Sustainable Chemistry and Pharmacy 6 (2017) 3756

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Sustainable Chemistry and Pharmacy

journal homepage: www.elsevier.com/locate/scp

Lipid nanoparticles: Dierent preparation techniques, characterization, MARK

hurdles, and strategies for the production of solid lipid nanoparticles and
nanostructured lipid carriers for oral drug delivery

Poovi Ganesana,b, Damodharan Narayanasamya,
a
Department of Pharmaceutics, College of Pharmacy, SRM University, Kattankulathur 603203, Tamil Nadu, India
b
Department of Pharmaceutics, College of Pharmacy, Mother Theresa Post Graduate and Research Institute of Health Sciences, (A Govt. of Puducherry Institution),
Puducherry 605006, India

A R T I C L E I N F O A B S T R A C T

Keywords: The bioavailability of an orally administered drug primarily depends on its solubility in the GIT and its per-
Solid lipid nanoparticle meability across cell membranes. Also, a drug in solution form is preferred for conducting pharmacological,
Nanostructured lipid carrier toxicological and pharmacokinetic studies during the drug development stage. Thus, poor water solubility not
Hydrophobic drug only limits a drugs biological application but also challenges its pharmaceutical development. The use of lipid
Bioavailability
nanoparticles (LNs) in pharmaceutical technology has been reported for several years due to its important in
green chemistry for several reasons specically for its biochemical as green materials and biochemical pro-
cesses as green processes that can be very environmentally friendly. Also, the physiological/physiologically
related lipids (GRAS) made LNs usually enhance the drug absorption in the GIT. Hence, the pathways for ab-
sorption, metabolism, and transportation are present in the body, which may contribute to a large extent to the
bio-fate of the lipidic carrier. Moreover, the LNs improves the mucosal adhesion and increases their GIT re-
sidence time. The LNs with a solid matrix are two types: solid lipid nanoparticle (SLN) and nanostructured lipid
carrier (NLC). Also, their hydrophobic core provides a suitable environment for entrapment of hydrophobic
drugs to improve its bioavailability. This review highlights and discusses the simple and easily scaled-up novel
SLN and NLC along with their dierent production techniques, hurdles, and strategies for the production of LNs,
characterization, lyophilization and drug release. Also, this review summarizes the research ndings reported by
the dierent researchers regarding the dierent method of preparation, excipients and their signicant ndings.

1. Introduction the case of polymeric nanoparticles, the in vivo degradation of the

In the last few decades, various drug-delivery technologies have
emerged (Jaiswal et al., 2016), and an interesting part of this has been
the development of nanoscale drug delivery devices (Jaiswal et al.,
2004, 2016). Many nano particulate systems based on biocompatible
polymers, lipids and oils have come to the fore, which can be eciently
used to increase the oral bioavailability of drugs either by increasing
the drug permeability or by overcoming the rst-pass eect and/or P-gp
eux (Harde et al., 2011). Among these, lipid-based nanoparticles have
the advantage of being the least toxic for in vivo applications, and
dynamic progress has been made in the area of DNA/RNA and drug
delivery using lipid-based nano assemblies (Puri et al., 2009). The lipids
used to prepare lipid nanoparticles are usually physiological lipids
(biocompatible and biodegradable) (Kaur et al., 2015) with low acute
and chronic toxicity (Das and Chaudhury, 2011; Mller et al., 1996). In
polymer might cause toxic eects (Das and Chaudhury, 2011; Mller
et al., 1996; Kumar, 2000). The physiochemical diversity and bio-
compatibility of lipids and their ability to enhance oral bioavailability
of drugs have made lipid nanoparticles very attractive carriers for oral
drug delivery (Das and Chaudhury, 2011). Moreover, the lipid-based
formulations can positively inuence drug absorption in a number of
ways including; increasing solubilization capacity, preventing drug
precipitation on intestinal dilution, enhancing membrane permeability,
inhibiting eux transporters, reducing CYP enzymes, enhancing chy-
lomicron production and lymphatic transport (O'driscoll and Grin,
2008; Porter et al., 2007; Gursoy and Benita, 2004).
Lipid nanoparticles with a solid matrix are two types: solid lipid
nanoparticle (SLN) and nanostructured lipid carrier (NLC) (Das and
Chaudhury, 2011). The solid lipid nanoparticles (SLN) was introduced
as the rst generation of lipid nanoparticles (Iqbal et al., 2012;

Corresponding author.
E-mail address: poovinano@gmail.com (D. Narayanasamy).

http://dx.doi.org/10.1016/j.scp.2017.07.002
Received 22 May 2017; Received in revised form 24 July 2017; Accepted 25 July 2017
2352-5541/ 2017 Elsevier B.V. All rights reserved.
P. Ganesan, D. Narayanasamy
Basavaraj, 2012), whereas the nanostructured lipid carrier (NLC), often
referred to as the second generation of SLN (Puri et al., 2009). The main
reasons for the development of SLNs are combinational advantages
from dierent carrier systems such as liposomes and polymeric NPs.
Similar to liposomes and nanoemulsions, they are composed of phy-
siologically accepted biocompatible excipients (lipids and fatty acids).
Also, identical to polymeric nanoparticles, their solid matrix can e-
ciently protect the loaded active pharmaceutical ingredients against
chemical degradation under harsh biological milieu and provide the
maximum exibilities in the modication of the release proles of the
drug. Further, they can be produced at large industrial scale by high-
pressure homogenization (Harde et al., 2011; Kayser et al., 2005;
Muller et al., 2000; Mller et al., 1997; Freitas and Mller, 1999). All
these constructive attributes make the SLNs an excellent carriers for the
oral drug delivery (Harde et al., 2011) and also for the pharmaceutical
formulation production process.
Because pharmaceutical manufacturing is the most solvent-in-
tensive and the least ecient of all chemical industries regarding waste
generated per unit of product. Statistics compiled across the industry
point to an average waste-to-product ratio of 200. In other words,
factories generate 200 kg of waste for every kilogram of active phar-
maceutical ingredient produced and the nancial burden associated
with the processing and disposal of these sizeable waste-streams is
considerable (Rajagopal, 2014). Furthermore, pharmaceutical manu-
facturing plants devote exorbitant amounts of money each year for the
fuel and electricity they need to keep their facilities running (Galitsky
et al., 2008). As a counter to this, various green approaches have
become popular as a means to reduce the ecological impact of the
pharmaceutical industry including the use of solvent-free synthetic
procedures and alternative energy sources (Markarian, 2016).
The eld of green and sustainable chemistry has rapidly grown in
the past few decades. Both in science and research as well as in seg-
ments of the industry there have been many independent activities.
(Cannon and Warner, 2011; Kmmerer and Hempel, 2010; Angrick
et al., 2006) Green chemistry is a prerequisite and a core part of sus-
tainable chemistry. Most important for green chemistry are the 12
Principles of Green Chemistry (Anastas and Warner, 1998; Voutchkova-
Kostal et al., 2012). Green chemistry and sustainable chemistry have in
common a benign design, manufacture, and use of chemical products
and services which are ecient, eective, safe and environmentally
harmless. However, whereas green chemistry strives primarily at en-
gineering and technical issues, like synthesis, atom economy and use of
solvents, and thereby derives from a perspective of design and pro-
duction, sustainable chemistry encompasses all life cycle stages as well
as direct and indirect implications in surrounding areas and addresses
dierent perspectives besides environmental aspects like economy and
society.
In this sense, the avoidance of organic solvents in the production
process of SLNs and NLCs and its physiological lipid component makes
this system as a one of the challenging approaches among the for-
mulation scientist. Also, it complies the key objectives of Green
chemistry and sustainable chemistry. This review highlights and dis-
cusses the two types of simple and easily scaled-up novel lipid nano-
particles with solid matrix (Solid lipid nanoparticles and
Nanostructured lipid carriers) along with their dierent production
techniques, hurdles and strategies for the production of lipid nano-
particles, characterization, lyophilization and drug release. Also, this
review summarizes the research ndings reported by the dierent re-
searchers regarding the dierent method of preparation, excipients and
their signicant ndings.
2. Solid lipid nanoparticles
Solid lipid nanoparticles are nanosphere composed of a solid lipids
core with a mean photon correlation spectroscopy (PCS) diameter be-
tween approximately 50 and 1000 nm (Battaglia and Gallarate, 2012).
38
Sustainable Chemistry and Pharmacy 6 (2017) 3756
These lipidic materials may contain puried triglycerides, complex
glyceride mixtures, or waxes that are solid at both room temperature
and human body temperature (Wissing and Mller, 2003; Wissing et al.,
2004) and are stabilized by suitable surfactant(s) (Kumar et al., 2012;
Wissing et al., 2004; Wissing and Mller, 2003). Actually, SLN is an
alternative carrier system to traditional colloidal carriers such as
emulsions, liposomes, and polymeric micro- and nanoparticles (Kumar
et al., 2012) and are interesting lipid-based drug-delivery carriers for a
number of reasons, including i) particle size is on the nano- to sub-
micron scale (501000 nm) after drug encapsulation; ii) they are
composed of biocompatible and biodegradable components (i.e., phy-
siological lipids or lipid molecules) and do not require the use of or-
ganic solvents for their assembly; and iii) the particle synthesis process
(e.g., high-pressure homogenization) can be performed at a lower cost
and are easily scaled up (Mudshinge et al., 2011; Wang et al., 2015;
Puri et al., 2009). Therefore, these nanoparticles bear the positive as-
pects of other nano-lipid carrier systems, and they also overcome sev-
eral of their disadvantages. For example, SLN is similar in nature to
nanoemulsions but feature a solid lipid core as opposed to a liquid lipid
version. As a result, drug mobility decreases in the solid lipid state
compared with the oily phase, thereby enhancing the controlled release
of loaded drugs. SLN stability can be further improved by the addition
of a surfactant coating (Mller et al., 2002; Pardeshi et al., 2012;
Martins et al., 2007). An additional benet involves the production of
SLN in a powder form, which may be loaded into pellets, capsules, or
tablets for further development of drug delivery (Poovi, 2016; Puri
et al., 2009).
Despite these advantages, SLNs suer from few limitations, such as
low loading efciency (Pathak and Raghuvanshi, 2015), drug expulsion
after polymorphic transition during storage, and relatively high water
content of the dispersions (7099.9%) (Kumar et al., 2012; Schwarz
et al., 1994; Westesen et al., 1997). The poor drug loading capacity of
conventional SLN is due to a densely packed lipid crystal network,
which allows little room for incorporation of drugs (Kumar et al., 2012)
or by the solubility of drug in the lipid melt, miscibility of drug melt and
lipid melt, the polymorphic state of the lipid matrix, and structure of
the solid matrix lipid (Schwarz et al., 1994, 2007).
To overcome the negative feature of SLN, a system of NLCs was
produced. The NLCs is composed of a mixture of spatially dierent lipid
molecules, normally the mixture of liquid lipid and solid, which makes
more imperfection in the matrix to incorporate more drug molecules
than solid lipid nanoparticles. Despite the presence of liquid lipid, NLC
matrix is solid at body/room temperature. NLCs adopt mixtures of a
liquid lipid and solid lipid and remain in the solid state by controlling
the content of liquid lipid (Kaur et al., 2015). NLCs can more strongly
immobilize drugs and prevent the particle from coalescing by the solid
matrix compared to emulsions. NLCs also have the advantages of SLNs
including low toxicity, biodegradation, drug protection, slow release
and avoidance of organic solvents in production (Liu and Wu, 2010; Das
and Chaudhury, 2011).
In SLNs, the drug is mainly dispersed in molecular form, for ex-
ample, located in between the fatty acid chains of the glycerides
whereas in NLCs, a blend of solid and liquid lipids are used, and due to
their dierences in the structure they cannot t together very well to
form a perfect crystal. This arrangement creates a lot of imperfections
in matrix leading to an accommodation of more drugs in molecular
form and amorphous clusters (Domingo and Saurina, 2012; Pardeshi
et al., 2012).
3. Types of SLN/NLC
Based on the chemical nature of the active ingredient and lipid,
nature and concentration of surfactants, the solubility of the drug in the
melted lipid, type of production and the production temperature the
SLNs and NLCs are classied into three types (Table 1) (Figs. 1 and 2).
P. Ganesan, D. Narayanasamy Sustainable Chemistry and Pharmacy 6 (2017) 3756

Table 1
Description of SLNs and NLCs.

Type Nature of matrix Descriptions

Types of SLNs (Mehnert and Mder, 2001; Souto and Muller, 2007, 2010, 2006; Souto et al., 2004; Westesen et al., 1997; Muller et al., 2000)
Type I Homogeneous matrix model The SLN Type I is dened as the homogeneous matrix model because the API is molecularly dispersed in the lipid core or is
present in the form of amorphous clusters. This model is obtained when using optimized ratios of API and lipid passing
through the HPH at above the melting point of the lipid, or when using the cold HPH technique. As consequence of their
structure, SLN Type I can show controlled release properties.
Type II Drug enriched shell model It is obtained when the API concentration in the melted lipid is low. After applying the hot HPH technique, during the cooling
of the homogenized nanoemulsion, the lipid phase precipitates rst, leading to steadily increasing the concentration of API in
the remaining lipid melt with increased fraction of solidied lipid. An API free lipid core is formed; when the API reaches its
saturation solubility in the remaining melt, an outer shell containing both API and lipid will solidify around this core which
contains a low amount of API. This model is not suitable for prolonged API release; nevertheless, it may be used to obtain a
burst release of API, in addition to the occlusive properties of the lipid core.
Type III Drug enriched core model A drug enriched core model is obtained when the recrystallization mechanism is the opposite of that described for the drug
enriched shell model. In this method, a drug is solubilized in the lipid melt close to its saturation solubility. Subsequent
cooling of the lipid emulsion causes super-saturation of the drug in the lipid melt; this leads to the drug recrystallizing before
lipid recrystallization. Additional cooling leads to lipid recrystallization that forms a membrane around the already
crystallized drug-enriched core. This structural model is suitable for drugs that require prolonged release over a period.
Types of NLCs (Mller et al., 2002; Schfer-Korting, 2010; Shah et al., 2015; Jenning et al., 2000)
Imperfect Imperfectly structured solid matrix It is termed the imperfect crystal model and consists of a matrix with many voids and vacancies that can accommodate the
API. These particles are obtained when mixing solid lipids with a sucient amount of liquid lipids (oils). Because of the
dierent chain length of the fatty acid and the mixture of mono-, di- and triacylglycerols, the matrix of NLC is not able to form
a highly ordered structure, thus creating available spaces (structural imperfections).
Amorphous Structureless solid amorphous It is obtained when mixing special lipids (hydroxyl octacosanyl hydroxy stearate, isopropyl myristate, dibutyl adipate) that do
matrix not recrystallize after homogenization and cooling of the nanoemulsion (Gaba et al., 2015). These lipids create amorphous
matrices and during shelf life, thus minimizing API expulsion during storage time.
Multiple Multiple oils in fat in water The solubility of lipophilic the drug in liquid lipids (oils) is higher than in solid lipids. This principle can be used to develop
the multiple type NLC. In this type of NLC, a higher amount of oil are blended in solid lipids. At low concentrations, oil
molecules are easily dispersed into the lipid matrix. Additional of oil in excess of its solubility leads to phase separation
producing tiny oily nano-compartments surrounded by the solid lipid matrix. Such models allow controlled drug release, and
the lipid matrix prevents drug leakage. Lipophilic drugs can be solubilized in oils, and multiple types of NLCs are formed
during the cooling process of a hot homogenization process.

hazard generation ease of applicability and feasibility, and higher yield

potential (Malik et al., 2014). Major inroads have been made by
methods like ultra-sonication (Malik et al., 2014), Supercritical uid
technique (Konwarh et al., 2012), high-pressure homogenization
(Bevilacqua et al., 2007), ultraltration (Medina-Gonzlez et al., 2011),
occulation with surfactants (Malik et al., 2014), and many others
(Malik et al., 2014). All these green methods are most commonly used
method for the formulation of lipid nanoparticles (SLNs/NLCs)
The dierent approaches used for the production of SLNs/NLCs are
lavishly discussed and tabulated along with its advantages, dis-
advantages, mechanism, and limitations in Table 2. As well as, the
Fig. 1. Types of SLNs.
hurdles and strategies for the manufacturing SLNs and various SLNs/
NLCs formulations studied by dierent researchers to improve the oral
bioavailability of drugs and are also discussed in Tables 3 and 4 re-
spectively.

4.1. High energy approaches

4.1.1. High-Pressure Homogenization (HPH) technique

Fig. 2. Types of NLCs.
4. Methods of preparation
A number of interesting chemical approaches have been developed
for the synthesis of nanoparticles. The most signicant and challenging
parts concerned with the green method selection are the optimization of
energy needs of the synthesis method and the corresponding energy
constraints of the process. A number of traditional physical methods
with reasonable modication in their methodology have been mastered
for controlled synthesis of nanoparticles. The distinguishing benets of
these methods range from their energy requirements, far less degree of
HPH is a reliable, well-established and powerful technique for the
large scale production. HPH has been used for years for the production
of nanoemulsions for parenteral nutrition (Lippacher et al., 2000;
Mehnert and Mder, 2001). Recently, it has been applied for SLN and
NLC production and represents the main method established for these
nanoparticles (Battaglia and Gallarate, 2012). In this technique, High-
pressure homogenizers push a liquid with high pressure (1002000 bar)
through a micron size gap: by applying high pressure, the liquid ac-
celerates to high velocity (over 1000 km/h), and the resulting shear
stress and cavitation forces break down the accelerated particles to
submicron size (Mehnert and Mder, 2001). It can be performed either
at elevated temperature (hot homogenization) or below room tem-
perature (cold homogenization) (Schwarz et al., 1994). In both cases,
the drug is dissolved or dispersed in the melted lipid at approximately
510 C above its melting point (All Rights are Reserved by Mrs and
Gupta, 2009; Emeje et al., 2012).

39
P. Ganesan, D. Narayanasamy Sustainable Chemistry and Pharmacy 6 (2017) 3756

Table 2
Comparison of various processes used for the preparation of SLNs/NLCs.

Comparison of various processes used for preparation of SLNs/NLCs

Method High-Pressure Homogenization (HPH) (Jorgensen and Nielson, 2009; Yadav et al., 2013; Yang et al., 1999; Mller et al., 2006; Almeida et al.,
1997; Harde et al., 2011; Mishra et al., 2012; Mudshinge et al., 2011)
Mechanism Shear due to intense turbulent eddies
Advantages Very eective dispersing technique
Disadvantages Extremely energy intensive process
Limitations for hot and cold Complete evasion of drug exposure to high temperature is not possible. Not appropriate for thermolabile drug (Iqbal et al., 2012). High
HPH polydispersity

Hot HPH (Jorgensen and Nielson, 2009; Yadav et al., 2013; Yang et al., 1999; Mller et al., 2006; Almeida et al., 1997; Harde et al., 2011; Mishra
et al., 2012; Mudshinge et al., 2011)
Mechanism Intense cavitations because of the large pressure drop through the valve
Advantages Scalable, commercially available
Disadvantages Drug distribution into the water phase during homogenization, Temperature-induced drug degradation (Swathi and Bala, 2013), Complexity of
crystallization step of nanoemulsion leading to several modications and supercooled melts

Cold HPH (Jorgensen and Nielson, 2009; Yadav et al., 2013; Yang et al., 1999; Mller et al., 2006; Almeida et al., 1997; Harde et al., 2011;
Mishra et al., 2012; Mudshinge et al., 2011)
Advantages No temperature induced drug degradation or crystalline modication
Disadvantages Not reported

Method Microemulsion Technique (Zara et al., 2002; Cavalli et al., 2003; Gasco, 1993; Harde et al., 2011; Mudshinge et al., 2011; Mishra et al., 2012;
Yadav et al., 2013)
Mechanism Spontaneous interfacial tension reduction
Advantages Low energy input, Theoretical stability
Disadvantages Extremely sensitive to change, Labor intensive formulation work, Low nanoparticle conc.
Limitations Strong dilution of particle suspension due to the use of the large volume of water.
High concentration of surfactant and co-surfactant is not desired.

Method Solvent Emulsication Evaporation Method (Conlin et al., 2010; Kang et al., 2010; Harde et al., 2011; Mudshinge et al., 2011; Yadav et al.,
2013; Sjstrm and Bergensthl, 1992)
Mechanism Emulsication (or diusion) of globules followed by evaporation leads to precipitation as particles
Advantages Small particle size 24 nm, Avoidance of heat, The low viscous system formed, Low energy input,
Lipids are dissolved in an aqueous immiscible solvent, e.g., cyclohexane, chloroform, Appropriate for thermolabile drugs (Iqbal et al.,
2012).
Disadvantages Low dispersing degree, Instability of emulsion, Insolubility of lipids in organic solvents, Additional solvent removal procedure, Toxicological
issue (residual solvent)
Limitations Production of very dilute nanoparticle dispersion is not required (Iqbal et al., 2012), An additional step is required. e.g. ultraltration or
evaporation, The organic solvent may remain in the nal preparation.

Method Solvent Emulsication Diusion Method (Conlin et al., 2010; Kang et al., 2010; Harde et al., 2011; Mudshinge et al., 2011; Yadav et al., 2013;
Trotta et al., 2003)
Mechanism Emulsication (or diusion) of globules followed by evaporation leads to precipitation as particles
Advantages Avoidance of heat during the production procedure, Lipids are dissolved in partially miscible solvent e.g. benzyl alcohol, Tetrahydrofuran.
Disadvantages Low dispersing degree, Instability of emulsion, Insolubility of lipids in organic solvents, Additional solvent removal procedure, Toxicological
issue (residual solvent)
Limitations Ultraltration or lyophilisation techniques are required, Residue of organic solvent may remain in the nal preparation.

Method Solvent Injection/Solvent Displacement Method (Schubert and Mller-Goymann, 2003; Iqbal et al., 2012)
Advantages Easy handling and fast production process, Lipids are dissolved in water missicible solvent. e.g. ethanol, methanol, acetone (Iqbal et al.,
2012) without using a sophisticated instrument (e.g., High-pressure homogenizer).

Method Membrane contractor (Ahmed El-Harati et al., 2006; Charcosset et al., 2005; Harde et al., 2011; Yadav et al., 2013)
Mechanism Lipid phase is forced through the membrane pores allowing the formation of small droplets (Iqbal et al., 2012)
Advantages Large-scale production, Facility of use, Control of size, In this case, the lipid phase is forced through the membrane pores to form small
droplets. Under cooling at room temperature (Iqbal et al., 2012), these droplets recrystallize forming the lipid nanoparticles.
Disadvantages Clogging of membrane

Method Phase Inversion Techniques (Montenegro et al., 2011a; Anton et al., 2008; Harde et al., 2011; Heurtault et al., 2002; Iqbal et al., 2012)
Mechanism Spontaneous inversion of o/w to w/o transitional emulsion with increase in temperature
Advantages Less energy intensive, Solvent free Good for heat liable molecules
Disadvantages Incorporation of additional molecules inuence inversion phenomenon
Instability of emulsion
Limitations Cumbersome technique

Method Coacervation Technique (Shah et al., 2015; Battaglia et al., 2010; Bianco et al., 2010; Chirio et al., 2011; Gallarate et al., 2010)
Mechanism Decrease in pH of micellar solution of alkaline salts of fatty acids by acidication (coacervating solution) in the presence of a polymeric stabilizer
causes proton exchange a lipid precipitation (coacervation)
Advantages Suitable for lipophilic drugs (by solubilising in the micellar solution after coacervation), Suitable for hydrophobic ion pairs of hydrophilic drugs,
Solvent-free technique, Use of sophisticated technique not required, Monodispersity, Simple to scale-up
Disadvantages Suitable for lipids that an form alkaline salts,
Not suitable for pH-sensitive drugs

Method Micro emulsion cooling technique

(Koziara et al., 2004, 2005; Mumper et al., 2006)
Mechanism Emulsication of globules followed by cooling leads to precipitation as particles
Advantages This method is reproducible, simple and easy to scale up; all the ingredients used are biocompatible; no organic solvents are used

Method Super Critical Fluid Method (Yadav et al., 2013; Chattopadhyay et al., 2006, 2007)
Mechanism Parallel processes of supercritical uid extraction (diusion) of organic solvent from emulsions and lipid dissolution;
Expansion of organic phase; leads to lipid crystallization
(continued on next page)

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P. Ganesan, D. Narayanasamy Sustainable Chemistry and Pharmacy 6 (2017) 3756

Table 2 (continued)

Comparison of various processes used for preparation of SLNs/NLCs

Advantages Particles are obtained as a dry powder, Avoid the use of solvents; in preference to suspensions, Mild temperature and pressure conditions, Carbon
dioxide solution is the good choice as a solvent (Iqbal et al., 2012).
Disadvantages Very expensive method

Method Gas Assisted Melting Atomisation (Salmaso et al., 2009, Vezz et al., 2010)
Mechanism The lipid or protein/lipid mixtures were loaded into a thermostated mixing chamber (CM) where they were melted under supercritical CO2 at
selected temperature and pressure conditions. Then, the lipid saturated uid is forced through the nozzle by opening the valve at the bottom of
the CM, in order to produce microparticles.
Advantages Produce ne and non-agglomerated low density powders. Suitable operating conditions for protein-loaded lipid submicron particle preparation
were selected in order to obtain solid colloidal formulations and high protein loading while maintaining native activity and suitable release
proles.

Method Ultrasonication (Zhang et al., 2006; Xie et al., 2011; Mei et al., 2005; Harde et al., 2011)
Mechanism Formation and implosive collapse of bubbles due to cavitation, i.e., the formation, growth, and implosive collapse of bubbles in a liquid
Advantages Low particle size: 30180 nm, Low shear stress
Disadvantages Metal shading leads to contamination, Less entrapment eciency, Energy intensive process, Unproven scalability
Limitations During sonication, metallic contamination of the product may occur (Iqbal et al., 2012).

Mechanism of particle formation
High mechanical shear due to strong turbulent eddies.
Lowering of pressure across the valves of homogenizers.
Strong cavitation forces.
4.1.2. Hot homogenization technique
In the hot homogenization method, the procedure is carried at
temperatures above the melting temperature of the lipid (Svilenov and
Tzachev, 2014) (Fig. 3a). Here, the lipid and drug are melted and
combined with an aqueous surfactant at the same temperature. By using
the high shear device, a hot pre-emulsion is formed. Usually, a Piston-
gap homogenizer or a jet-stream homogenizer is used to homogenize
the pre-emulsion to produce a hot colloidal emulsion. The droplets of
the hot colloidal emulsion are recrystallized by cooling the emulsion to
room temperature in order to generate SLNs/NLCs. In some exceptional
cases, specic thermal treatment of emulsions such as cooling to re-
frigeration conditions or even sub-zero temperatures may be required
(Bunjes et al., 1996; Lim and Kim, 2002; Schwarz and Mehnert, 1997;
Unruh et al., 2001).
The pre-emulsion quality aects the quality of the nal product to a
large extent, and it is required to obtain droplets in size range of a few
micrometers (Waghmare et al., 2012). In general, lower particle sizes
was obtained as a result of higher temperatures due to the decreased
viscosity of the inner phase (Lander et al., 2000). However, high tem-
peratures may also increase the degradation rate of the drug and the
carrier. In most of the cases, the homogenization step can be repeated
several times. It should always be kept in mind, that high-pressure
homogenization increases the temperature of the sample (approxi-
mately 108 C for 500 bar (Mehnert and Mder, 2001; Benita and Bhm,
1998). In most cases, 35 homogenization cycles at 5001500 bar are
sufcient. Increasing the number of cycles or the homogenization
pressure often results in an increase of the particle size (Waghmare
et al., 2012) due to particle coalescence which occurs as a result of the
high kinetic energy of the particles (Benita and Bhm, 1998; Mehnert
and Mder, 2001). Then, the obtained nanoemulsion is cooled down to
room temperature where the lipid recrystallizes and leads to the for-
mation of nanoparticles (Zur Mhlen et al., 1998).
4.1.3. Cold homogenization technique
Cold homogenization has been developed to overcome the problems
of the hot homogenization technique (Jaiswal et al., 2016) such as a)

Table 3
Hurdles and strategies for the manufacturing of SLNs formulation (Mudshinge et al., 2011; Wu et al., 2011; Mishra et al., 2012) (Adapted and modied with permission from (Mishra
et al., 2012)).

Hurdles in SLN manufacture Strategies

1. High pressure-induced drug degradation High shear stress is the major cause of free radical formation and which results in decreased molecular weight of polymers
simultaneously causes:
Cavitation: can be solved by application of back pressure
As high molecular weight compounds are more sensitive to degradation, therefore low molecular weight compounds can be used

2. Lipid crystallization and drug incorporation Considerations:

The shape of lipid nanodispersions
Gelation phenomena
The presence of several lipid modications
The existence of super cooled melts
Co-existence of several colloidal species
Low drug loading capacity
Kinetics of distribution process
Platelet shapes have much larger surface areas compared to spheres; therefore, higher amount of the drug will be localized
directly on the surface of the particles
Gelation phenomena describes the transformation of a low-viscosity SLN dispersion into a viscous gel. It generally happens
during the i.v. injection into a living species, the life of this organism is put at risk. Gelation can be retarded or prevented by the
addition of co-emulsifying surfactants with high mobility (e.g. glycocholate); maintenance at optimum temperature range and
other environmental conditions
Lipid modications include improvement of quality like, lower density and ultimately, a higher capability to incorporate guest
molecules (e.g. drugs) which should be characterized by DSC, Xray, and NMR techniques
The main reason for the formation of supercooled melts is the size dependence of crystallization processes and thus provides
stability. The size of particles should be monitored maintained throughout the process
The presence of several colloidal species is an important point to consider as it may cause the degradation of the formulation. The
kinetics of the degradation will be determined by (1) the chemical reactivity of the drug, and (2) the concentration of the drug in
the aqueous medium or at the lipid/ water interface. By increasing the matrix, viscosity will decrease the diusion coecient of
the drug inside the carrier and therefore, will stabilize the formulation
Improved by selection of proper drug carrier (nanosphere, nano pellets, etc.); use of the optimized drug: polymer ratio; selection
of suitable drug loading technique, etc.
The promoters of gelation (like high temperature, light, shear stress) increase the kinetic energy of the particles and favor
collision of the particles which produces instabilities to the formulations, therefore should be considered.

41
 Table 4
Various research ndings of SLNs/NLCs formulations reported by dierent researches.

Type Drug Excipients Method Size (nm) Ref.

NLC Acitretin Precirol ATO 5, Labrasol Solvent diusion technique 223 8.92 nm Greater ecacy in the treatment of Psoriasis along with a reduction (Agrawal et al., 2010)
in side eects.
SLN All-trans retinoic acid Compritol 888 ATO, Soy HPH 150200 nm, 50100 nm Enhancement of GI absorption and improvement of oral (Hu et al., 2004b)
Lecithin/Pluronic F68 Or Soy bioavailability
P. Ganesan, D. Narayanasamy

Lecithin/Tween 80
NLC Alpha lipoic acid(LA) Apil, Miglyol 812, HPH 103 9 Suitable colloidal carrier for water insoluble LA and potential use for (Ruktanonchai et al.,
pluronic F68 topical delivery. 2009)
NLC Amphoteric B Theobroma Oil/Oleic Acid Solvent diusion method 479.67 11.56 nm Imparting stability to the NLC (Tan et al., 2010)
SLN Apomorphine Glyceryl monostearate, PEG, Probe soniation 63.20 0.98 nm to 174.63 3.19 nm Enhanced the bioavailability in rats (Tsai et al., 2011)
monostearate
SLN -Asarone Glyceryl caprate, Ultrasonic homogenization 199 nm Enhancement of GI absorption, Improvement of oral bioavailability, (Subedi et al., 2009)
Polyethylene glycol 660 tissue uptake and distribution
hydroxystearate
NLC Ascorbyl palmitate Imwitor 900, Labral, M1944 high pressure homogenization 170240 nm. Viscoelastic measurements is appropriate for topical/dermal (Teeranachaideekul
technique application et al., 2008)
SLN Baclofen Stearic Acid, Epikuron 200, Multiple (w/o/w) warm 161.4 nm Signicantly higher drug concentrations in plasma (Priano et al., 2011)
Propionic Acid, Butyric Acid, microemulsion
Sodium Taurocholate
NLC Benzocain Comprotol888 ATO, Ultrasonication 386.1 65.6 Targeting and prolonged release eects in dermal delivery. (Puglia et al., 2011)
Miglyol812, LutrolF68
SLN Buspirone HCl Cetyl Alcohol/Spermaceti, Emulsication-evaporation 86123nm Improvement of oral bioavailability (Varshosaz et al.,
Tween 20 or Poloxamer followed by ultrasonication 2010b)
NLC Calcipotriol Myverol 18-04K, Precirol Solvent evaporation method 267.3 12.3 Enhanced skin permeation, negligible skin irritation, and the (Lin et al., 2010)
Methtrexate ATO 5, Squalene, Pluronic compatibility of the two drugs.
F68

42
SLN Calcitonin Trimyristin w/o/w emulsion technique 200 nm Improvement of the eciency of such carriers for oral delivery of (Martins et al., 2009)
proteins
SLN Camptothecin Stearic acid, Soya lecithin, Hot HPH 196.8 21.3 Improved stability and sustained release eect (Yang et al., 1999)
Poloxamer 188
NLC Camptothecin Precirol ATO5, Compritol 888 HPH 192.3 10.2 Sustained drug release manner in decreasing order as follows (Huang, 2008)
ATO5, Myverol 18-04K, LE > NLC > SLN-P > SLN-C
Pluronic F68
NLC Camptothecin Monostearin, Soybean, Oil High pressure homogenize 117.3 2.8 nm Stable and high performance delivery system (Zhang et al., 2008)
788 and spray drying method. 216.6 4.1 nm
SLN Camptothecin Stearic Acid, Camptothecin, HPH 196.8 21.3 nm Sustained release and tissue targeting (Yang et al., 1999)
Soya Lecithin, Poloxamer
188, Glycerol
SLN Carvedilol Stearic Acid, Poloxamer 188, Microemulsion 120200 nm and 600800 nm Enhancement of oral bioavailability, Lymphatic uptake and bypass (Sanjula et al., 2009)
Sodium Taurocholate the hepatic rst-pass metabolism
SLN Clozapine Dynasan 114, Dynasan 116, Homogenization 96.7 163.3 Increased BA, high distribution to brain and reticuloendothelial cells (Manjunath et al.,
Dynasan 118, Epikuron 200, ultracentrifugation 2005)
Poloxamer 188
SLN Clozapine Trimyristin, tripalmitin, Hot homogenization, 96.7 3.8 to 163.3 0.7 nm Improvement of bioavailability (Manjunath and
tristearin ultrasonication method Venkateswarlu, 2005)
SLN Clozapine Trimyristin, Tripalmitin, Microemulsion method 87.2 46.9 nm Improvement of bioavailability (Xu et al., 2011)
Tristearin
SLN Clozapine Trimyristin, Tripalmitin, Hot homogenization followed 96.7 3.8 to 163.3 0.7 Improvement of oral bioavailability and tissue distribution (Manjunath and
Tristearin, Soylecithin 95%, by ultrasonication Venkateswarlu, 2005)
Poloxamer 188, Stearylamine
NLC Coenzyme Q 10 Miglyol812, Precifac ATO, HPH 195.9 3.6 Good physical stability and showed biphasic release pattern i.e. a fast (Obeidat et al., 2010)
Labrasol, Tegocare 450 release initially for skin saturation then slow and prolong release
prole to maintain the skin concentration of Q10.
(continued on next page)
Sustainable Chemistry and Pharmacy 6 (2017) 3756
 Table 4 (continued)

Type Drug Excipients Method Size (nm) Ref.

SLN Crypto Tanshinone Glyceryl monostearate
(GMS), Compritol 888 ATO
(CP), Soya lecithin, Tween80,
Sodium dehydrocholate
SLN Crypto tanshinone Soy Lecithin, Tween 80,
Ultrasonic and high-pressure 121.4 6.3 (GMS) and 137.5 7.1 (CP) Increases the solubilization capacity, changes the metabolism (Hu et al., 2010)
homogenization method behavior and improved the oral bioavailability
Ultrasonic and HPH 121.4 6.3 nm, 137.5 7.1 nm Enhancement of GI absorption and improvement of oral (Hu et al., 2010)
P. Ganesan, D. Narayanasamy

bioavailability.
NLC Curcumin GMS/MCT Nano-emulsication and between 120 and 250 nm Two fold increase in the anti-malarial activity (Nayak et al., 2010)
ultrasonication
SLN Curcumin Polysorbate 80, Soy Lecithin Microemulsion 134.6 nm Improvement of oral bioavailability and prolonged release (Kakkar et al., 2011)
SLN Cyclosporin A Glyceryl Monostearate, Melt- homogenization using a 131 nm and 158 nm Controlled release (Sawant et al., 2008)
Glyceryl Palmitostearate high-pressure homogenizer
SLN Cyclosporine A Imwitor, Tagat, sodium HPH 157 nm, 962 nm Low variation in bioavailability and avoidance of the huge initial (Mller et al., 2006)
cholate plasma concentration
SLN Cyclosporine A Imwitor 900, Tagat S, sodium Hot HPH 157 Improved bioavailability, less variation in plasma concentration (Mller et al., 2008)
cholate
NLC Cyproterone acetate Precirol, Oleic acid, Miglyol, HPH 200250 CPA incorporation in the NLC resulted in a 23 fold increase in (tecov et al., 2007)
poloxamer 188. CPA absorption.
SLN Dexamethasone Compritol 888 ATO Hot dispersion-ultrasonic 106.8 nm Drug delivery topical use (Chen et al., 2008)
technique
SLN Diazepam Compritol ATO 888, Imwitor Modied high-shear less than 500 nm Prolonged release (Abdelbary and
900 K homogenization and Fahmy, 2009)
ultrasound techniques
NLC Dihydroartemisnin GMS/Miglyol 812 Solvent diusion method 198 4.7 nm biphasic drug release pattern with burst release at the initial stage (Zhang et al., 2010)
and sustained release subsequently
NLC Docetaxel GMS, Soyabean lecithin, Ultrasonication dispersion 193.47 5.69 Sustained and continuous release pattern (Liu et al., 2011)
Stearic acid, Oleic acid,

43
Pluronic F68
NLC Domperidone Dynasan 114, Cetyl HPH 32.23 Fairly spherical shaped, a stable particle with controlled release. (Thatipamula et al.,
Resinoleate, Soy 2011)
Phosphatidylcholine, Tween
80
SLN Doxorubicin Glyceryl caprate Solvent emulsication- 199 nm Enhanced apoptotic death (Kang et al., 2010)
diusion method
NLC Etoposide GMS/soyabean oil Emulsication and low 125.991.2 nm Increased oral bioavailability and high cytotoxicity against human (Zhang et al., 2011)
temperature solidication epithelial- like lung carcinoma cells.
SLN Fenobrate Vitamin E TPGS, Vitamin E Hot HPH 58 Improved oral bioavailability (Hanafy et al., 2007)
6100
NLC Fluconazole Compritol 888 ATO (CA)/ Solvent diusion method 178 and 134 nm Good targeting eect along with sustained release and localized (Gupta and Vyas,
Oleic Acid eect 2012)
NLC Flurbiprofen (FB) Compritol 888 ATO, SA, HPH 179.7_3.102 highly eective, a non-irritant carrier for topical administration of (Gonzalez-Mira et al.,
Miglyol1 812, Castor Oil, FB and improved drug permeation 2010)
NLC Flurbiprofen Compritol ATO 888, Miglyol Probe ultrasonicator 55.4 Longer retention time due to mucoadhesive nature and improved (Liu et al., 2011)
812, Gelucire 44/14, Solutol penetration rate.
HS Tween 80 Glycerol
NLC Fluticasone Precirol ATO 5/labrasol Modied microemulsion Between 380 and 408 nm Improved the stability and loading capacity of the drug. (Doktorovov et al.,
Method 2010)
NLC Fluticasone Precirol ATO5, Labrasol, Microemulsion technique 316408 Particle size less than 1 m maintained over 60 days, and high EE (Doktorovov et al.,
propionate Tween80, Soyabean lecithin was achieved. 2010)
SLN Gonadotropin release Monostearin, Monoglyceride, Novel solvent diusion 421.7 nm Prolonged release (Hu et al., 2004a)
hormone chain method
SLN Hydrocortisone Length of the fatty acid Hot high pressure 151 4.2461 9.2 nm, Improved the stability and release properties of the drug (Jensen et al., 2010)
moiety homogenization
SLN Ibuprofen Stearic Acid, Triluarin, Solvent-free high-pressure 175189 nm Stable formulation and negligible cell cytotoxicity (Potta et al., 2011)
Tripalmitin homogenization (HPH)
SLN Idarubicin Stearic acid, Epikuron 200, Microemulsion 80 10 Improved BA, modies the PK and tissue distribution (Zara et al., 2002)
sodium taurocholate
Sustainable Chemistry and Pharmacy 6 (2017) 3756

(continued on next page)

 Table 4 (continued)

Type Drug Excipients Method Size (nm) Ref.

SLN Idarubicin Emulsifying wax, Stearic acid, Microemulsion less than or around 100 nm Potential to deliver anticancer drugs (Ma et al., 2009)
octadecy alcohol, cetyl
palmitate,
NLC Indomethacine Compritol888ATO5, Ultrasonication 44.7191.8 High encapsulation eciency and delayed and sustained release (Ricci et al., 2005)
MiglyolATO5, LutrolF68, properties of the drug
P. Ganesan, D. Narayanasamy

Xanthum gum,
Carbopol934P
SLN Insulin Stearic acid, WGA-N-glut-PE, Ultrasonication 5860 Improved stability (Zhang et al., 2006)
Poloxamer 188, Soyalecithin
SLN Insulin Glyceryl Monostearate, Double emulsion method 216.8 30.9 nm Promising for oral delivery of proteins (Yang et al., 2011)
Glyceryl Palmitostearate,
Glyceryl Tripalmitate,
Glyceryl Behenate
SLN Insulin Cetyl Palmitate, Poloxamer Emulsion solvent diusion 320 26 nm and 361 30 nm Improvement of oral bioavailability (Sarmento et al., 2007)
407
NLC Itraconazole GMS, Precirol/Oleic Acid, Hot high-pressure 177 nm Stable NLCs were prepared which retained their properties during (Pardeike et al., 2011)
Miglyol homogenization nebulisation for pulmonary delivery.
NLC Ketoprofen Compritol888 ATO, Labrafac Ultrasonication 494 47 Improvement in the dissolution and skin permeation properties. (Cirri et al., 2012)
lipophile, Lutrol F68,
Xanthum gum
SLN Ketoprofen Mixture of beeswax and Microemulsion technique 75 4 nm to 250 9.38 nm Faster drug release (Kheradmandnia et al.,
carnauba wax 2010)
NLC Ketoprofen Compritol 888 ATO/ Labrafac Nanoemulsication and 300500 nm Improvement in both the dissolution and the skin permeation (Cirri et al., 2012)
Lipophile ultrasonication properties of drug
NLC Lidocaine Compritol888ATO, Ultrasound dispersion 72.1 Long duration of deep local anaesthesia in guinea pig. (Pathak and
PrecirolATO5, Nagarsenker, 2009b)

44
Miglyol812,T80
NLC Lidocaine Compritol 888 ATO/Miglyol Ultrasound dispersion method 78.1 nm Long duration of local anaesthesia in guinea pigs. (Pathak and
810 Nagarsenker, 2009a)
SLN Lopinavir Compritol 888 ATO, Pluronic Hot homogenization- 230 Avoid rst-pass metabolism (Alex et al., 2011)
F 127 ultrasonication
SLN Lovastatin Triglyceride, Hot homogenization- 60119 Avoid rst-pass metabolism and improved bioavailability (Suresh et al., 2007)
Phosphatidylcholine 95%, ultrasonication
poloxamer 188
NLC Lovastatin Squalene, Pluronic F68, Probe sonicator 180290 Controlled release of drug (Chen et al., 2010)
Precirol, ATO5, Myverol
1804k, Soyabean
phosphatidyl choline.
NLC Lutein Precirol ATO 5 Nano emulsication and 110 20 nm Lutein loaded NLC showed no release in simulated gastric uid and (Taratula et al., 2013)
ultrasonication slow release of lutein in simulated intestinal uid.
NLC Lutin Precirol ATO5, Myverol 18- Ultrasonic Emulsication 134 8 Lutein loaded NLC showed no release in simulated gastric uid and (Liu and Wu, 2010)
04k, CentrolN2F-SB, T20, slow release of lutein in simulated intestinal uid.
T80, Span 60 Pluronic F68,
Lauric, Palmitic, Myristic,
Stearic acid.
SLN Lysozyme/ peptides/ Witepsol E85, Softisan 142, Cold homogenization 540660 Improved stability, permeability and retention of integrity and (Rao, 2008)
vaccine cetyl alcohol, Poloxamer 182 activity
SLN Methotrexate Stearic acid, Monostearin, Solvent diusion method 120167 Improved oral bioavailability, enhancement of GI absorption and (Paliwal et al., 2009)
Tristearin, Compritol 888 lymphatic transport
ATO, L-a-soya lecithin
SLN N3-O-toluyl- ATO888, Soya Lecithin, Tfu Film 178.8 9.99 nm Enhancement of GI absorption and improvement of oral (Liu et al., 2010b)
uorouracil dispersionultrasonication bioavailability
SLN N3-O-toluyl- Lecithin, Compritol 888, Film 150200 nm Improvement of intestinal transport (Liu et al., 2010a)
uorouracil And Tfu dispersionultrasonication
(continued on next page)
Sustainable Chemistry and Pharmacy 6 (2017) 3756
 Table 4 (continued)

Type Drug Excipients Method Size (nm) Ref.

NLC Nevirapine Steric Acid (SA), Oleic Acid Microemulsion 159.6 Uniform distribution of the particles and accelerated the release of (Kuo and Chung,
(OA), Compritol 888 ATO eective formulations in the delivery of drug for viral therapy. 2011)
Tween 80
SLN Nimesulide Palmitostearate, Glyceryl Hot homogenization process 230.4 5.6 nm Sustained drug release (Alex et al., 2011)
Tristearate
P. Ganesan, D. Narayanasamy

SLN Nitrendipine Triglyceride, Hot homogenization- 102123 Improved bioavailability (Manjunath and
Phosphatidylcholine 95%, ultrasonication method Venkateswarlu, 2006)
Poloxamer 188
SLN Nitrendipine Tripalmitin, Glyceryl Hot homogenization 110.6115.4 nm, 116.4122.3 nm, Improvement of oral bioavailability and reduction of rst-pass (Kumar et al., 2007)
Monostearate, Cetyl Palmitate ultrasonication 132.6137.4 nm metabolism
SLN Octa decylamine- Stearic acid, Polyethylene Solvent diusion method 202.7 4025 Improved bioavailability (30%) (Yuan et al., 2007a)
uorescein glycol monostearate
isothiocyanae
NLC Oridonon GMS/Medium chain Low temperature solidi 232.1 nm Prolonged drug release (Jia et al., 2010)
triglyceride(MCT) cation
SLN Otcadecylamine Stearic acid, Poloxamer 188, Solvent diusion 202.7 4.25 nm Enhancement of GI absorption, ymphatic transport and prolonged (Yuan et al., 2007a)
Otcadecylamine, release
Polyethylene glycol
monostearate
NLC Oxybenzone GMS, Miglyol 812, Oleic acid, Solvent diusion 327 30 to 797 100 Enhanced the sunscreen ecacy to about six fold while reducing its (Sanad et al., 2010)
PVA, Carbopol934P side eects.
NLC Oxybenzone GMS/Miglyol Solvent diusion method 0.5280.641 increased the in vitro sun protection factor and erythemal UVA (Sanad et al., 2010)
protection factor of oxybenzone more than 6- and 8-folds,
respectively, with fewer side eects
SLN Pentoxifylline Pluronic F-68, Soy Lecithin, Homogenization followed by 255 nm and 4 m Improvement of oral bioavailability and reduction of rst-pass (Varshosaz et al.,
Stearic Acid, Cetyl Alcohol, the ultrasonication metabolism 2010a)

45
Tween 20,
SLN Praziquantel Hydrogenated castor oil, Poly Hot homogenization and 344.0 15.1 nm, Improvement of bioavailability and prolonged systemic circulation (Xie et al., 2010)
vinyl alcohol, ultrasonication
NLC Progesterone Monostearin, Stearic Acid, Melt-emulsication technique 321.7485.5 nm Potential drug delivery system for oral administration (Yuan et al., 2007b)
Oleic Acid
NLC Psoralens Precirol/Squlaene High-pressure 300 and 200 nm Enhanced permeation and controlled release of the drug (Fang et al., 2008)
homogenization
SLN Puerarin Monostearin Soya lecithin, Solvent injection method 160 Improved bioavailability (Luo et al., 2011)
Poloxamer188
SLN Quercetin Glyceryl monostearate, Soya Emulsication-solidication 155.3 22.1 Improved bioavailability (Li et al., 2009)
lecithin, Tween-80 and PEG
400
NLC Quercetin GMS/MCT Emulsion evaporation solidi 215.2 nm Increased drug retention in epidermis and enhanced the therapeutic (Chen-Yu et al., 2012)
cation eect.
SLN Repaglinide Glycerol Monostearate, Modied solvent injection 175350 nm Well tolerated toxicity level (Rawat et al., 2011)
Tristearin method
NLC Resveratrol Compritol 888 ATO/Miglyol High shear homogenization 287.2 nm 5.1 and 110.5 nm 1.3, The drug loaded NLCs with smaller particle size and high drug (Gokce et al., 2012)
loading showed greater antioxidant activity as compared to SLNs.
SLN Rifampicin, Isoniazid Stearic Acid, Polyvinyl Emulsion-solvent diusion 70100 Improved bioavailability, stability and reducing dosing frequency (Pandey et al., 2005)
and Pyrazinamide Alcohol
NLC Tacrolimus GMS/Oleic Acid Hot sonication and 123.4 0.3 nm Penetration rate is 1.64 times increased than the commercial (Nam et al., 2011)
homogenization method tacrolimus ointment, Protopic
SLN Tobramycin Stearic acid Epikuron 200, Microemulsion 116 Improved bioavailability, sustained drug release and lymphatic (Cavalli et al., 2003)
Sodium taurocholate targeting
NLC Topotecan Stearic Acid/Oleic Acid Micro-emulsication 108168 nm Sustained release, improved chemical stability and cytotoxicity. (Souza et al., 2011)
technique
(continued on next page)
Sustainable Chemistry and Pharmacy 6 (2017) 3756
P. Ganesan, D. Narayanasamy Sustainable Chemistry and Pharmacy 6 (2017) 3756

temperature-induced drug degradation, b) drug distribution into the

(Arajo et al., 2011)

aqueous phase during homogenization, c) complexity of the crystal-

(Mei et al., 2005)

(Luo et al., 2006)

lization step of the nanoemulsion leading to several modications and/
or supercooled melts (Mehnert and Mder, 2001).
In Cold HPH, similar to hot homogenization, the solid lipid is he-
Ref.

ated, and drug molecules are incorporated into the matrix by dissolving
or dispersing them in molten lipid (Fig. 3b). The drug-containing lipid
Increase bioavailability, controlled release and decrease toxicity with

melt is rapidly solidied by cooling with dry ice or liquid nitrogen.

Improved oral BA by increased saturated solubility and reduced

Rapid cooling favours homogenous distribution of the drug within the

lipid material. The solid is then ground into a ne powder by milling
into microparticles. The microparticles are subsequently dispersed in a
cold aqueous surfactant solution. The dispersion is subjected to high-
pressure homogenization to generate SLNs. Cold homogenization in-
volves homogenization of solid lipids as opposed to a lipid melt in hot
homogenization. This dispersion of solid lipids requires high energy
input which in turn requires harsh homogenization conditions. Thus
homogenization itself is more eective for the hot case, and smaller
particles which are the more monodisperse result (Mder et al., 2004).

4.1.4. High shear homogenization and/or ultrasonication technique

High shear homogenization and ultrasonication are dispersing
Improved stability

protective eect

techniques (Fig. 4). Lipid nanoparticle dispersions are obtained by

dispersing the melted lipid in the warm aqueous phase containing
metabolism

surfactants by high sheer homogenization followed by ultrasonication.

This method primarily involves heating of a solid lipid to approximately
510 C above its melting point. The lipid melt is dispersed in an aqu-
eous surfactant solution at the same temperature under high speed
stirring to form an emulsion. Subsequent sonication reduces the droplet
size of the emulsion. Gradual cooling of the warm emulsion below the
crystallization temperature of the lipid yields a lipid nanoparticle dis-
persion. Concentrated lipid nanoparticle dispersions can be obtained by
ultracentrifugation (Shah et al., 2015).
Mechanism of particle formation

Shear between adjacent particles Formation, growth and implosive

173.30 0.32

collapse of bubbles due to cavitation forces.

70200 nm
Size (nm)

116.1 nm

4.2. Low energy approaches

High pressure homogenization

4.2.1. Microemulsion technique

Microemulsion formation is used as a stage in the production of SLN
and NLC since the early 90s (Gasco, 1993). In this method, the micro-
emulsion is spontaneously formed due to the high surfactants/lipid
Ultrasonic-solvent
Probe soniation

ratio (Fig. 5). The proportions of the excipients are essential, and in
emulsication

most cases, pseudo-ternary diagrams are used to study and describe the
Method

areas of microemulsion formation. This method is simple and is per-

formed by several common steps. Initially, the lipids are melted and
mixed with hot surfactant solution. Gentle stirring is applied until the
microemulsion is formed. In the second stage, the hot microemulsion is
Glyceryl monostearate, Soya
Poloxamine 908, Soybean

dispersed in a high volume of cold water (23 C) under moderate

Precirol ATO 5/Squalene

hydrogenated castor oil

stirring. This causes the liquid droplets to solidify. SLN or NLC obtained
Tristearin Glyceride,

lecithin, Tween80,

by this technique are spherical in shape and have narrow size dis-
Polyoxyethylene

tribution. However, the method suers from several drawbacks the

nal dispersion is very diluted (ranging between 1:25 up to 1:50 with
Excipients

Lecithin

respect to the hot emulsion). This may require further concentration by

ultraltration, lyophylization or other methods. The high concentration
of surfactants/co-surfactants used is another major disadvantage of this
technique (Gasco, 1993; Svilenov and Tzachev, 2014).
Mechanism of particle formation
Triamcinolone

Vinpocetine

Lipid crystallization due to rapid solidication of microemulsion.

Triptolide
acetonide
Table 4 (continued)

Drug

4.2.2. Membrane contactor technique

This method employs a cylindrical membrane module: aqueous
Type

NLC

SLN

SLN

phase containing a surfactant is circulated in internal channel of the

membrane, and melted lipid is pressed through pores of the membrane

46
P. Ganesan, D. Narayanasamy
Fig. 3. Homogenization technique. a). Hot homogenization technique b). Cold homogenization technique.
into internal water ow allowing the formation of small droplets which
are swept away by the aqueous phase; water is maintained at lipid
melting temperature. SLNs/NLCs are then formed by cooling the pre-
paration to room temperature (Charcosset et al., 2005) (Fig. 6). The
method is scalable, and the particle size can be tuned by using mem-
branes with a dierent pore size (Svilenov and Tzachev, 2014).
Mechanism of particle formation
Lipid/oil phase infuses through membrane pores into the tangen-
tially owing aqueous phase to form droplets.
Oil droplets crystallize to form lipid nanoparticles.
4.2.3. Phase inversion temperature (PIT) technique
Transformation of an o/w type to a w/o type of emulsion is termed
phase inversion, can be induced by changing the temperature, and
the temperature at which the inversion occurs is referred to as the PIT
Fig. 4. High shear homogenization/ultrasonication technique.
47
Sustainable Chemistry and Pharmacy 6 (2017) 3756
(Shah et al., 2015). This technique mainly depends on the change in the
properties of polyoxyethylated surfactants at dierent temperatures
(Fig. 7). The hydrophilic-lipophilic balance (HLB) value of surfactants
dened by Grin is valid at 25 C. At this temperature, the hydrophilic
parts of the surface-active compounds are hydrated to a certain extent.
Moreover, the dehydration of the ethoxy groups occurs when an in-
crease in temperature. Thus, the lipophilicity of the molecules of the
surface-active compounds rises with the decrease in HLB value. At a
certain point, the surface-active compounds of the anity to the aqu-
eous and lipid phase is equal - this temperature is called as the phase
inversion temperature. This particulate state is characterized by very
low surface tension and the presence of complex structures in the
system. If the temperature is further increased the anity of the sur-
face-active compounds becomes higher enough to the lipid phase to
stabilize emulsions of W/O type.
If cooled down the system goes through the reverse process. Due to
P. Ganesan, D. Narayanasamy
Fig. 5. Micro emulsion technique.
Fig. 6. Membrane contactor technique.
the specic properties of the system around the PIT, very small particles
are spontaneously formed just below that temperature. If rapid cooling
is applied at this point stable particles with a desirable size and poly-
dispersity can be obtained (Izquierdo et al., 2002). In this method, lipid,
drug, water and surfactant are mixed together on magnetic stirring,
three heating and cooling cycles are performed which is then diluted
Fig. 7. Phase inversion temperature (PIT) technique.
48
Sustainable Chemistry and Pharmacy 6 (2017) 3756
with cold water causing phase inversion of the emulsion and breaking
resulting in SLNs/NLCs
Mechanism of particle formation
Spontaneous inversion of o/w emulsion to w/o emulsion due to
thermal treatment (subsequent heating- cooling cycles).
Lipid crystallization as a result of emulsion breakage due to irre-
versible shock induced by rapid cooling.
4.2.4. Coacervation technique
Lipid nanoparticles are produced by acidication of a micellar so-
lution of fatty acid alkaline salts (Battaglia et al., 2010; Bianco et al.,
2010; Chirio et al., 2011; Gallarate et al., 2010) (Fig. 8). Before pre-
paration of lipid nanoparticles, a stock solution of the polymeric sta-
bilizer is prepared by heating in hot water. A sodium salt of the fatty
acid is homogenously dispersed in the polymeric stabilizer stock solu-
tion, and the solution is heated above the Krat point of the sodium salt
of the fatty acid (Battaglia et al., 2014), under constant stirring, to
obtain a clear solution. The drug (solubilized in ethanol) is later
added to the clear solution, with constant stirring, until a single phase is
obtained. The gradual addition of a coacervating solution (or on acid-
ifying the solution) to this mixture yields a suspension. Further cooling
of the suspension in a water bath, under constant agitation, yields drug-
loaded nanoparticles which are well dispersed (Shah et al., 2015;
Battaglia et al., 2010,).
Mechanism of particle formation
Decrease in pH of micellar solution of alkaline salts of fatty acids by
acidication (coacervating solution) in the presence of a polymeric
P. Ganesan, D. Narayanasamy
Fig. 8. Coacervation technique.
stabilizer causes proton exchange a lipid precipitation (coacerva-
tion).
4.2.5. Double emulsion technique
The double emulsion technique in the preparation of SLN and NLC is
suitable for hydrophilic active pharmaceutical ingredients and peptides
(Svilenov and Tzachev, 2014). In this method, an aqueous solution of
the drug is emulsied in melted lipid blend to form primary W/O
emulsion stabilized with suitable excipients (Fig. 9). The primary W/O
emulsion is dispersed in aqueous solution of hydrophilic emulsier to
form a double W/O/W emulsion. Then the double emulsion is stirred
and isolated by ltration. Relatively large particles are obtained with
this technique, but beside the incorporation of hydrophilic molecules, it
oers the possibility of surface modication, e.g. with PEGs.
Mechanism of particle formation
Lipid crystallization due to solidication of emulsion.
4.2.6. Micro emulsion cooling technique
Recently, Mumper and Jay (Koziara et al., 2004, 2005; Mumper
et al., 2006) patented a micro emulsion based method for preparation
of SLN. This method involves preparation of o/w micro emulsion where
an emulsifying wax is melted at 3755 C and addition of water which
heated at the same temperature with minimal stirring so as to form a
homogenous milky slurry. Further, after addition of specied amounts
of a suitable pharmaceutically acceptable polymeric surfactant in
water, a stable and clear o/w micro emulsion in the form of a liquid
Fig. 9. Double emulsion technique.
49
Sustainable Chemistry and Pharmacy 6 (2017) 3756
matrix is produced. This o/w micro emulsion is further cooled at room
temperature or at 4 C so as to precipitate SLN from it. This method is
reproducible, simple and easy to scale up. Moreover, all the ingredients
used are biocompatible; no organic solvents are used in the preparation
method.
4.3. Approaches with organic solvents
4.3.1. Emulsication-solvent evaporation technique (Pedersen et al., 2006)
This technique involves three steps of preparation. Such as (i) pre-
paration of organic phase: lipophilic material is rst dissolved in an
appropriate volume of organic solvent by magnetic stirring. (ii) Pre-
emulsication step: lipid-containing organic phase is dispersed in an
appropriate volume of an aqueous solution using a high-speed homo-
genizer in order to form a coarse pre-emulsion. (iii) Nano emulsication
step: the resulting coarse pre-emulsion is immediately passed through a
high-pressure homogenizer at an operating pressure to obtain nano-
dispersion. Obtained nanodispersion is then kept on the magnetic
stirrer overnight, sometimes in a fume hood to drive o the organic
solvent. Upon solvent evaporation, nanodispersion is formed by pre-
cipitation of lipid material in the aqueous medium. Solidied nano-
dispersion is then ltered through a sintered glass lter to remove lipid
and drug agglomerates (Fig. 10). Nanoparticles obtained by this method
are small, monodisperse with high encapsulation eciency. The pro-
cess can be automated and scaled-up for the production of a large
amount of nanoparticles (Jaiswal et al., 2004).
Mechanism of particle formation
P. Ganesan, D. Narayanasamy Sustainable Chemistry and Pharmacy 6 (2017) 3756

Fig. 10. Emulsication-solvent evaporation technique.

Lipid crystallization due to solvent evaporation in an anti-solvent.

4.3.2. Emulsication solvent diusion technique
Partially water-miscible solvents are used to solubilize the solid li-
pids. A number of solvents partially soluble in water such as benzyl
alcohol, butyl lactate, isobutyric acid, isovaleric acid and tetra-
hydrofuran have been used in the preparation of lipid nanoparticles
(Battaglia et al., 2007; Shahgaldian et al., 2003a, 2003b, 2003c). To
ensure initial thermodynamic equilibrium, organic solvents are satu-
rated with water. The transient oil- in-water emulsion is passed into
water under continuous stirring, which leads to solidication of dis-
persed phase forming lipid nanoparticles due to diusion of the organic
solvent. Typical emulsion: water ratios are 1:5 or 1:10 (Shah et al.,
2015) (Fig. 11).
Mechanism of particle formation:

Lipid crystallization due to diusion of solvent from internal organic

phase to external aqueous phase.
Fig. 12. Solvent injection technique.

4.3.3. Solvent injection technique

The basic principle of the solvent injection method is similar to the
solvent diusion method. In the case of solvent injection method, lipids
are dissolved in a water-miscible solvent (e.g. acetone, isopropanol, and
methanol) or water-miscible solvent mixture and quickly injected into
an aqueous solution of surfactants through an injection needle
(Schubert and Mller-Goymann, 2003) (Fig. 12). Two simultaneous
eects contribute to the eective formation of SLNs/NLCs:
1. Gradual solvent diusion out of lipid-solvent droplets into water
causes reduction of droplet size and simultaneously increases lipid
concentration
2. Diusion of pure solvent from the lipid-solvent droplet causes local
variations in the interfacial tension at droplet surface, inducing re-
duction of size of droplets In this process particle size of SLNs/NLCs
can be inuenced and controlled by variation of process parameters

Fig. 11. Emulsication solvent diusion technique.

50
P. Ganesan, D. Narayanasamy
such as injected solvent, lipid concentration, injected volume of
solvent, lipid concentration in the solvent phase and viscosity of the
aqueous phase (Schubert and Mller-Goymann, 2003).
Mechanism of particle formation:
Lipid crystallization due to rapid diusion of solvent from internal
organic phase to external aqueous phase.
4.3.4. Supercritical uid (SCF) technique
The process of preparing lipid nanoparticles from emulsions using
SCF technology is referred to as supercritical uid extraction of
emulsions (SFEE) (Chattopadhyay et al., 2006, 2007). The organic
solution is prepared by solubilizing the lipid material and the drug in an
organic solvent such as chloroform with the addition of a suitable
surfactant. The organic solution is dispersed into an aqueous solution
(which may contain a co-surfactant), and the mixture is subsequently
passed through a high-pressure homogenizer to form an o/w emulsion.
The o/w emulsion is introduced from one end of the extraction column
(usually the top) at a constant ow rate, and the supercritical uid
(maintained at constant temperature and pressure) is introduced
counter-currently at a constant ow rate. Lipid nanoparticle dispersions
are formulated by continuous extraction of solvent from the o/w
emulsions (Shah et al., 2015, Svilenov and Tzachev, 2014) (Fig. 13).
Mechanism of particle formation:
Parallel processes of supercritical uid extraction (diusion) of or-
ganic solvent from emulsions and lipid dissolution.
Expansion of organic phase; leads to lipid crystallization.
4.3.5. Particle from Gas Saturated Solution (PGSS) technique and Gas
Assisted Melting Atomisation (GAMA) technique
PGSS involves melting of the material to be processed, which then
dissolves the SCF under pressure. The saturated solution is then ex-
panded across a nozzle where the SCF, which is more volatile, escapes,
leaving dry ne particles. As the solubilities of compressed gases in li-
quids and solids are usually high, and much higher than the solubilities
of such liquids and solids in the compressed gas phase, the process
Fig. 13. Supercritical uid (SCF) technique.
51
Sustainable Chemistry and Pharmacy 6 (2017) 3756
consists in solubilizing CO2 in melted or liquid suspended substance(s)
(Reverchon and Porta, 2001), leading to a so-called gas-saturated so-
lution/suspension that is further expanded through a nozzle with the
formation of solid particles or droplets. The advantage of this process is
that the substances need not be soluble in CO2 (Byrappa et al., 2008).
In literature some examples of PGSS applied to lipid nano-and micro
particles can be recovered. The most important are the so called Gas
Assisted Melting Atomisation (GAMA) (Salmaso et al., 2009, Vezz
et al., 2010). Lipids are placed in a thermo stated mixing chamber (CM),
where they are melted and kept in contact with supercritical CO2 at
selected temperature and pressure conditions. Then, the saturated lipid
uid is forced through the nozzle by opening the valve at the bottom of
the CM, to produce micro particles. A CO2 reservoir is allowed to keep
constant the pressure in the CM, and the ow rate through the nozzle as
well. Particles are gathered by a collection system and dispersed in
water by vortexing and sonicating, to obtain suspensions. Polyethylene
glycol (PEG) can be added to the formulation to increase the rate of
dispersion in water.
5. Lyophilization
Stability of SLNs/NLCs mainly depends on the physicochemical
stability of solid lipid in their nano particles form, since they are more
prone to degradation and coalescence. The physical stability of the SLN
during prolonged storage can be determined by monitoring changes in
particle size, zeta potential, drug content, appearance, and viscosity as a
function of time (Wu et al., 2011; Schwarz et al., 1994; Mishra et al.,
2012). In the case of chemical stability, the SLN ingredients should have
a very narrow size distribution to avoid crystal growth by Ostwald ri-
pening (Mehnert and Mder, 2001). External parameters such as tem-
perature and light appear to be of primary importance for long-term
stability during the storage and shipping. In most cases, an increase in
particle size will be observed in a shorter period of time (Mishra et al.,
2012).
The zeta potential should, in general, remain higher than 60 mV
for a dispersion to remain physically stable. This fact, in turn, is
achieved by lyophilization. Lyophilization is a promising way to in-
crease physical and chemical SLN stability over extended periods of
P. Ganesan, D. Narayanasamy Sustainable Chemistry and Pharmacy 6 (2017) 3756

Table 5 cryoprotectants during the freezing step. Sugars isolate individual

Characterization of SLNs/ NLCs.
Characterization parameters
Shape and surface morphology
Vesicle size and size distribution
Electrical surface potential and surface
pH
Surface charge and electrophoretic
mobility
Analytical methods/
instrumentations
Transmission electron microscopy
(TEM)
Scanning electron microscopy (SEM)
Phase contrast optical microscopy
(PCM)
Atomic force microscopy (AFM)
Freeze fracture microscopy
Electron microscopy (SEM/TEM)
Optical microscopy
Photon correlation spectroscopy (PCS)
Zeta potential measurement
pH-sensitive probes
Laser light scattering technique
particles in unfrozen fraction and thereby prevent particle aggregation
during freezing above Tg. Sugar vitrication is not required for this
eect (Allison et al., 2000; Pardeshi et al., 2012).
Similarly, water replacement hypothesis is a major mechanism for
nanoparticle stabilization by lyoprotectants during the drying step.
These lyoprotectants are known to form hydrogen bonds with the sur-
face polar groups of nanoparticles and serve as water substitutes to
preserve the native structure of nanoparticles, thereby stabilizing the
system (Pardeshi et al., 2012; Crowe et al., 1998).
Freeze dried nanoparticles should have the following desirable
characteristics:
(i) Preservation of primary physical and chemical characteristics of
the product.
(ii) Long-term stability.
(iii) Acceptable relative humidity.

Surface hydrophobicity Hydrophobic interaction
chromatography
Two-phase partition
Radiolabel probe
Contact angle measurement
X-ray photoelectron spectroscopy
Synchrotron radiation X-ray (SAX)
Density Gas pycnometre
Molecular weight Gel permeation chromatography (GPC)
Rheology Viscometer
In vitro release Dialysis membrane dissolution test
apparatus
time. Also, transformation into a solid form will prevent Ostwald ri-
pening and avoid hydrolysis reactions (Mishra et al., 2012; Mehnert and
Mder, 2001; Swathi et al., 2012). Stresses that destabilize the colloidal
nanoparticulate suspension may be generated during freeze drying,
particularly stresses of freezing and dehydration. Aggregation and
sometimes an irreversible fusion of nanoparticles may destabilize the
colloidal nanoparticulate system (Pardeshi et al., 2012). Obviously, two
additional transformations between the formulations are necessary
which might be the source of additional stability problems. The rst
transformation is from an aqueous dispersion to powder, which in-
volves the freezing of the sample and the evaporation of water under
vacuum. Freezing of the sample might cause stability problems due to
the freezing out eect which results in changes of the osmolarity and
the pH. The second transformation is resolubilization, which involves,
at least in its initial stages, situations which favor particle aggregation
(low water and high particle content, high osmotic pressure) (Mehnert
and Mder, 2001).
To get rid of this problem, special excipients must be added before
freezing to protect the nanoparticulate suspension. The added ex-
cipients that protect the system from freezing stress are called cryo-
protectants and those protecting from the drying stress are called lyo-
protectants (Pardeshi et al., 2012). The addition of cryoprotectors will
be necessary to decrease SLN aggregation and to obtain a better re-
dispersion of the dry product (Mehnert and Mder, 2001; Crowe et al.,
1986; Madden et al., 1985; Strauss et al., 1986; Hauser and Strauss,
1988; Shulkin et al., 1984). Typical cryoprotective agents are sorbitol,
mannose, trehalose, glucose, and polyvinylpyrroli- done. They decrease
the osmotic activity of water and crystallization and favor the glassy
state of the frozen sample (Shiau, 1990; Phan and Tso, 2001; Porter and
Charman, 2001; O'driscoll and Grin, 2008; Porter et al., 2007).
Cryoprotectors are place holders which prevent the contact between
discrete lipid nanoparticles. Furthermore, they inter-act with the polar
head groups of the surfactants and serve as a kind of pseudo hydration
shell (Mobley and Schreier, 1994). In addition, particle isolation hy-
pothesis is one of the mechanisms for nanoparticle stabilization by
The efciency of the cryoprotectors decreases in the following
order: trehalose > sucrose > > glucose and maltose. The addition of
the time of the cryoprotector inuences the quality of the nal for-
mulation. The cryoprotector was added to the sample when prior to
homogenization the best results were obtained. The average particle
size remained almost unchanged under these circumstances (Swathi
et al., 2012). Storage over one year caused signicant increases in
particle size (Mehnert and Mder, 2001). Besides, Schwarz et al. studied
the eect of cryoprotectors during the lyophilization of SLN by using
glucose, mannose, maltose and trehalose in concentrations between
10% and 15% and reported the best results (Schwarz and Mehnert,
1997; Madden et al., 1985; Crowe et al., 1985; Mehnert and Mder,
2001). Cavalli et al. also reported in the case of trehalose that the 2%
concentration of trehalose was insufcient to prevent lyophilization-
induced particle aggregation and 15% concentration of trehalose was
sufcient to produce particle sizes of around 100 nm and in poly-
dispersity indices of 0.25 after reconstitution (Cavalli et al., 1997;
Mehnert and Mder, 2001).
To transform an aqueous SLN dispersion into a dry product the
spray drying might be an alternative procedure to lyophilization. This
method has been used scarcely for SLN formulation (Hanumanaik et al.,
2013), although spray drying is cheaper compared to lyophilization
(Mehnert and Mder, 2001).
6. Characterization of SLNs/ NLCs (Seetapan et al., 2010; Mller
et al., 2008; Silva et al., 2011, 2007; Subedi et al., 2009; Mishra
et al., 2012)
Dierent techniques used for the characterization of SLNs/NLCs are
tabulated in the Table 5.
7. Drug release
Investigations of drug incorporation and release served as an im-
portant tool in the design, development, and evaluation of potential
drug carrier systems (Pardeshi et al., 2012). Drugs incorporated into
SLN are released by degradation and surface erosion of the lipid matrix
and by diusion of drug molecules through the lipid matrix (Mehnert
and Mder, 2001). Drug release from SLN is mainly aected by loca-
lization of the drug (Muchow et al., 2008):
1. Localization of the drug within the core of solid lipid matrix oers
the possibility to obtain a prolonged drug release.
2. Localization of drug molecules on particle surface often leads to
burst eect (fast initial drug release). SLN can show a biphasic drug
release prole: an initial burst release, due to the drug localized at
the surface, is followed by a more gradual release due to the drug
localized in the lipid matrix.

52
P. Ganesan, D. Narayanasamy
Therefore, the extent of burst release can be controlled by control-
ling drug solubility in the aqueous phase during production, which, in
turn, can be controlled via the temperature employed and the surfac-
tant concentration used. Higher temperature and higher surfactant
concentration increase the burst whereas production at room tem-
perature avoids partitioning of the drug into a water phase and sub-
sequent re-partitioning into lipid phase, thereby showing no burst re-
lease at all. To avoid or minimize the burst release, SLN can be
produced surfactant-free or with surfactants unable to solubilize the
drug (Muller et al., 2000; Pardeshi et al., 2012). The possible presence
of alternative colloidal species always has to be taken into account for
drug release characterization: stabilizing agent cannot be localized
exclusively on the lipid surface as expected, but also in the aqueous
phase forming micelles, mixed micelles or liposomes that can solubilize
the drugs and constitute alternative drug incorporation sites (Mehnert
and Mder, 2001).
8. Links to green and sustainable chemistry
Nowadays the poorly water-soluble drug candidates are challenging
candidates not only in the formulation aspect but also for conducting
pharmacological, toxicological and pharmacokinetic studies during the
drug development stage and in biological conditions. Also, it is mainly
responsible for toxicity problem associated with the drug design, de-
velopment, optimization and in the biological fate of the drug in the
body. But all these problems can be overcome by formulating them as a
lipid nanoparticles which facilitates the absorption into the systemic
circulation through the intestinal lymphatic pathway and avoiding the
rst-pass eect, also facilitates the below-mentioned advantages which
is related to green chemistry.
When compared to synthetic, semisynthetic excipients used in the
formulation of pharmaceutical formulations, the excipients used in
this lipid nanoparticles are composed of physiological or physiolo-
gically related lipids. Hence, the pathways for absorption, metabo-
lism and transportation are present in the body, which may con-
tribute to a large extent to the bio fate of lipidic carrier.
Furthermore, the excipients of lipid nanoparticles (lipid, surfactants
and cosolvents) have important role in physiology of the body, such
as energy storage (lipids), a part of biomembranes (phospholipids),
and have key function in metabolism (bile acids), hence considered
as harmless and usually scheduled in the generally recognized as
safe category which is US FDA-approved.
Since the lipid nanoparticles composed of physiological lipids and
its digestion and absorption is similar to physiological lipids, it not
possess any toxic eects and decreases the adverse side eects of the
drug delivery systems when compared to other of metal or poly-
meric nature. Due to its biodegradation and biocompatible nature, it
secures the title of "Nano safe carrier".
Moreover, in the formulation point of view, lipid nanoparticles are
much easier to manufacture than bio polymeric nanoparticles. Also,
it possess many advantages such as
Good production scalability (sustainability).
Avoidance of organic solvents in the formulation process.
No special solvent required.
Conventional emulsion manufacturing methods applicable.
Easy to scale up and sterilize.
Industrial adaptability.
Also, lipid nanoparticles combine the attributes of both nanosized
particles and lipid carriers to improve the bioavailability of active
pharmaceutical ingredients (APIs).
From all these advantages, such as preparation by using physiolo-
gical or physiologically related lipids which simulate physiological
lipids, lack of organic solvent usage during the production processes
53
Sustainable Chemistry and Pharmacy 6 (2017) 3756
using the high-pressure homogenization method with existing ma-
chinery, ease of large-scale manufacturing and avoidance of toxicity
makes the lipid nanoparticle as a suitable condition for drug de-
livery and potentially attractive and marketable choices.
9. Conclusion
From the review, it was evident that the various research groups are
increasingly attracted with lipid nanoparticles (SLNs & NLCs) due to its
unique properties and a lot of advantages over traditional dosage forms
and their colloidal counterpoints. Hence, lipid nanoparticles are pro-
mising drug delivery system for the formulation of poorly water soluble
drug in the pharmaceutical industry.
Conicts of interest
The authors declare no conict of interest.
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