30 to 80
Mixed glycerides or triglycerides (%) 100 40 to 80 40 to 80 Less than 20 –
Hydrophilic co-solvents (%) – – 0 to 40 20 to 50 0 to 50
Dispersion particles size (nm) 100 to 250 100 to 250 100 to 250 50 to 100 Less than 50
Advantage Simple; GRAS status; On dispersion not likely Dispersion is clear or almost clear The formulation has a
capsule compatible to lose solvent capacity good solvent capacity for
many drugs
Disadvantage The formulation has low Turbid o/w dispersion Possible loss of solvent capacity on dispersion; less Likely loss of solvent
solvent capacity unless easily digested capacity on dispersion;
the drug is highly may not be digestible
lipophilic
Importance of aqueous dilution Limited importance Solvent capacity Some solvent capacity is Phase changes are Phase changes are
unpretentious lost significant and possible significant and possible
loss of solvent capacity loss of solvent capacity
Importance of digestibility Significant prerequisite, Not significant but likely Not significant but may Not essential Not essential, system
non-dispersing to occur, SEDDS formed be impeded disperses to form a
in absence of water- micellar solution
soluble components
Page 3 of 14 323
323 Page 4 of 14 AAPS PharmSciTech (2019) 20: 323

The use of vegetable oils with triglyceride has several

advantages of SEDDS since they are usually in food,
metabolized and absorbed, therefore does not manifest any
safety concerns and are generally considered as safe (GRAS).
The vegetable oils are commonly known as long-chain
triglycerides because they are long-chain mixed unsaturated
fatty acids glyceride esters (17).

Surfactants

SEDDS has surfactants as one of its components; non-

ionic surfactants are commonly used and their concentrations
range from 30 to 60% (28). The use of a non-ionic surfactant
Fig. 1. Formulation of self-emulsifying drug delivery systems is well thought-out to be safe compared to ionic surfactant
(SEDDS) and is commonly acceptable for oral intake. The non-ionic
surfactant is meant to deliver stability to the emulsion over a
Lipids/Oils wide range of pH and ionic strength (29). The surfactants can
be categorized in accordance with their HLB values as
The core of the emulsion is formed by the lipid part in hydrophilic (HLB > 10) or lipophilic (HLB < 10). SEDDS
SEEDS and the lipids usually include polar class I lipids of and SMEDDS usually require non-ionic hydrophilic surfac-
small’s lipid classification system and non-polar lipids (10,23). tants with HLB value greater than 12 (examples are
The critical factor in the selection of oils is the drug solubility Labrasol®, Cremophor® EL, Gelucire® 50/13, Cremophor®
in oil. Since the nano-emulsion capability in keeping the drug RH 40, Gelucire® 44/14, etc.) that are required in the
in solubilized form is significantly affected by the drug formation of systems that form oil-in-water dispersion spon-
solubility in the oil phase, this is significant for oral taneously upon dilution with the GIT fluids with a droplet
formulations (24). The oil content is usually saturated size below 100 nm (30). The surfactant which possesses good
medium-/long-chain or a partially unsaturated or unsaturated drug solubilizing property may not exhibit good oil affinity.
hydrocarbon which at room temperature can exist in liquid, The criteria for selection of co-surfactant and surfactant will
semisolid, or solid form. Mineral oil, silicone oil, vegetable oil, be decided based on the efficiency of emulsification for the oil
fatty acid, mono-/di-/tri-glyceride, fatty alcohol, and lanolin than drug solubilizing ability (29). When surfactant or
are examples (25). In SEDDS formulation, both medium- and cosurfactant contribute to solubilization of the drug, the drug
long-chain triglyceride oils of different degree of saturation precipitation could be a risk as there could be lowering of the
are used (21). Even though the edible oils may perhaps be the solvent capacity of surfactant or cosurfactant because of
preferred and also logical choice of the excipient of lipid in dilution of nanoemulsion in the gastrointestinal tract. The
SEDDS development, the use of them is limited owing to hydrophilic surfactant and cosurfactant favor the interface
their poor capacity to dissolve lipophilic drugs (21,24). and they also lower the energy required to produce o/w
Recently, the hydrolyzed or modified vegetable oil have been nanoemulsion, hence enhances the stability. For example, the
generally used as this show better emulsification property essential HLB value required to produce o/w nanoemulsion is
with a wide range of approved surfactants for oral adminis- more than 10. The stable nanoemulsion formation upon
tration and show great property of the drug solubility (21). dilution is achieved by the right blend of high and low HLB
The lipid phase used in the formulation of SEDDS/ surfactants. Some selected surfactants in the formulations
SMEDDS can be classified into three classes based on the based on the drug solubility (29) while others suggested
fatty acids chain length namely medium-chain emulsification properties of surfactant and its affinity towards
triglycerides(MC), short-chain triglyceride (SC), and long- oil as vital factors (24). In another way, there comes a
chain triglycerides (LC) as described in Table II (1,3,26,27). possibility that selected surfactant of good drug solubilizing
The natural oils and fats consist of triglyceride mixtures property could not be able to exhibit a good affinity towards
comprising of fatty acids of varying lengths and degrees of the oil. Therefore, the co-surfactant and surfactant have to be
unsaturation (17). carefully chosen based on their oil emulsification properties
than their drug solubilizing ability (29).

Table II. Different Types of Oils Used in SEDDS

Type of oil Examples

Long-chain triglycerides (LCT) Peanut oil, Castor oil, Sesame oil, Soya bean oil, Oleic acid
Medium-chain triglycerides (MCT) Capmul MCM, Capmul PG 12
Capric/caprylic triglycerides (Velsan® CCT, CCT), Pecola
(glycerol monooleate)
Mixed mono-, di-, and triglyceride Capmul MCM EP (caprylic/ capric mono- and diglycerides)
Small-chain triglycerides (SCT) Triacetin
AAPS PharmSciTech (2019) 20: 323 Page 5 of 14 323

Co-surfactants

Usually, alcohols of medium- to short-chain length (C3-

C8) are used as co-surfactants, which tend to increase the
fluidity of the interface and reduce the interfacial tension. The
mobility of the hydrocarbon chain is increased by the co-
surfactant and it also allows the higher penetration of the oil
into this region. The use of alcohol as co-surfactant will
enhance the miscibility of oily and the aqueous phase because
of its division among these two phases (24). Research study
by Soliman et al. pointed out that the formulations failed to
produce nanoemulsion in the absence of cosurfactants (31).
Commonly used co-surfactants are ethanol, isopropyl alcohol,
1-butanol, propylene glycol, and transcutol HP (24,31).
Selection of the co-surfactant was dependent on its capability
to maximize the nanoemulsion area along with the selected
surfactant. At the interface, the surfactant and co-surfactant
will get adsorbed preferentially thereby providing a mechan-
ical barrier to coalescence as well as reducing the interfacial
energy. The lower the free energy of nanoemulsion, the
higher will be its thermodynamic stability (29). Fig. 2. Different methods used for the preparation of solid self-
emulsifying drug delivery systems (S-SEDDS)

Solid SEDDS (S-SEDDS)

bridging agent (33). The spherical agglomeration comprises
of the process of crystallization of fine drug crystals and then
The liquid SEDDS require the usage of soft gelatin
the aggregation of these crystals using water-immiscible
capsule which is an expensive approach and the oily
solvents like methylene chloride or chloroform as the binder
substance could leach out from the capsules or the fill
liquid. On the other hand, the solvent left in the samples can
material can interact with the capsule shell. In addition to
lead to human and ecological safety worries, hence are not
this, liquid SEDDS may also exhibit chemical instability, drug
recommended for the routine process of production
precipitation, portability issues, and limited choices of dosage
(34). Advantages.
forms; hence, the solid self-emulsifying drug delivery systems
(S-SEDDS) have been considered as an appropriate ap- & Solidification method is a simple process,
proach for enhancing the stability, patient complaince, and & Low cost,
dosing accuracy (3,6,18). & Exclusion of high temperature
& High drug encapsulation capacity
Preparation Methods of Solid SEDDS (S-SEDDS)

Different methods used for the conversion of liquid Disadvantages.

SEDDS to solid SEDDS (S-SEDDS) are enlisted in Fig. 2. & The S-SMEDDS prepared by spherical crystal-
The most common approach is done by incorporating the line technology showed the increase in particle size as
liquid formulation into a capsule shell (4). the microspheres aggregated as cluster on storage at
high temperature (4,33).
Spherical Crystalline Technology

Spherical crystallization is a technique of particle design, Case Studies.

where the agglomeration and crystallization can be per-
formed in a single step simultaneously. The flowability and & Cheng et al. prepared the puerarin L-SMEDDS
compactibility of the crystalline drugs have been improved consisting of castor oil, Cremophor RH40, and 1,2-
successfully by utilizing the spherical crystalline technology propanediol and had final puerarin content were fixed at
(32). Spherical crystalline technology may happen via two 7%. One-step solidification was performed in the liquid
mechanisms namely emulsion solvent diffusion (ESD) and phase by the spherical crystallization technology. Here, the
spherical agglomeration (SA). The agglomeration process L-SMEDDS and the silica powder were uniformly dis-
requires three-solvent system, i.e., a liquid bridging agent, persed in ethanol (the good solvent and the bridging agent)
poor and good solvent. In the agglomeration method of the containing ethyl cellulose at room temperature. This
emulsion solvent-diffusion, when the solution of good solvent solution was added to liquid paraffin (poor solvent) under
containing drug substance is transferred under agitation into a stirring (using agitator of paddle type with four blades) to
poor solvent, the droplets of quasi-emulsion are formed of the form agglomerates, then filtered, dried overnight, and
drug solution due to the very strong interaction between the stored. The puerarin S-SMEDDS showed a particle size
good solvent and the drug. The crystallization would occur in and zeta potential of 19.66 nm and − 28.3 mV respectively
the droplets as the good solvent diffuses into the poor solvent. with a spherical shape and was able to disperse within 60 s
The precipitated crystals would be agglomerated by the liquid along with an angle of repose of 30° showing very good
323 Page 6 of 14 AAPS PharmSciTech (2019) 20: 323

fluidity. The puerarin S-SMEDDS showed 100% release through a device of atomization which results in the
within 24 h and the AUC of S-SMEDDS and L-SMEDDS formation of tiny droplets that sprayed into the stream of
after oral administration increased by 27.03 and 23.23-fold hot air for the facilitation of speedy drying and thereby to
respectively (4). yield a fine powder of the product (6). The schematic diagram
& The L-SMEDDS of osthole formulated by Sun of spray drier is given in Fig. 3 and the process of spray drying
et al. comprised of 10.5% castor oil, 54.1% is as follows; the polymer and API are dissolved in a common
Cremophor RH40, and 32.4% 1,2-propylene glycol. solvent—a spray solution, along with a drying hot gas spray
Optimized S-SMEDDS utilized ethyl cellulose and solution sent to an atomizer within a spray drying chamber.
Eudragit S100 (1:2) (polymeric materials), anhydrous Since the water solubility of API is poor, organic solvents are
ethanol (good solvent), and dichloromethane (bridg- used, and during the processing of organic solvents, the inert
ing agent) in 5:3 ratio and 0.08% sodium dodecyl atmosphere is made available with the nitrogen drying gas.
sulfate (SDS) (poor solvent). The prepared S- The spray nozzle atomizes the droplets from the spray
SMEDDS showed encapsulation efficiency of 78.39 solution. The spray dried product is obtained when the
± 2.25% and mean particle size and zeta potential of solvent in the droplet evaporates as the spray solution comes
23.35 nm, and − 1.80 mV respectively. The in vitro in contact with hot drying air exiting from the drying
release for L-SMEDDS and S-SMEDDS was 95% chamber. A cyclone separator usually separates the particles
and 15% respectively. After the accelerated stability from the gas stream (35). Various operating parameters that
studies (40°C, 75% RH), S-SMEDDS indicated the influence the physical characteristics of the spray dried
particle size and entrapment efficiency as 25.94 ± powder are the type of nozzle, temperature and air flow, the
0.27 nm and 45.12% ± 0.45% referring to aggregation temperature of the nozzle, properties of feed solution, and
of microspheres, but S-SMEDDS was stable and flow of feed. As the feed concentration and viscosity increase,
uniform when stored at low temperature (4°C) for the particle size is also increased. The characterization of
10 days. In vivo studies indicated an increase in solid spray dried powder can be performed by differential
AUC(0-t) of S-SMEDDS on comparison with suspen- scanning calorimetry (DSC) X-ray powder diffraction and
sion (2.05-fold) and L-SMEDDS (1.52-fold). En- scanning electron microscopy (SEM). Advantages.
hancement of bioavailability of osthole is indicated
by increased solubility and prolonged mean residence & The solid particles produced have relatively
time which is due to the sustained release property of narrow size distribution with scale ranging from
osthole from S-SMEDDS (33). submicron to micron
& Improved flow properties than the pure form of
the drug
Spray Drying & Increased dissolution rate

Spray drying is a continuous process which includes an

Disadvantages.
amalgamation of more than a few steps, viz. atomization,
mixing of spray with the hot air, evaporation, and the product & Not applicable for heat-sensitive drugs like
segregation. It is a process of pumping the feed (liquid) proteins and enzymes.

Fig. 3. Schematic diagram of a spray-drying equipment

AAPS PharmSciTech (2019) 20: 323 Page 7 of 14 323

& Drug loading capacity is affected due to reduc- was converted into solid SMEDDS by spray drying
tion in volume of volatile surfactant in L-SMEDDS at technique (Buchi 190 nozzle-type mini-spray dryer)
high-temperature stream (35). using spray drying an aqueous solution of gelatin and
liquid SMEDDS. The particle size of solid SMEDDS
formulation was 4.43 ± 1.41 mm. The PDI values of
Case Studies. liquid SMEDDS and solid SMEDDS prepared with
gelatin were 0.156 ± 0.004 and 0.261 ± 0.009. The
& Madagul et al. formulated chlorthalidone (CTD)
SSMEDDS formed gave more drug release from the
solid SMEDDS using spray drying method. The L-
formulation than the commercial product and also
SMEDDS consisted of Tween 20, PEG 200, and
showed the improved bioavailability in rats. The use
Oleic Acid and Aerosil 200 was used as an adsorbent.
of gelatin as a solid carrier in the formulation of
The L-SMEDDS was added into a suspension of
SSSMEDDS can be supported by this study (38).
Aerosil 200 in ethanol and spray dried using labora-
& Docetaxel super saturable solid SEDDS was for-
tory mini spray dryer. The droplet size of optimized
mulated by spray drying technology using lactose as a
formulation was 159.4 nm and polydispersity index
solid carrier and hydroxypropyl methylcellulose
was 0.30. In vitro release study depicted a better
(HPMC) as supersaturation promoter. The optimized
release profile of CTD from S-SMEDDS when
liquid SEDDS consisted of Cremophor RH40, Labrafac,
compared to the marketed tablet and the pure drug.
and Transcutol P. The super saturable solid SEDDS
The drug release for S-SMEDDS was 97% within 30
showed an increase in the oral bioavailability on
minutes and for the marketed tablet and the pure
comparison with the docetaxel powder suspension (39).
drug were 88.65% and 59.12% respectively within 60
min. Evident increase in permeability of the drug in
S-SMEDDS was seen in ex vivo permeation study Adsorption onto a Solid Carrier
when compared to the pure drug (6).
& Balakrishnan et al. formulated a solid SMEDDS Adsorption is a surface-oriented exothermic process
for dexibuprofen by spray drying the L-SMEDDS onto where an adsorbate (molecules of a compound) get accumu-
a solid inert carrier Aerosil 200. The optimized L- lated on an adsorbent surface. A schematic diagram of
SMEDDS consisted of Capryol 90, Labrasol, and adsorption between adsorbent and adsorbate is given in Fig.
Labrafil M 1944 CS. Using a magnetic stirrer, Aerosol 4. The physical adsorption involves the weak forces like Van
200 was suspended in ethanol and then the L-SMEDDS der Waals forces and electrostatic interactions and adsorp-
was added to give a good Aerosil 200 suspension. The tion can be in multilayers on the surface of adsorption (40).
resulted suspension was spray dried using a Buchi B- The most economical and the simplest method of formulat-
190 mini spray dryer. Dexibuprofen liquid and solid ing solid SMEDDS is the adsorption technique which yields
SMEDDS exhibited the mean emulsion droplet size of the free-flowing, stable solid SMEDDS. The adsorbent used
212 ± 13 and 224 ± 19 nm and with PDI values of 0.198 ± is usually porous in nature and they have high liquid
0.018 and 0.219 ± 0.012 respectively. So, there is an adsorption capacity. Neusilin US2 (magnesium alumino-
increase in the mean droplet size and PDI values before metasilicate), Sylysia 350 (amorphous silica gel), Aerosil
and after solidification. The study showed a significant 200 (Silicon dioxide), Florite RE (porous silicate carrier),
increase in the bioavailability of solid SMEDDS in and Syloid 244 FP (porous silicon dioxide), colloidal silica,
contrast to the powdered drug (36). dextran, magnesium trisilicate, etc are some of the commonly
& Rajesh et al. formulated glimepiride solid SNEDDS used adsorbents. Neusilin US2 is widely explored as an
using spray drying technology. The optimized liquid adsorbent due to its excellent flow characteristics, good
SNEDDS comprised of tween 80, Lauroglycol FCC, and ability of liquid adsorption because of large surface area
ethanol. The oil adsorption efficiency of different and small particle size, and the compaction properties in
hydrophilic and hydrophobic adsorbents was studied comparison to other adsorbent powders which helps to avoid
and Aerosil 200 was selected among them and also the use of a binder for tableting (41,42). The lipid-loaded
selected as a solid carrier. Solid SNEDDS was prepared solid carriers can be either filled in the hard gelatin capsules
with Aerosil 200 and the spray-dried substance exhibited
good micromeritic characteristics. The particle size and
PDI of liquid and solid SNEDDS was 117.91 ± 1.18 nm,
0.436 ± 0.06, and 126.18 ± 3.38 nm, 0.456 ± 0.09
respectively. Zeta potential of S-SNEDDS was −
18.16 mV and transmission electron microscopic (TEM)
images showed the spherical particle at the scale of 200
nm. The in vitro permeation study for the optimized
SNEDDS was performed in Caco-2 cell monolayers and
it showed higher drug permeation (1.54 times) and lesser
drug excretion (0.57 times) compared to the marketed
tablets at 4 h of time (p < 0.01) (37).
& Flurbiprofen liquid SMEDDS consisting of
Labrafil M 1944 CS (oil), Labrasol (surfactant), and
Transcutol HP (co-surfactant) was formulated and Fig. 4. Adsorption onto the solid carrier
323 Page 8 of 14 AAPS PharmSciTech (2019) 20: 323

or can be mixed with other excipients to be compressed into reduction in the degree of release of the drug was
tablets (43). Advantages. explained as the outcome of lipid formulation drifting
deep into silicate pores upon storage which makes
& Easy process emulsification and hydration difficult since silicates
& Economical are mesoporous in nature (pore size < 50 nm). Also,
the degree of the drug release on storage was affected
by the molecular weight of PVP. When Neusilin US2
Disadvantages.
was precoated with PVP K-90 (20% w/w), the lipid-
& During compression of liquid adsorbed solid carrier, based formulation displayed complete release of the
liquid component may exudate out and may result in soft drug (> 90%) upon storage for 6months (44).
tablets, sticking, chipping, and hardness variation
& Requirement of large quantity of solid carrier,
resulting in large volume of final dosage form (41,43) Hot Melt Extrusion Technique

Hot melt extrusion (HME) is an emerging technique where

Case Studies. the material is melted or softened with the application of pressure
and heat through an orifice to yield a product of uniform density
& M. Cirri et al. formulated liquid SMEDDS for the
and shape. The substance is forced through an orifice on a hot
drug glyburide and converted to solid SMEDDS by
melt extruder under controlled conditions due to which the
adsorption onto Neusilin US2 (amorphous magnesium
physical properties of the substance get changed. The extruder
alumino-metasilicate). The average particle size of
consists of an extrusion barrel, motor, rotating screw, heater, and
SMEDDS was 12 ± 0.5 nm and the adsorption process
an orifice at the end. The heat and the friction produced by the
of liquid SMEDDS onto Neusilin US2 did not lead to an
screws in the barrel result in melting of the polymeric materials
increase of the particle size. The solid SMEDDS was
(45). During the process of HME, the carrier matrix and active
converted to a fast-dissolving tablet by direct compres-
pharmaceutical ingredient (API) are mixed or blended, and with
sion using Kollidon® CL which provided complete
the help of the shear stress provided by the extruder, the blend is
dissolution of the tablet within 10 to 15 min (41).
co-dispersed as a physical mixture of carrier and API. The
& M. Javed et al. converted Lovastatin L-SMEDDS
frictional energy necessary to overcome the energy of crystal
to S-SMEDDS using this adsorption technique. The L-
lattice is produced from the shear stress applied, the polymer gets
SMEDDS consisting of peceol, transcutol-P, and
softened, and the API gets embedded in the carrier matrix (46).
cremophor RH 40 was loaded directly onto the
The extruder can be a single screw or twin screw fixed. The feed
Neusilin® US2 liquid loadable tablet (LLT) by the
can be fed in two types either flood fed where feeder is positioned
method of simple adsorption. LLT comprising of
above the feed throat or starve fed with mass flow rate of the feed
Crosspovidone (Polyplasdone XL 10), talc, magnesium
system. Usually, the single screw extruder is flood fed and the
aluminometasilicate (MAMS), and magnesium stearate
twin-screw extruder is starve-fed. In twin screw extruder, the
were mixed and directly punched using 10mm flat round
screw can be counter rotating (rotation of the screws in opposite
punch. LLT was loaded with optimized lovastatin
direction) and co-rotating (rotation of the screws in the same
SMEDDS formulation and the liquid can be adsorbed
direction). The die forms the final part of the extruder and its
until a constant weight of the tablet; excess liquid was
purpose is to shape the molten material while leaving the
wiped and stored in a sealed container. The liquid and
extruder. The required dimension and the shape are given to
solid SMEDDS showed particle size of 72.2 ± 0.133 nm
the extrudate by the die like extrudate films, strands, granules,
and 78 ± 5.45 nm. The LLT adsorbed around 76% of L-
and sheets (45). The schematic diagram of hot melt extruder is
SMEDDS and showed hardness around 4–5 kg/cm2.
illustrated in Fig. 5. Advantages.
In vitro release study was conducted via USP Apparatus
type I at 37°C and 50 rpm. The LLT-loaded SMEDDS & A solvent-free process
exhibited slow release in contrast to L-SMEDDS in a & Production time required is less
hard gelatin capsule. The droplet size produced from & Efficiency of the process is high
LLT loaded L-SMEDDS is slightly greater than the & Ability to create novel formulation
liquid SMEDDS indicating that there is no influence of
the procedure used for the preparation of LLT-loaded
SMEDDS to the morphology of the droplets. The study Disadvantages.
concluded that LLTs can to be an alternative to the soft
& Energy input required is high
and hard capsules (43).
& Thermal degradation of API due to high
& Gumaste et al. presented the effect of storage
temperature
time under controlled temperature and humidity on
& Mechanical degradation of polymer due to high
the degree of drug release from the SMEDDS
shear force (45)
preconcentrate adsorbed on Neusilin US2 and the
effect of Neusilin US2 precoating with polyvinylpyr-
rolidone (PVP), a hydrophilic polymeric filler in Case Studies.
preventing the reduction in drug release. The study
revealed that the storage time and the hydrophilicity a. Carvedilol liquid SMEDDS consisting of capric/
of the formulation affected the drug release. The caprylic triglycerides (Velsan® CCT) as oil,
AAPS PharmSciTech (2019) 20: 323 Page 9 of 14 323

Fig. 5. Schematic diagram of hot melt extruder

Transcutol HP® (diethylene glycol monoethyl ether) drugs. The reduced inter and intra-subject variability of
as co-surfactant, and Plurol Isostearique® plasma profile can be obtained as a result of decreased
(polyglyceryl-6-isostearate) as surfactant was formu- variations in overall transit time and in the rates of gastric
lated and converted into solid SMEDDS by incorpo- emptying. Pellet SEDDS own the advantage of SEDDS and
ration into hydroxypropyl methylcellulose acetate also of pellets. The most commonly used techniques for the
succinate (HPMCAS) an enteric polymeric matrix production of pellets are solution/suspension layering, pow-
using the technique of hot melt extrusion. ANOVA der layering, and extrusion/spheronization. The extrusion/
analysis and Box-Behnken design were used for the spheronization is the widely explored technique for the
optimization of formulations during the study. With production of pellets as it has following advantages when
the lowest concentration of carvedilol, the highest compared to other methods, i.e., spherical shape, better flow
time of recirculation and temperature gave the result properties, a narrow distribution of size, ease in the coating
of complete and rapid reconstitution of the process, uniform compact packing, high surface area, and
microemulsion and higher drug release at pH 6.8, density (48–50). Advantages.
while the reconstitution and drug release in the acidic
medium were reduced. The particle size and PDI of & Flexibility in development and design of the
liquid SMEDDS ranged from 116.2 ± 12.1 nm to 149.2 dosage form
± 30.2 nm (p > 0.05) and 0.29 ± 0.03 to 0.38 ± 0.06 (p > & Variations in gastric emptying time and overall
0.05) whereas these parameters for solid SMEDDS transit time is reduced
ranged from 145.63 ± 2.00 nm to 164.72 ± 2.29 nm and & Avoid the problem of irritation by some active
from 0.209 ± 0.006 to 0.262 ± 0.004 (3). constituents (48–50)
b. Atovaquone solid self-emulsifying system was pre-
pared using PVPK30 as a polymer in the hot melt
Disadvantages.
extrusion process. The droplet size ranged from 51.0
to 122.4 nm. Each formulation was prepared by & Energy input required is high
compression of granules into tablets (47). & Requirement of high amount of adsorbent
& Prerequisite of a disintegrant when silicon diox-
ide is used as adsorbent (49)

Pellets Case Study.

& Abbaspour et al. formulated loratadine

The other technique used to convert liquid SEDSS to
SNEDDS pellets using extrusion spheronization
solid SEDDS is by the formulation of a multi-dosage form
technique. The liquid SNEDDS consisting of liquid
pellets. In case of pellets, the absorption of the drug is
paraffin (as oil), Capriole (surfactant), Span 20 (as a
maximum because of free dispersion of pellets in the GIT,
surfactant), and Transcutol (as co-surfactant) was
with reduced fluctuations in peak plasma, and thereby
adsorbed onto Aerosil and the adsorbed mixture
minimizing the potential side effects without affecting the
was blended with microcrystalline cellulose, lactose,
bioavailability. The pellets evade the irritation by some active
and sodium croscarmellose. The wet mass was
constituents as it lessens the high local concentration of the
323 Page 10 of 14 AAPS PharmSciTech (2019) 20: 323

extruded in a screw extruder and then the extrudate size of the capsule is selected. The handling of the formula-
was spheronized in a spheronizer; the pellets pro- tion is easier compared to the liquid formulation. The
duced were dried and stored. The particle size and compatibility of the excipients used with the capsule shell
PDI of liquid and solid SNEDDS was 190 ± 42 nm, should be well investigated. Capsule filling of SEDDS is
0.39 and 87.0 ± 27 nm, 0.34 respectively. The self- suitable for low-dose highly potent drugs and allows high
emulsifying pellets exhibited spherical shape and drug incorporation (52,53). Advantages.
uniform size and had a suitable hardness (50).
& The nitrendipine solid SEDDS was formulated as & Simple and conventional method
self-emulsifying (SE) pellets using extrusion & Economical method
spheronization technique. The optimized liquid SEDDS
comprised of nitrendipine (drug), Miglyol® (as oil),
Disadvantages.
Cremophor® RH40 and Tween80 (as a surfactant in ratio
2:1), and Transcutol® P (as cosurfactant). The SE pellets & Leakage from the capsule shell
were formulated using microcrystalline cellulose (MCC) & Limited amount of filling (52–54)
(adsorbent), Syloid® 244FP (adsorbent), Kollidon® DL-
SF (as disintegrant), and lactose (to improve appearance
and as a disintegrant). The droplet size was evaluated Case Study.
using laser diffractometer and the average values of SE
& Liquid SMEDDS comprising of Cremophor
pellets and liquid SEDDS were 72 ± 16 nm and 64 ± 12 nm
RH40 as a surfactant, capmul MCM as oil, and
respectively. The in vivo study was conducted in healthy
PEG 600 as cosurfactant was formulated and con-
beagle dogs and the results revealed that the relative
verted into solid form by loading into hard gelatin
bioavailability of liquid SEDDS and SE pellets were
capsule for vaginal delivery of antiretroviral UC-781.
192.64% and 159.87%, respectively on comparison with
The droplet size increased with an increase in the
nitrendipine conventional tablets (49).
proportion of oil to surfactant mixture (surfactant
& Abdalla et al. formulated liquid SMEDDS for
and cosurfactant mixture) and the zeta potential was
progesterone consisting of Solutol® HS 15 (water-
highly positive in charge. The in vitro study showed
soluble surfactant), Captex® 355 EP/NF (oil), and
rapid dispersion of the UC-781 SMEDDS capsule
Capmul® MCM (co-surfactant). The liquid SMEDDS
resulting in enhancement of diffusion across the
was mixed with Avicel PH 101 (microcrystalline cellulose
membrane (54).
(MCC)), wetted with water, and the wet mass was
& Fenofibrate solid SEDDS was formulated by
extruded in a radial screen twin-screw extruder. The
filling liquid SEDDS into a hard gelatin capsule. This
extrudate resulted was spheronized using a cross-hatch
work aimed at studying the effect of surfactant on the
frictional plate in a radial plate spheronizer and the SE
solid SEDDS where Labrafac WL 1394 was used as
pellets produced were spherical in shape with low
oil. One batch had Cremophor El (as surfactant),
friability and uniform size. Drug release study conducted
Gelucire 44/14 (as cosurfactant), and mixed with
with in vitro digestion buffer in the presence of
PEG 6000 (as solidifier) whereas the second batch
pancreatin either under fed (FeSSIF) and fasting
had d-a-tocopheryl polyethylene glycol 1000 succi-
(FaSSIF) conditions revealed that the amount of endog-
nate (TPGS 1000) as solidifier and surfactant. The
enously secreted materials like phospholipid and bile
TPGS-based formulation exhibited a faster rate of
salts will affect the progesterone solubilization (51).
dissolution when compared to cremophor/PEG-based
& Bhandari et al. developed carvedilol solid
formulation (53).
SEDDS as pellets by the technique of extrusion/
& Pioglitazone HCl solid SEDDS was formulated
spheronization. The liquid SEDDS comprising of
using capmul MCM and oleic acid in 2:1 ratio as oil,
capmul MCM EP (oil), cremophor EL (surfactant),
Cremophor RH 40 and Tween 80 as surfactant (in 3:1
and propylene glycol (co-surfactant) was converted
ratio), and transcutol P as cosurfactant. The band
into pellets using microcrystalline cellulose and
sealing process was used to solve the leakage
colloidal silicon dioxide (as a solid carrier), povidone
problem. The droplet size of the formulation was
K-30 (as a binder), and crospovidone (as
below 200 nm and the formulation gave complete and
disintegrant). Droplet size of liquid and solid SEDDS
quicker dissolution in comparison with the marketed
was found to be 142.89 nm and 160.47 nm respec-
formulation (52).
tively. The pellets formed were spherical in shape and
showed better dissolution property than the
marketed formulation (48).
Lyophilization

Use of Hard Gelatin Capsule Lyophilization is the common technique used for phar-
maceutical formulation to increase the stability. Lyophiliza-
The liquid SEDDS make an unacceptable approach tion or freeze drying is the drying process that includes the 2
because of its problem related to the palatability of the oily steps of drying namely sublimation (primary drying) and
liquid. The simple and economical method used to convert desorption (secondary drying). Lyophilization is the one of
liquid SEDDS to solid SEDDS is by use of hard gelatin the common methods used when the pharmaceutical formu-
capsules. Based on the final volume of the formulation, the lation is not stable for prolonged use or when it is
AAPS PharmSciTech (2019) 20: 323 Page 11 of 14 323

Fig. 6. Schematic diagram of lyophilizer

Table III. Advantages and Disadvantages of Different Methods Used in the Formulation of Solid SEDDS

Method Advantages Disadvantages

Spherical crystalline technology The solidification method is a simple The S-SMEDDS prepared by spherical
process. crystalline technology showed the in-
Low cost. crease in particle size as the micro-
Exclusion of high temperature. spheres aggregated as cluster on
High drug encapsulation capacity. storage at high temperature.
Spray drying The solid particles produced have Not be applicable for heat-sensitive
relatively narrow size distribution with drugs like enzymes.
scale ranging from submicron to micron. Drug loading capacity is affected due to
Improved flow properties than the pure reduction in volume of volatile
form of the drug. surfactant in L-SMEDDS at high tem-
Increased dissolution rate. perature stream.
Adsorption to a solid carrier Easy process. During compression of liquid adsorbed
Economical. solid carrier, liquid component may
exudate out and may result in soft
tablets, sticking, chipping, and hardness
variation.
Requirement of large quantity of solid
carrier, resulting in large volume of final
dosage form.
Hot melt extrusion technique A solvent free process. Energy input required is high.
Production time required is less. Thermal degradation of API due to high
Efficiency of the process is high. temperature.
Ability to create novel formulation. Mechanical degradation of polymer due
to high shear force.
Pellets Flexibility in development and design of Energy input required is high
the dosage form. Requirement of high amount of
Variations in gastric emptying time and adsorbent.
overall transit time is reduced. When silicon dioxide is used as
Avoid the problem of irritation by some adsorbent, there is prerequisite for a
active constituents. disintegrant.
Use of hard gelatine capsule Simple and conventional. Leakage from the capsule shell.
Economical method. Limited amount of filling possible.
Lyophilization Aseptic process leading to little Expensive method.
contamination. The high vacuum may remove volatile
Substances that can oxidize can be compounds.
protected with the vacuum. Stability linked with individual drugs.
Preservation period is longer because of
95–99.5% removal of water content.
The loss of volatile chemicals and heat-
sensitive nutrient is minimal. Stability
linked with individual drugs.
323 Page 12 of 14 AAPS PharmSciTech (2019) 20: 323

thermolabile. During sublimation, the solute will pass directly from advantages over the liquid SEDDS. Various methods have
solid state to gaseous state bypassing the liquid state. The material been explored for the conversion of liquid to solid SEDDS.
is first frozen and then exposed to high vacuum to high heat (either Solid SEDDS can be a promising pharmaceutical formulation
by radiation or conduction or both) so that the sublimation of approach in the enhancement of the solubility, stability, and
frozen liquid takes place leaving behind dried solid components of oral bioavailability of poorly water-soluble drugs. SEDDS
the original liquid formulation. During lyophilization, the concen- could be an effective formulation strategy for the formulation
tration gradient of water vapor between the condenser and drying of oil-soluble drugs with low oral absorption.
front is the driving force for removal of water. After primary drying,
the product may appear dry but the residual moisture content may
be 7–8%, so continual drying is necessary at warmer temperature REFERENCES
to decrease the content of residual moisture to optimum values. As
the water bound to the product is desorbed, this process is called as
Bisothermal desorption.^ Cryoprotectants can be included for their 1. Sharma S, Bajaj H, Bhardwaj P, Sharma AD, Singh R.
stabilizing effects. Once the water is removed, the vials containing Development and characterization of self emulsifying drug
delivery system of a poorly water soluble drug using natural
product are sealed under an inert gas head space (e.g., Ar, N2) or oil. Acta Pol Pharm Drug Res. 2012;69(4):713–7.
vacuum (55,56). This technique of conversion is depicted in Fig. 2. Chowdary KA, Babu VP, Baratam SR. Formulation and in vitro
6. Advantages. characterisation of self emulsifying drug delivery system of
Diclofenac. IJRASET. 2017;5(II):663–72.
& Aseptic process leading to little contamination 3. Silva LAD, Almeida SL, Alonso ECP, Priscila BR, Martins FT,
& Substances that can get oxidized can be stabi- Freitas LAP, et al. Preparation of a solid self-microemulsifying
lized with this process drug delivery system by hot-melt extrusion. Int J Pharm.
2018;541(1-2):1–10. https://doi.org/10.1016/
& Preservation period is longer because of 95– j.ijpharm.2018.02.020.
99.5% removal of water content 4. Cheng G, Hu R, Ye L, Wang B, Gui Y, Gao S, et al. Preparation
& Applicable to heat-sensitive compounds and in vitro / in vivo evaluation of puerarin solid self-
microemulsifying drug delivery system by spherical crystalliza-
tion technique. AAPS PharmSciTech. 2016;17(6):1336–46.
https://doi.org/10.1208/s12249-015-0469-8.
Disadvantages. 5. Kommuru TR, Gurley B, Khan MA, Reddy IK. Self-
emulsifying drug delivery systems (SEDDS) of coenzyme Q10:
& Expensive method formulation development and bioavailability assessment. Int J
& High vacuum may remove volatile compounds (56) Pharm. 2001;212:233–46.
6. Madagul JK, Parakh DR, Kumar RS, Abhang RR. Formulation
and evaluation of solid self micro-emulsifying drug delivery
Case Study. The study included the use of lyophilization in system (S-SMEDDS) of chlorthalidone by spray drying tech-
formulation of solid SEDDS for the drug Lornoxicam. Liquid nology. Dry Technol. 2016. https://doi.org/10.1080/
07373937.2016.1201833.
SEDDS comprised of Kolliphor HS 15 as surfactant, Transcutol 7. Chintalapudi R, Murthy TEGK, Lakshmi KR, Manohar GG.
HP as cosurfactant, and Labrafil M 1944 CS as oil phase. The Formulation, optimization, and evaluation of self-emulsifying
microemulsion systems were optimized using central composite drug delivery systems of nevirapine. Int J Pharm Investig.
design (CCD) response surface method and converted into solid 2015;5(4):205–13.
8. Gupta S, Kesarla R, Omri A. Formulation strategies to improve
SEDDS by the technique of lyophilization with the use of sucrose the bioavailability of poorly absorbed drugs with special
as cryoprotectant. The particle size of solid and liquid SMEDDS emphasis on self-emulsifying systems. ISRN Pharm. 2013.
was found to be 70.14 ± 1.06 nm and 38.42 ± 0.33 nm respectively https://doi.org/10.1155/2013/848043.
and the zeta potential of solid and liquid SMEDDS was and − 9. Gurav NP, Dandagi PM, Gadad AP. Solubility enhancement of
17.17 ± 1.13 mVand − 18.21 ± 0.11 mV respectively. TEM showed satranidazole using self emulsified drug delivery systems. Indian
J Pharm Educ Res. 2016;50(3). https://doi.org/10.5530/
that in liquid SMEDDS, the oil droplets were spherical with good ijper.50.2.2050(3).
integrity and homogenous. The in vitro drug release study for S- 10. Müllertz A, Ogbonna A, Ren S. New perspectives on lipid and
SMEDDS was carried out using reverse dialysis bag method. The surfactant based drug delivery systems for oral delivery of
lornoxicam S-SMEDDS showed significant increase in solubility poorly soluble drugs. J Pharm Pharmacol. 2010;62:1622–36.
https://doi.org/10.1111/j.2042-7158.2010.01107.x.
and rate of dissolution. The in vivo study performed in Wistar rats
11. Dokania S, Joshi AK. Self-microemulsifying drug delivery
showed an significant increase in AUC and Cmax for S-SMEDDS system (SMEDDS)—challenges and road ahead. Drug Deliv.
than marketed lornoxicam tablets (57). 2015;22(6):675–90. https://doi.org/10.3109/
Table III summarizes the various advantages and disad- 10717544.2014.896058.
12. Pouton CW. Lipid formulations for oral administration of the
vantages of different preparation methods of solid SEDDS.
drugs: non-emulsifying, self-emulsifying and Bself-
microemulsifying^ drug delivery systems. Eur J Pharm Sci.
2000;11(Suppl. 2):S93–8.
13. Pouton CW. Formulation of poorly water-soluble drugs for oral
administration: Physicochemical and physiological issues and
CONCLUSION the lipid formulation classification system. Eur J Pharm Sci.
2006;29:278–87. https://doi.org/10.1016/j.ejps.2006.04.016.
14. Pouton CW, Porter CJH. Formulation of lipid-based delivery
In the formulation development of poorly water-soluble systems for oral administration : materials , methods and
drugs, lipid-based formulation approaches like SEDDS form strategies. Adv Drug Deliv Rev. 2008;60:625–37.
key method for the enhancement of their solubility, oral 15. Myers RA, Stella VJ. Systemic bioavailability of penclomedine
absorption, and bioavailability. Presently, the research is more (NSC-338720) from oil-in-water emulsions administered
intraduodenally to rats. Int J Pharm. 1992;78(1–3):217–26.
focused towards the solid SEDDS because of their
AAPS PharmSciTech (2019) 20: 323 Page 13 of 14 323

16. Carrigan PJ, Bates TR. Biopharmaceutics of the drugs admin- 35. Dobry DE, Settell DM, Baumann JM, Ray RJ, Graham LJ,
istered in lipid-containing dosage forms I: GI absorption of Beyerinck RA. A model-based methodology for spray-drying
griseofulvin from an oil-in-water emulsion in the rat. J Pharm process development. J Pharm Innov. 2009;4(3):133–42. https://
Sci. 1973;62(9):1476–9. doi.org/10.1007/s12247-009-9064-4.
17. Rahman MA, Hussain A, Hussain MS, Mirza MA, Iqbal Z. 36. Balakrishnan P, Lee BJ, Oh DH, Kim JO, Hong MJ, Jee JP,
Role of excipients in successful development of self-emulsifying/ et al. Enhanced oral bioavailability of dexibuprofen by a novel
microemulsifying drug delivery system (SEDDS/SMEDDS). solid Self-emulsifying drug delivery system (SEDDS). Eur J
Drug Dev Ind Pharm. 2013;39(1):1–19. https://doi.org/10.3109/ Pharm Biopharm. 2009;72(3):539–45. https://doi.org/10.1016/
03639045.2012.660949. j.ejpb.2009.03.001.
18. Truong DH, Tran TH, Ramasamy T, Choi JY, Lee HH, Moon 37. Rajesh SY, Singh SK, Pandey NK, Sharma P, Bawa P, Kumar B,
C, et al. Development of solid self-emulsifying formulation for et al. Impact of various solid carriers and spray drying on pre/
improving the oral bioavailability of erlotinib. AAPS post compression properties of solid SNEDDS loaded with
PharmSciTech. 2016;17(2):466–73. https://doi.org/10.1208/ glimepiride: in vitro-ex vivo evaluation and cytotoxicity assess-
s12249-015-0370-5. ment. Drug Dev Ind Pharm. 2018. https://doi.org/10.1080/
19. Porter CJH, Pouton CW, Cuine JF, Charman WN. Enhancing 03639045.2018.1431656.
intestinal drug solubilisation using lipid-based delivery systems. 38. Kim DW, Kang JH, Oh DH, Yong CS, Choi HG. Development
Adv Drug Deliv Rev. 2008;60:673–91. of novel flurbiprofen-loaded solid self-microemulsifying drug
20. Strickley RG. Solubilizing excipients in oral and injectable delivery system using gelatin as solid carrier. J Microencapsul.
formulations. Pharm Res. 2004;21(2):201–30. 2012;29(4):323–30. https://doi.org/10.3109/
21. Gursoy RN, Benita S. Self-emulsifying drug delivery systems 02652048.2011.651497.
(SEDDS) for improved oral delivery of lipophilic drugs. 39. Chen Y, Chen C, Zheng J, Chen Z, Shi Q, Liu H. Development
Biomed Pharmacother. 2004;58(3):173–82. of a solid supersaturatable self-emulsifying drug delivery system
22. Khan BA, Bakhsh S, Khan H, Mahmood T, Rasul A. Basics of of docetaxel with improved dissolution and bioavailability. Biol
self micro emulsifying drug delivery system. J Pharm Alternat Pharm Bull. 2011;34(2):278–86.
Med. 2012;1(M):13–20. 40. Bushra R, Ahmed A, Shahadat M. Mechanism of adsorption on
23. Small DM. A classification of biologic lipids based upon their nanomaterials. Nanomater Chromatogr. 2017;2: 90-111 p.
interaction in aqueous systems. J Am Oil Chem Soc. https://doi.org/10.1016/B978-0-12-812792-6/00004-2.
1968;45:108–19. 41. Cirri M, Roghi A, Valleri M, Mura P. Development and
24. Azeem A, Rizwan M, Ahmad FJ, Iqbal Z, Khar RK, Aqil M, characterization of fast- dissolving tablet formulations of
et al. Nano emulsion components screening and selection: a glyburide based on solid self-microemulsifying systems. Eur J
technical note. AAPS PharmSciTech. 2009;10(1):69–76. https:// Pharm Biopharm. 2016. https://doi.org/10.1016/
doi.org/10.1208/s12249-008-9178-x. j.ejpb.2016.04.008.
25. Yetukuri K, Satisha P, Srinivasan S, Thakur RS, Uma Shankar 42. Patel H, Patel P, Patel M, Mehta D, Misan C. Development and
MS. Solid-self emulsifying drug delivery system : formulation characterization of liquid and solid self-microemulsifying drug
techniques and dosage forms. 2011;10(3):87–93. delivery system of Tacrolimus. Asian J Pharm. 2012;43:385–94.
26. Saurabh SS, Issarani R, Nagori BP. Formulation and evaluation https://doi.org/10.1007/s40005-013-0083-2.
of self-emulsifying drug delivery system of etoricoxib. Asian J 43. Javed M, Mallikarjun C, Gan W. Enhancement of solubility and
Pharm Clin Res. 2017;10(7):367–72. therapeutic potential of poorly soluble lovastatin by SMEDDS
27. Sinha VR, Ghai D. Formulation design and development of formulation adsorbed on directly compressed spray dried
self-nanoemulsifying drug delivery systems containing a hydro- magnesium aluminometasilicate liquid loadable tablets : a study
phobic selective β1-adrenoreceptor blocker. Int J Nanosci in diet induced hyperlipidemic. Asian J Pharm Sci.
Nanotechnol. 2010;6(3):154–67. 2015;10(1):40–56. https://doi.org/10.1016/j.ajps.2014.08.003.
28. Tang B, Cheng G, Gu JC, Xu CH. Development of solid self- 44. Gumaste SG, Freire BOS, Serajuddin ATM. Development of
emulsifying drug delivery systems: preparation techniques and solid SEDDS, VI: effect of precoating of Neusilin® US2 with
dosage forms. Drug Discov Today. 2008;13(13/14):606–12. PVP on drug release from adsorbed self-emulsifying lipid-based
29. Khan AW, Kotta S, Ansari SH, Sharma RK, Ali J. Self- formulations. Eur J Pharm Sci. 2017. https://doi.org/10.1016/
nanoemulsifying drug delivery system (SNEDDS) of the poorly j.ejps.2017.02.022.
water-soluble grapefruit flavonoid Naringenin: design, charac- 45. Tan DK, Maniruzzaman M, Nokhodchi A. Advanced pharma-
terization, in vitro and in vivo evaluation. Drug Deliv. ceutical applications of hot-melt extrusion coupled with fused
2015;22(4):552–61. https://doi.org/10.3109/ deposition modelling (FDM) 3D printing for personalised drug
10717544.2013.878003. delivery. Pharmaceutics. 2018;10:203. https://doi.org/10.3390/
30. Zvonar A. Lipid-based systems as a promising approach for pharmaceutics10040203.
enhancing the bioavailability of poorly water-soluble drugs. 46. Tiwari RV, Patil H, Repka MA. Contribution of hot-melt
Acta Pharma. 2013;63:427–45. https://doi.org/10.2478/acph-2013- extrusion technology to advance drug delivery in the 21st
0040. century. Expert Opin Drug Deliv. 2016;13(3):451–64. https://
31. Soliman KAB, Ibrahim HK, Ghorab MM. Formulation of doi.org/10.1517/17425247.2016.1126246.
risperidone as self-nanoemulsifying drug delivery system in 47. Takabe H, Warnken ZN, Zhang Y, Davis DA, Smyth HDC,
form of effervescent tablets. J Dispers Sci Technol. Kuhn JG, et al. A repurposed drug for brain cancer: Enhanced
2012;33(8):1127–33. https://doi.org/10.1080/ atovaquone amorphous solid dispersion by combining a spon-
01932691.2011.599235. taneously emulsifying component with a polymer carrier.
32. Nokhodchi A, Maghsoodi M. Preparation of spherical crystal P h a r m a c e u t i c s . 2 0 1 8 ; 1 0 : 6 0 . h t t p s : / / d o i . o rg / 1 0 . 3 3 9 0 /
agglomerates of naproxen containing disintegrant for direct pharmaceutics10020060.
tablet making by spherical crystallization technique. AAPS 48. Bhandari V, Avachat A. Formulation and characterization of
PharmSciTech. 2008;9(1):54–9. https://doi.org/10.1208/s12249- self emulsifing pellets of carvedilol. Braz J Pharm Sci.
007-9019-3. 2015;51(3):663–72. https://doi.org/10.1590/S1984-
33. Sun C, Gui Y, Hu R, Chen J, Wang B, Guo Y, et al. Preparation 82502015000300018.
and pharmacokinetics evaluation of solid self-microemulsifying 49. Zhiyuan W. Solid self-emulsifying nitrendipine pellets: prepara-
drug delivery system ( S-SMEDDS ) of osthole. AAPS tion and in vitro/in vivo evaluation. Int J Pharm. 383:1–6. https://
PharmSciTech. 2018;19(5):2301–10. https://doi.org/10.1208/ doi.org/10.1016/j.ijpharm.2010;2009.08.014.
s12249-018-1067-3. 50. Abbaspour M, Jalayer N, Makhmalzadeh BS. Development and
34. Maghsoodi M, Nokhodchi A. Agglomeration of celecoxib by evaluation of a solid self-nanoemulsifying drug delivery system
quasi emulsion solvent diffusion method: effect of stabilizer. for loratadin by extrusion-spheronization. Adv Pharm Bull.
Adv Pharm Bull. 2016;6(4):607–16. https://doi.org/10.15171/ 2014;4(2):113–9. https://doi.org/10.5681/apb.2014.018.
apb.2016.075. 51. Abdalla A, Klein S, Mäder K. A new self-emulsifying drug
delivery system (SEDDS) for poorly soluble drugs:
323 Page 14 of 14 AAPS PharmSciTech (2019) 20: 323

characterization, dissolution, in vitro digestion and incorpora- 55. Tsinontides SC, Rajniak P, Pham D, Hunke WA, Placek J,
tion into solid pellets. Eur J Pharm Sci. 2008;35(5):457–64. Reynolds SD. Freeze drying—principles and practice for
52. Madan J, Sudarshan B, Kadam V, Kamal D. Formulation and successful scale-up to manufacturing. Int J Pharm. 2004;280:1–
development of self-microemulsifying drug delivery system of 16.
pioglitazone hydrochloride. Asian J Pharm. 2014; Available 56. Gaidhani KA, Harwalkar M, Bhambere D. Lyophilization /
from: http://www.asiapharmaceutics.info/text.asp 2014/8/1/27/ freeze drying—a review. World J Pharm Res. 2015;4(8):516–43.
134097. 57. Yang X, Li F, Guo Y, Zhang X, Pan W, Zhao Q, et al.
53. Kanaujia P, Ng WK, Tan RBH. Solid self-emulsifying drug Preparation and pharmacokinetics evaluation of oral self-
delivery system (S-SEDDS) for improved dissolution rate of emulsifying system for poorly water-soluble drug Lornoxicam.
fenofibrate. J Microencapsul. 2014. https://doi.org/10.3109/ Drug Deliv. 2014. https://doi.org/10.3109/10717544.2014.885615.
02652048.2013.843601.
54. Mcconville C, Friend D. Development and characterisation of a Publisher’s Note Springer Nature remains neutral with regard to
self-microemulsifying drug delivery systems ( SMEDDSs ) for jurisdictional claims in published maps and institutional
the vaginal administration of the antiretroviral UC-781. Eur J affiliations.
Pharm Biopharm. 2013;83:322–9. https://doi.org/10.1016/
j.ejpb.2012.10.007.