International Journal of Pharmaceutics 546 (2018) 194–214

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International Journal of Pharmaceutics

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

Review

Nano spray drying for encapsulation of pharmaceuticals T

a b b c c,⁎
Cordin Arpagaus , Andreas Collenberg , David Rütti , Elham Assadpour , Seid Mahdi Jafari
a
NTB University of Applied Sciences of Technology Buchs, Institute for Energy Systems, Buchs, Switzerland
b
BÜCHI Labortechnik AG, Flawil, Switzerland
c
Department of Food Materials and Process Design Engineering, Gorgan University of Agricultural Sciences and Natural Resources, Gorgan, Iran

A R T I C LE I N FO A B S T R A C T

Keywords: Many pharmaceuticals such as pills, capsules, or tablets are prepared in a dried and powdered form. In this field,
Nano spray drying spray drying plays a critical role to convert liquid pharmaceutical formulations into powders. In addition, in
Pharmaceuticals many cases it is necessary to encapsulate bioactive drugs into wall materials to protect them against harsh
Encapsulation process and environmental conditions, as well as to deliver the drug to the right place and at the correct time
Powder properties
within the body. Thus, spray drying is a common process used for encapsulation of pharmaceuticals. In view of
Nanoparticles
the rapid progress of nanoencapsulation techniques in pharmaceutics, nano spray drying is used to improve drug
formulation and delivery. The nano spray dryer developed in the recent years provides ultrafine powders at
nanoscale and high product yields. In this paper, after explaining the concept of nano spray drying and un-
derstanding the key elements of the equipment, the influence of the process parameters on the final powders
properties, like particle size, morphology, encapsulation efficiency, drug loading and release, will be discussed.
Then, numerous application examples are reviewed for nano spray drying and encapsulation of various drugs in
the early stages of product development along with a brief overview of the obtained results and characterization
techniques.

1. Introduction
Spray drying is a simple, fast, reproducible, and scalable drying
technology (Arpagaus and Schwartzbach, 2008), allowing mild tem-
perature conditions suited to heat-sensitive biopharmaceutical com-
pounds. It is well established in the food (Anandharamakrishnan, 2014;
Celli et al., 2015; Esfanjani et al., 2015; Gharsallaoui et al., 2007; Jafari
et al., 2008b, 2007; Mahdavi et al., 2014; Murugesan and Orsat, 2012;
Rajabi et al., 2015), chemical (Masters, 1991; Okuyama and Lenggoro,
2003), and pharmaceutical industries (Bürki et al., 2011; Cal and
Sollohub, 2009; Vehring, 2008; Wang et al., 2005; Wendel and Celik,
2005). Compared to other drying technologies used in drug delivery
applications, spray drying is a continuous process to directly transform
various liquids (e.g. solutions, emulsions, dispersions, slurries, pastes or
even melts) into solid particles with adjustable size, distribution, shape,
porosity, density, and chemical composition. Spray drying equipment is
commercially available and the production cost is typically lower
compared to other drying technologies like for example freeze drying
(Arpagaus et al., 2017; Celli et al., 2015; Gharsallaoui et al., 2007).
The process steps of spray drying are basically (1) heating of the
drying gas, (2) droplet generation, (3) drying of the droplets, and (4)
particle collection. Fig. 1 illustrates a principle flow diagram of a spray
⁎
Corresponding author.
E-mail addresses: cordin.arpagaus@ntb.ch (C. Arpagaus), smjafari@gau.ac.ir (S.M. Jafari).
dryer. First, the liquid feed is atomized in a nozzle. The reduction in
droplet size leads to a large increase in the surface area. In the drying
chamber, the solvent in the sprayed droplets is quickly removed by the
continuous flow of a hot drying gas. Dry particles are formed and se-
parated from the gas stream and are collected in a collection vessel.
In the context of pharmaceuticals encapsulation applications, the
main benefits of spray drying are (Arpagaus et al., 2017, 2013; Wong
and John, 2015):
• Control of particle size, shape, and morphology (amorphous/crys-
talline form, porosity)
• One-step process to directly convert various liquid feeds into dry
powders
• Process simplicity and ease of operation
• Low operating costs, energy efficient technology, and fast process
• Scale-up capability
• Open and closed cycle design for aqueous and organic solvents spray
drying
• Processing of heat-sensitive substances with low risk of degradation
• Design of particles with controlled drug release properties
• High encapsulation efficiency and extended shelf life
• Versatile technique for the formulation of nanocapsules with various

https://doi.org/10.1016/j.ijpharm.2018.05.037
Received 2 March 2018; Received in revised form 14 May 2018; Accepted 15 May 2018
Available online 17 May 2018
0378-5173/ © 2018 Elsevier B.V. All rights reserved.
C. Arpagaus et al. International Journal of Pharmaceutics 546 (2018) 194–214

Nomenclature SEM scanning electron microscopy

SLS static light scattering
AFM atomic force microscopy TEM transmission electron microscopy
ANOVA analysis of variance Tg glass transition temperature (°C)
C relative atomic concentration of carbon Tm melting point (°C)
CLSM confocal laser scanning microscopy Tm inlet drying temperature (°C]
Cp heat capacity (kJ/kg K) WPC whey protein concentrate
DLS dynamic light scattering XPS X-ray photoelectron spectroscopy
DOE design of experiments
DSC differential scanning calorimetry Subscripts
FTIR Fourier transform infrared spectroscopy
FESEM Field emission SEM E encapsulated in powder
LIBD Laser-induced breakdown detection S on the powder surface
NMR nuclear magnetic resonance O fish oil
N relative atomic concentration of nitrogen P protein
O relative atomic concentration of oxygen α, β, γ percentage (%)
PDI polydispersity index

encapsulating excipients various advantages, such as a higher surface-volume ratio, a higher

A spray dried powder form offers higher stability, better protection
from the environment (e.g. oxidation, light, and temperature), easier
handling and storage, and redispersibility in aqueous solutions
(Murugesan and Orsat, 2012; Okuyama et al., 2006). The produced
powders are high in quality and have typically low moisture contents
(Schmid, 2011), resulting in high shelf life stability
(Anandharamakrishnan and Ishwarya, 2015). The cooling effect of the
evaporating solvent conserves the droplet temperature relatively low.
Therefore, heat-sensitive products can be dried with negligible de-
gradation (Masters, 1991). In addition, spray drying offers high flex-
ibility to control particle size and morphology by optimizing the process
parameters and feed formulation (Nandiyanto and Okuyama, 2011).
Smooth and spherical, collapsed, dimpled, wrinkled, raisin-like, and
highly crumpled or folded particles can be obtained (Arpagaus et al.,
2017; Nandiyanto and Okuyama, 2011). Various particle designs can be
prepared by spray drying encapsulation, such as single core, irregular,
multi-wall, multi-cores, or composites.
The main advantage of nano spray drying is the production of drug-
loaded nanoscale particles that can be used for drug delivery purposes.
Nano spray drying enables the generation of smaller particle sizes than
conventional spray dryers, which improves bioavailability and release
of bioactive components and drugs. Drug-loaded nanoparticles offer
Fig. 1. Principle flow diagram of a traditional spray dryer (Arpagaus et al.,
2017).
penetration rate into the cells, higher stability, higher possibility of
targeted release through surface decoration, etc.
The definition of a nanoparticle in the pharmaceutical industry can
be described as solid colloidal particles with sizes below 1 µm (Kaialy
and Al Shafiee, 2016; Lee et al., 2011; Li et al., 2010; Wong, 2015;
Wong and John, 2015). Fig. 2 illustrates distinct application areas
where nano spray drying plays a crucial role in the formulation of
pharmaceuticals in powder form. The particle formation process during
nano spray drying can be described by solvent evaporation and diffu-
sion of solutes in the droplet because of simultaneous heat and mass
transfer (Vehring, 2008). A solution of the product (A) is dispersed into
fine droplets (B). The solvent evaporates immediately, the droplets
shrink, and a solid powder is formed. The final product (C) is a fine
powder that can be amorphous or crystalline. Feed dilution results in a
final product with smaller particle sizes. Practical applications include
for example polymeric wall materials, like Arabic gum, whey protein,
polyvinyl alcohol, modified starch, or maltodextrin (Li et al., 2015,
2010), as will be discussed in more detail in Section 4. Nanonization or
structural change is used to change the particle morphology from a
coarse grain to a very fine powder. This improves the solubility of the
final drug product due to the higher surface-to-volume ratio of nano
particles and due to more amorphous structures, which the solvent (e.g.
water) can penetrate more efficiently. Typical examples are drugs with
poor solubility in water (Li et al., 2010; Martena et al., 2012a; Schmid
et al., 2011) and salts (Moncada et al., 2015). A main advantage of
nanonization is that particles of very uniform size are achieved. A
crystalline product (A) is dissolved in a solvent (B) and this solution (C)
is dispersed into tiny droplets (D). The result is a final product (E) si-
milar to the final product described in nano spray drying. A change of
crystalline drugs into more amorphous structures provides faster drug
release kinetics.
In nanoencapsulation, typically a liquid product is embedded inside
a solid matrix. Encapsulated oil-in-water nanoemulsion are common
examples, where the oil droplets serve as the reservoir for a lipophilic
drug product (A). Together with a carrier substance (B), and a filmogen
solution (C), an emulsion (D) is created. Organic binders like polymeric
wall materials (Ezhilarasi et al., 2013; Fathi et al., 2014; Gharsallaoui
et al., 2007; Mahdavi et al., 2014; Ngan et al., 2014; Rajabi et al., 2015;
Sabliov and Astete, 2015) are frequently used to reach high en-
capsulation efficiency and capsule stability (see more details on dif-
ferent wall materials in Table 2). The emulsion is then sprayed into
small droplets (E) and the solvent evaporates leaving a solid matrix
around the dispersed second phase (F). This results small droplets of the
product (A) stored in the carrier substance (B) and embedded in the
filmogen (C). Capsules smaller than 1 µm in diameter are known as

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C. Arpagaus et al.
Fig. 2. Application areas for a nano spray dryer (Arpagaus et al., 2017).
nanocapsules (Arpagaus et al., 2017; Couvreur et al., 1995; Jafari et al.,
2008b). Jafari et al. (2007, 2008a,b) proposed the term “nanoparticle
encapsulation” for cases where the core material is within the nano size
range and is encapsulated into a matrix of micron sized powder parti-
cles. In drug delivery, due to their small sizes and high specific surface
areas, nanocapsules offer improved dissolution rates and bioavailability
of the bioactive compounds compared to microcapsules (Lee et al.,
2011). Nanoenglobing is similar to nanoencapsulation, but a solid
material is embedded in another solid or liquid product. Examples are
carotenoids in gelatine or magnetic iron oxide nanoparticles in Eudragit
or maltodextrin (Perecin et al., 2014). A nanodispersion (D) is created
from a solid product (A), a matrix material (B), water, and a filmogen
solution (C). This suspension is then sprayed into small droplets (E).
The matrix and the filmogen lead to an agglomeration or coating of the
suspended particles (A), resulting in nanocomposite particles (F).
The recent advances in nanomedicine and nanotherapeutics have
increased the need for spray dryers that allow high yields of nanoscale
particles with narrow size distribution. Several extensive reviews on the
Fig. 3. Schematic of a nano spray dryer and its functional principles: Tin, Tout: inlet and outlet drying gas temperature (Arpagaus, 2012, 2011, Arpagaus et al., 2017,
2010a, 2010b, Büchi Labortechnik, 2013, 2010).
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International Journal of Pharmaceutics 546 (2018) 194–214
subject of nano spray drying technology have already been published
(Arpagaus, 2012, 2011; Arpagaus et al., 2017; Heng et al., 2011; Lee
et al., 2011; Nandiyanto and Okuyama, 2011; Okuyama et al., 2006;
Sosnik and Seremeta, 2015; Wang et al., 2005). The actual experiences
gained from published works on nano spray drying for drug delivery
applications are reviewed in this paper. After explaining the concept of
nano spray drying and understanding the key elements of the equip-
ment, the influence of the process parameters on the final powder
properties, such as particle size, morphology, encapsulation efficiency,
drug loading and release, will be discussed. Then, numerous applica-
tions of nano spray drying for the formulation and encapsulation of
different pharmaceuticals will be presented along with a brief overview
of the obtained results and characterization techniques.
2. Elements of a nano spray dryer
In order to produce nanoscale particles using spray drying tech-
nology, some modifications to the experimental setup of conventional
C. Arpagaus et al.
spray dryers are necessary. A significant constraint is the limited effi-
ciency of the separation and collection of submicron particles by cy-
clone separators. Typical cyclones are unable to collect particles below
2 µm (Bowen et al., 2013; Chan and Kwok, 2011; Heng et al., 2011; Maa
et al., 1998; Maltesen et al., 2008; Schmid et al., 2009). Even with high-
performance glass cyclones (Brandenberger, 2003), the median particle
size cannot be reduced below 1.4 µm (Maltesen et al., 2008). In other
words, particles of submicron size can only be collected to a very lim-
ited extent with conventional spray dryers. A feasible way to collect
nanoscale particles is to use electrostatic particle collectors (Arpagaus,
2011, 2010; Bürki et al., 2011; Heng et al., 2011; Li et al., 2010; Schmid
et al., 2011, 2009; Schön and Baumgartner, 2009). In addition, tradi-
tional atomizers do not allow the generation of very fine droplets in
order to achieve dried solid particles in the submicron range. Further-
more, a turbulent gas flow in the drying chamber may lead to increased
particle deposits on the chamber wall. Recent advances in nano spray
dryer technology and the introduction of the Nano Spray Dryer B-90 by
Büchi Labortechnik AG (Switzerland) in 2009 have made it possible to
produce submicron particles (Arpagaus, 2011; Arpagaus et al., 2017,
2010a, 2010b, Büchi Labortechnik, 2013, 2010). Fig. 3 shows a sche-
matic representation of the nano spray dryer and its functional princi-
ples.
The droplet generation is based on vibrating mesh technology,
which has been adapted from nebulizers used in aerosol drug delivery
(Dhand, 2002; Knoch and Keller, 2005; Lass et al., 2006; Smart et al.,
2002; Vecellio, 2006). A piezoelectric actuator vibrates a spray nozzle
at ultrasonic frequency (80–140 kHz). Attached to the nozzle is a small
replaceable spray cap, which comprises a thin perforated metal plate,
containing a series of tiny laser drilled holes. The piezoelectric vibration
leads to a fast upward and downward movement of the spray mesh,
thus ejecting millions of precisely sized droplets through the holes into
the drying chamber (glass cylinder, 80 cm height, 20 cm diameter). The
droplet size depends on the mesh size and the physicochemical prop-
erties of the fluid, such as viscosity and surface tension. Spray meshes
are available with 4.0, 5.5, and 7.0 µm hole diameters. With a 4.0 µm
spray mesh, water droplets of approximately 3–8 µm are produced
Fig. 4. Process parameters and formulation variables for a nano spray dryer (Arpagaus et al., 2017).
197
International Journal of Pharmaceutics 546 (2018) 194–214
(Arpagaus et al., 2017; Schmid, 2011; Schmid et al., 2011). The co-
current drying gas flow is heated up to the set inlet temperature (Tin)
and directs the submicron particles to the electrostatic particle col-
lector. The dried particles are electrostatically charged and collected at
the collecting electrode. At the same time, particle adhesion to the side
walls of the drying chamber is minimized, thus resulting in high particle
collection efficiency (Arpagaus, 2012; Lee et al., 2011). The flow of the
drying gas is laminar, which makes the system suitable for gentle drying
heat-sensitive products with a low risk of degradation or loss of activity.
The drying gas exits the spray dryer in a purified form and the outlet
temperature is measured.
A high voltage of 17 kV at the collecting electrode (electrical current
of a few 10 mA) enables the efficient recovery of submicron particles at
a separation efficiency greater than 99% for small solid batches of
10 mg–2.7 g (Arpagaus et al., 2010b; Arpagaus and Meuri, 2010; Bürki
et al., 2011; Lee et al., 2011; Li et al., 2010; Schmid, 2011; Schmid
et al., 2011, 2009). The electrostatic particle collector can even collect
thin-walled particles without breaking (Feng et al., 2011; Sun et al.,
2011). Finally, the particles are gently removed from the surface of the
collecting electrode by using a scraper. Variations in the yield may
occur due to the manual collection of the powder with a scraper. It is
recommended to recover the powder from the collecting electrode cy-
linder in a controlled and dry atmosphere, and to store the samples
afterward in glass vials inside a desiccator at room temperature for
further characterization to prevent crystallization and moisture uptake
(Schmid, 2011).
For aqueous feeds, the typical system configuration is an open mode
with air as drying gas. When using flammable organic solvents, a closed
mode operation with an Inert Loop B-295 (Büchi Labortechnik, 2010)
and solvent resistant tubing is applied. The Inert Loop B-295 separates
the organic solvents from the drying gas and provides safe and clean
handling of organic solvents during nano spray drying. Inert gases like
nitrogen and carbon dioxide are typically used as drying gases to pre-
vent the formation of an explosive gas mixture. The oxygen con-
centration is controlled below 4% and the inert gases are recirculated
throughout the entire circuit.
C. Arpagaus et al.
3. Formulation of drugs for nano spray drying and process
efficiency
Fig. 4 illustrates the main adjustable process parameters and for-
mulation variables for a nano spray dryer (marked black), as well as the
output parameters (marked grey). The most important input parameters
identified are the spray mesh size, the spray rate intensity, the solid
concentration, the polymer and surfactant concentrations, the drying
gas inlet temperature, the solvent type, and the drying gas flow rate.
Table 1 gives an overview of the main process parameters and their
influence on the output parameters (i.e. outlet temperature, droplet
size, feed rate) and final product properties (i.e. particle size, moisture
content, yield, stability). The thickness of each arrow illustrates the
strength of the related influence.
Of primary interest for pharmaceuticals are the effects on the par-
ticle size, morphology, product yield, productivity, encapsulation effi-
ciency, drug loading, drug release profile, and stability. Depending on
the application, an optimized set of process parameters is found. The
optimization of the process parameters is usually done by trial and
error. However, design of experiment (DOE) studies help to optimize
the nano spray drying process, as shown by several authors (Arpagaus
et al., 2017; Bürki et al., 2011; Draheim et al., 2015; Durli et al., 2014;
Gu et al., 2015; Harsha et al., 2017, 2013b; Lee et al., 2011; Li et al.,
2010; Littringer et al., 2013; Schafroth et al., 2012; Schoubben et al.,
2014).
DOE studies enable to determine the optimal process conditions
with fewer experiments, thereby reducing the cost of experiments and
material usage. Factorial experimental designs and the Taguchi method
are the main used statistical approaches. Bürki et al. (2011) in-
vestigated the effects of the inlet temperature of the drying air, the
ethanol content of the spray solution and the spray mesh on particle
size by a 33 full factorial design, focusing on nano spray drying a pro-
tein. For salbutamol, Littringer et al. (2013) studied the influence of
mesh size, feed concentration and drying air temperature on particle
size, product quantity per time and product yield with a 33 full factorial
design. Schoubben et al. (2014) developed inhalable capreomycin
powders with a desired particle diameter and highest yield using a 23
factorial design. Durli et al. (2014) evaluated the influence of the type
of organic solvent and surfactant on powder properties of anti-in-
flammatory dexamethasone using a 32 full factorial analysis design
composed of two variables at three levels. Gu et al. (2015) applied a
central 3-factor 5-level composite design to study the effects of polymer
concentration, inlet temperature and air flow on the yield, spray rate
and drying efficiency for the preparation of solid dispersions. More
recently, Harsha et al. (2017) optimized the nano spray drying process
for albumin particles loaded with salbutamol using a central composite
design. Analysis of variance (ANOVA) is typically used to determine the
statistical significance of each factor on individual responses. Lee et al.
(2011) applied the Taguchi design method (based on five variables and
three levels) to identify the dominant factors affecting the size and
Table 1
Influence of the main process parameters in nano spray drying ( / strong increasing/decreasing influence, ↑/↓ weak increasing/decreasing influence, – minimal or
no influence) ().
adapted from Arpagaus et al. (2017)
Process parameter Outlet temperature Droplet size Particle size
Drying gas flow rate↑ – –
Drying gas humidity↑ ↑ – – –
Inlet temperature↑ – ↑
Spray mesh size↑ ↓ –
Spray rate intensity↑ ↑ ↑
Circulation pump rate↑ – ↑ ↑ ↑
Solid concentration (viscosity)↑ ↑ –
Surfactant/stabilizer in feed↑ – ↓ ↓ ↑
Solvent instead of water ↓ ↓
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International Journal of Pharmaceutics 546 (2018) 194–214
morphology of nano spray dried bovine serum albumin particles.
As shown in Table 1, the key parameters controlling the final par-
ticle size are the spray mesh size (Baba and Nishida, 2013, 2012; Lee
et al., 2011) and the solid concentration (Lee et al., 2011; Li et al.,
2010; Schmid, 2011; Schmid et al., 2011, 2009). Smaller droplets are
favored by a higher viscosity, a lower surface tension, and a smaller
spray mesh (Beck-Broichsitter et al., 2012; Bürki et al., 2011; De Cicco
et al., 2014; Lee et al., 2011; Littringer et al., 2013). The submicron
particle size region is typically reached when using a 4.0 µm spray mesh
and diluted solutions of 0.1–1% (w/v). Further reduction of particle
size is possible by further dilution, as demonstrated in several studies
(Baba and Nishida, 2013; Beck-Broichsitter et al., 2015a, 2012; Lee
et al., 2011; Li et al., 2010; Nandiyanto and Okuyama, 2011; Ngan
et al., 2014; Pérez-Masiá et al., 2015). The typical organic solvents used
in nano spray drying of pharmaceuticals are:
• dichloromethane (DCM) (Beck-Broichsitter et al., 2012; Bege et al.,
2013; Dahili et al., 2015; Dahili and Feczkó, 2015; Draheim et al.,
2015; Panda et al., 2014; Schafroth et al., 2012),
• acetone (Beber et al., 2014; Beck-Broichsitter et al., 2015b; Draheim
et al., 2015; Durli et al., 2014; Fontana et al., 2014; Gu et al., 2015;
Li et al., 2010; Perecin et al., 2015),
• ethanol (Baba and Nishida, 2013, 2012; Bürki et al., 2011; Maged
et al., 2017; Zellnitz et al., 2015a),
• methanol (Basran, 2017; Öztürk et al., 2017, 2015; Schmid, 2011;
Suryaprakash et al., 2014),
• acetonitrile (Amsalem et al., 2017; Denora et al., 2016),
• ethylacetate (Draheim et al., 2015), and
• mixtures thereof with water (Aquino et al., 2014; Dimer et al.,
2015a; Kaewjan and Srichana, 2016; Martena et al., 2012a;
Schoubben et al., 2015, 2013a; Son et al., 2013b).
The selection of the organic solvent is based on the solubilization of
the drug and the encapsulating wall materials. The mixing ratio is ad-
justed to allow the complete dissolution of the compounds (Schoubben
et al., 2013a). For example, acetone–water mixtures dissolve steroidal
dexamethasone well, and the low viscosity of the acetone allows higher
flow rates through the vibrating spray mesh, which shortens the pro-
cessing time (Fontana et al., 2014). Compared to water, organic sol-
vents generate slightly smaller droplets due to their lower surface
tension, viscosity, and density (Suryaprakash et al., 2014). In addition,
organic solvents enable lower drying temperatures because of the lower
boiling points. Dichloromethane (40 °C) or acetone (56 °C) lead to fast
drying and prevent particles from sticking to the walls or agglomer-
ating. The evaporation temperature is lower than the melting tem-
perature or the glass transition temperature of certain polymers. A
drawback of toxic solvents (such as methanol or chloroform) is the
potential residual content in the final product as an impurity. Poly
(lactic-co-glycolic acid) (PLGA) is one of the most commonly used
materials for spray dried biomedical applications due to its well
Feed rate Moisture content Yield Stability
– – –
↓ –
– ↓ ↑
– ↑
↑ –
– – ↑
↓ ↑ –
– ↑
↑ ↑ –
C. Arpagaus et al.
established biocompatibility and biodegradability (Arpagaus and
Schafroth, 2009, 2007). As an example, the optimum inlet drying
temperature of PLGA dissolved in dichloromethane is in the range of
29–32 °C (Schafroth et al., 2012). For water applications, the outlet
temperatures range between 28 and 59 °C (Arpagaus et al., 2017),
which makes nano spray drying a very suitable process for heat-sensi-
tive drugs (Amsalem et al., 2017; Aquino et al., 2014; Heng et al.,
2011). The outlet gas temperature is mainly controlled by the inlet
drying gas temperature, the drying gas flow rate, and the fluid feed rate
(Arpagaus et al., 2017). In a spray dryer, the droplet temperature rises
initially to the saturated wet-bulb surface temperature, remains con-
stant during evaporation, and approaches the temperature of the sur-
rounding gas at the dryer outlet. A lower drying gas flow rate leads to a
lower outlet temperature. A smaller feed rate increases the outlet
temperature because less fluid is evaporated over the same period of
time (Beck-Broichsitter et al., 2015b; Littringer et al., 2013). A higher
inlet temperature reduces the relative humidity of the drying gas and
forms particles with less moisture content leading to a drier powder
with less stickiness onto the drying chamber. Considering electrostatic
interactions, at higher zeta potentials, more repulsion of particles will
occur resulting in less stickiness. Residual moisture contents of lower
than 0.5% in mannitol and 2–5% in trehalose powders have been ob-
served (Schmid, 2011). To achieve a final product with low residual
moisture contents, the inlet temperature needs to be set as high as
possible and the difference in temperatures of the inlet and the outlet
has to be as small as possible (Arpagaus et al., 2013). The drying times
for water droplets in a nano spray dryer are in the order of 10 ms, as-
suming 7 µm droplets, 75 °C drying temperature and 100 L/min drying
air flow rate (Feng et al., 2011).
The feed rate increases primarily with the spray mesh size, the
setting of the relative spray rate intensity, the recirculation pump rate,
and it depends on the feed formulation (i.e. the substance, the solid
concentration, the solvent type, and the addition of surfactant). For
pure water, the specified feed rates are in the ranges of 10–20, 25–50,
and 80–150 mL/h for a 4.0, 5.5, and 7.0 µm spray mesh, respectively
(Büchi Labortechnik, 2010). When using an aqueous substance and a
4.0 µm spray mesh, the feed rates may vary in a range of about
3–25 mL/h (Arpagaus et al., 2010b; Li et al., 2010; Schmid, 2011;
Schmid et al., 2011; Sun et al., 2011). With a 5.5 µm spray mesh and
0.1% (w/v) chitosan in 1% (v/v) acetic acid, feed rates up to about
50 mL/h were measured by Gautier et al. (2010). Generally, a higher
solid concentration results in a lower feed rate (Beck-Broichsitter et al.,
2015b; Gu et al., 2015; Schmid, 2011; Schoubben et al., 2013a). The
addition of organic solvents to the water tends to increase the feed
rates, which can be attributed to the lower surface tensions. The further
admixture of a small amount of surfactant (e.g. Tween) into the feed
may also improve the throughput, as reported for example by Schmid
et al. (2011) for trehalose solutions. The added surfactant leads to a
reduction of the surface tension and the formation of a more uniform
spray. This is also a strategy to reduce the stickiness of atomized dro-
plets and to produce of a spray with smaller droplets. A lower relative
spray rate intensity reduces the feed rate almost linearly (Beck-
Broichsitter et al., 2015b). Moreover, a faster circulation rate of the
peristaltic pump increases the fluid pressure on the spray mesh, thus
increasing the initial droplet size and consequently the feed rate
(Suryaprakash et al., 2014).
The morphology of particles prepared by nano spray drying depends
on the drying conditions and the feed properties. Dense, hollow,
porous, and encapsulated structures with spherical, wrinkled, shriveled,
or even doughnut-like shapes are possible (Arpagaus et al., 2017). In
general, slow drying yields more compact particles, while fast and high
temperature drying leads to the formation of more hollow particles with
a thin shell (Feng et al., 2011; Kaewjan and Srichana, 2016; Nandiyanto
and Okuyama, 2011; Sun et al., 2011). Surface-active compounds in the
formulations, such as leucine also promote the formation of hollow
particles (Feng et al., 2011). The smoothness and sphericity of the
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International Journal of Pharmaceutics 546 (2018) 194–214
particles have been optimized by several researchers (Bürki et al., 2011;
Li et al., 2010; Schmid, 2011; Schmid et al., 2011, 2009) through
adding surfactants, which balance the surface-to-viscous forces inside
the drying droplet and enable the formation of a smooth spherical
surface on the dry particle. More corrugated surfaces are observed for
example for pure dexamethasone without an encapsulating polymer
(Fontana et al., 2014), or levofloxacin encapsulated in chitosan
(Merchant et al., 2014). Shriveled (Harsha, 2015) and wrinkled (Torge
et al., 2017) particles are obtained from surfactant-free formulations
(Lee et al., 2011) and are more likely for larger particles (Bürki et al.,
2011). Doughnut-like particles are the result of hydrodynamic effects
and the loss of structural stability of the sprayed droplets (Dahili et al.,
2015; Lee et al., 2011). Composite particles, formed from suspensions
prior to the nano spray drying, consist of agglomerated nanoparticles,
which give rise to a high specific surface area (Beck-Broichsitter et al.,
2012). Torge et al. (2017) embedded PLGA nanoparticles in a mannitol
matrix. The encapsulated nanoparticles may preserve their integrity,
specific properties, redispersibility, enhanced solubility, and targeting
capacity (Sarma et al., 2014).
As shown in several studies, the nano spray drying process itself has
a negligible or only a marginal impact on the product degradation or
aggregation. Schultz et al. (2015) showed that the activity of insulin-
like growth factor encapsulated in trehalose remained unaffected.
Schmid (2011) detected a slight reduction in L-lactic dehydrogenase
enzyme activity during pump circulation. An option to minimize the
risk of activity loss during the nano spray drying process is to cool the
feed vessel in ice (Amsalem et al., 2017; Schoubben et al., 2013a; Torge
et al., 2017) or to use a larger spray mesh to reduce the mechanical
shear of atomization, as shown by Bürki et al. (2011) with β-galacto-
sidase enzyme. After nano spray drying, the activity of the encapsulated
product is preserved if the powder is stored under controlled conditions
and if a stabilizer is added into the feed formulation. Most nano spray
dried powders tend to be amorphous due to the too short drying time to
form crystalline structures. Examples include salbutamol (Chan and
Kwok, 2011; Littringer et al., 2013), albuterol in mannitol (Son et al.,
2013a) and trehalose (Schmid, 2011; Schmid et al., 2011), levofloxacin
in chitosan (Merchant et al., 2014), or clozapine-risperidone in PLGA
(Panda et al., 2014). To prevent recrystallization of amorphous drugs,
the powders are stored under dry conditions (Littringer et al., 2013;
Pinto et al., 2017; Zellnitz et al., 2015a). Bürki et al. (2011) showed that
nano spray dried β-galactosidase enzyme in trehalose lost only 3% of its
activity during three weeks of storage at 70 °C. Dahili and Feczkó
(2015) enhanced the activity of peroxidase enzyme by immobilization
in ethylcellulose and PLGA. Pérez-Masiá et al. (2015) observed bioac-
tive stability of folic acid (vitamin B9) in whey protein after 60 days
under dry storage conditions and in darkness. Merchant et al. (2014)
found no evidence of changes in the crystallinity of chitosan powder
after storage for 60 days at room temperature and ambient humidity.
Martena et al. (2012a) did not observe any changes in the physical
properties of amorphous nano spray dried blood pressure regulation
nicergoline at accelerated storage conditions (60% RH, 25 °C) during
the testing period of 6 months. The amorphous form was stable for at
least a period of 1 year when stored at 3 °C. Also, De Cicco et al. (2014)
conducted accelerated storage stability tests of antibacterial gentamicin
in alginate-pectin powders at 40 °C and 75% relative humidity. The
drug was preserved for 6 months. Finally, Harsha (2013) kept nano-
particle formulations of antibiotic amoxicillin stable for 24 months at
25 °C and 60% RH.
4. Nanoencapsulation of various drugs by nano spray drying
Nano spray drying has received a widespread application in the
formulation of pharmaceutical dosage forms to transform solutions,
suspensions, emulsions, liposomes, and others liquid feeds into a dry
solid submicron powder. Since the market introduction of the Nano
Spray Dryer B-90 by Büchi Labortechnik AG (Switzerland) in 2009,
C. Arpagaus et al. International Journal of Pharmaceutics 546 (2018) 194–214

there have been a great number of research papers published (at least
over 160) in the field of nano spray drying of pharmaceuticals. This

Beck-Broichsitter et al. (2012)

Beck-Broichsitter et al. (2012)
Schmid (2011), Schmid et al.
section reviews the accumulated application experience. Different wall
materials (excipients) applied in nano spray drying of pharmaceuticals

Draheim et al. (2015)

has been listed in Table 2. Table 2 also summarizes the process para-

Gautier et al. (2010)

Dahili et al. (2017)

Torge et al. (2017)
Feng et al. (2011)
Blasi et al. (2010)
meters for pure excipients used as dispersing agents, binders and sta-

Gu et al. (2015)
Li et al. (2010)
bilizers (Beck-Broichsitter et al., 2012; Blasi et al., 2010; Dahili et al.,

(2011, 2009)
References
2017; Draheim et al., 2015; Feng et al., 2011; Gautier et al., 2010; Gu
et al., 2015; Li et al., 2010; Schmid et al., 2009; Schmid, 2011; Schmid
et al., 2011; Torge et al., 2017). This includes numerous compounds,
such as:

Product yield
• water-soluble carbohydrates (i.e. Arabic gum, alginate, chitosan,
cyclodextrin, cellulose derivatives, modified starch, maltodextrin,

43–95

50–78

60–85

75–91
> 90

n.a.

n.a.

n.a.
n.a.
n.a.
n.a.
(%)
pectin, mannitol, lactose trehalose),
• proteins (i.e. gelatin, serum albumin, whey protein, sodium case-
inate, silk fibroin, leucine),
•

Solid sample amount

water-soluble synthetic polymers (i.e. poly(vinyl alcohol), poly
(ethylene glycol) or poly(acrylic acid) (Carbopol)),
• hydrophobic synthetic polymers (i.e. poly(lactic-co-glycolic acid),

1’080–1’350
poly(ε-caprolactone), poly(vinyl pyrrolidone), Kollidon, Eudragit),

30–300

10–50
and

(mg)

800
n.a.

n.a.

n.a.

n.a.
n.a.
n.a.
n.a.
•
Different wall materials (excipients) which have been applied in encapsulation of pharmaceuticals by nano spray drying (n.a. = not available).
fats (i.e. stearic acid and glyceryl behenate (Compritol)).

In this paper, published studies on nano spray dried pharmaceu-

Particle size
ticals have been structured according to the following routes of ad-

1.0–16.0

2.0–10.0
0.2–1.1

0.4–1.2
0.3–3.0

2.1–5.4

1.1–7.2

0.6–1.6
2.8–4.4
0.3–1.7

2.4–8.0
ministration:
(µm)
• Pulmonary
• Oral
Drying gas (L/

100 (N2/CO2)
115 (N2/CO2)
• Intravenous
• Topical

90–120
• Ophthalmic
min)

100

100
115

100

140

130
100
100
• Intraperitoneal
• Intravesical
T out (°C)

• Cerebral
38–60

30–45

32–39

20–30
20–30

29–36
n.a.

n.a.

n.a.
45

55
The experimental process parameters for nano spray drying (i.e.
T in (°C)

60–100

30–50
30–50

50–90

36–68
inlet and outlet drying temperatures, drying gas flow) have been
100

110

120

n.a.
75

80

summarize in the relevant Tables for the following sections which can
be used as first guess values for applying the nano spray dryer to
Dichloro-methane (DCM)

identical or similar substances. In addition, there are many applications

Acetone, Ethylacetate,

of nano spray dried particles containing drugs and excipients for the
Water, Acetic acid

treatment of various diseases, including:

• tuberculosis,
Acetone

• asthma,
Solvent

Water

Water
Water

Water

Water

DCM,
DCM
DCM

• inflammation,
• cystic fibrosis,
Nanosuspension of mannitol and poly(lactic-co-glycolic acid)
Leucine (Aminoacid, dispersing agent), Trehalose (Stabilizer,

• diabetes,
Arabic gum, whey protein, maltodextrin, polyvinyl alcohol

• Alzheimer’s and Parkinson’s diseases,

Hypromellose (Hydroxypropyl-methylcellulose, for oral
Trehalose, mannitol or disodium phosphate surfactant,

• fungal infection,
Encapsulation wall materials (excipient), application

• ophthalmic disorders,
• cancer,
PLGA and stabilizers (Poloxamer, surfactant)

• high blood pressure,

• congestive heart failure,
• edema
Chitosan (Biopolymer, fat blocker)
Sodium alginate (Polysaccharide)

PLGA (Biodegradable polymer)

PLGA (Fine carrier supports)

and others, thus underlining the versatility of the nano spray drying
and modified starch

increases shelf life)

technology to develop nanomedicines.

As can be seen in the following sections, the organic solvents used to
medicaments)
PLGA suspensions
polysorbate

dissolve poorly water soluble drugs are mainly ethanol, methanol,

(PLGA)

acetone, ethylacetate, and dichloromethane. With highly diluted solu-

tions containing 0.1–1% (w/v) solids concentrations, finest solid par-
Table 2

ticles down to 100 nm can be obtained by nano spray drying. Pure drug
particles in the nanosize dimensions and the amorphous state offer

200
 Table 3
Published studies on nano spray dried drug delivery applications by pulmonary (lung) route (Drug loading (%) = Amount of drug in particles/Mass of particles; Encapsulation efficiency (%) = Amount of drug in
particles/Initial drug amount; n.a. = not available; – = not relevant).
Type of drug, application, wall material (excipient) Solvent T in (°C) T out (°C) Drying gas Particle size Solid sample Product Drug Encap-sulation References
C. Arpagaus et al.

(L/min) (µm) amount (mg) yield (%) loadi- efficiency (%)

ng
(%)

Bacitracin (Polypeptide antibiotic) Water 100–120 n.a. n.a. 3.1–6.6 20–200 18–82 – Schoubben et al. (2014)
Ciprofloxacin and gatifloxacin (Antiinflammatory, antibacterial) Water 120 40–45 100 (N2) 0.8–3.6 n.a. 70–80 Lee et al. (2013)
Ethambutol dihydrochloride (Antituberculosis drug for inhalation) Water 110 n.a. n.a. 0.2 n.a. n.a. Ahmad et al. (2014)
mixed with chitosan carrier particles
Salbutamol sulfate (Asthma) Water, 80–120 40–50 110 1.0–6.4 25–2’500 41–90 Faulhammer et al. (2018,
Ethanol 2015), Littringer et al. (2013),
Zellnitz et al. (2015a,b, 2014)
Salbutamol sulphate (Asthma) Water 120 49 110 0.6–7.6 n.a. n.a. Pinto et al. (2017)
Alkaline phosphatase (Model protein for β-cyclodextrin, L-leucine Water n.a. n.a. n.a. ∼1 n.a. n.a. n.a. n.a. Guo and Li (2013)
pulmonary delivery)
Amoxicillin (Antibiotic to treat Chitosan nanosuspension Water, Acetic 120 80 120 0.2–1.2 n.a. n.a. 90 n.a. Nguyen et al. (2017)
pneumococcal disease) by ionic gelation acid
Azithromycin (Antibiotic to treat cystic Mannitol, Leucine, Sodium Water 80 45 120 1.0–5.0 500 n.a. 30–40 n.a. Hindle et al. (2015)
fibrosis) chloride
Bovine serum albumin (Model protein Surfactant, Water 80–120 36–55 150 0.5–2.6 n.a. 68–76 n.a. n.a. Lee et al. (2011)
derived from cows) Polyoxyethylene, Sorbitan
monoleate
Capreomycin (Pulmonary tuberculosis) Leucine Ethanol, 80–120 n.a. 100 1.0–5.0 20–200 71–82 10–21 n.a. Schoubben et al. (2015, 2014,
Acetone, 2013a,b)
Water
Ciprofloxacin (Antibiotics) Mannitol, L-leucine, Water, 70 40 120 0.5–5.0 n.a. 50–60 n.a. n.a. Farkas et al. (2015), Longest

201
Poloxamer Ethanol et al. (2015)
Clarithromycin (Antibacterial to treat Leucine, Chitosan Water, 80 n.a. 120 0.3–2.5 150 58–63 35–37 n.a. Dimer et al. (2015a)
lung infections) Ethanol
Cyclosporin (Immune system PLGA DCM, Ethanol 29–32 28–32 102–132 0.9–2.2 600 20–56 13–14 38–41 Schafroth et al. (2012)
suppressant) (N2/CO2)
Dexamethasone (Steroid, anti- PLGA DCM, Ethanol 29–30 30–32 111–132 0.9–1.7 600 32–54 21–27 62–81 Schafroth et al. (2012)
inflammatory) (N2/CO2)
Dexamethasone (Steroid, anti- Poly(ε-caprolactone), Acetone 55 34 110 0.6–1.6 210 65–80 43 93–97 Fontana et al. (2014)
inflammatory) Deoxycholate Water
Fluticasone propionate (Asthma) Lactose Water 120 45–56 130 0.5–3.0 2’700 77 10 n.a. Arpagaus et al. (2010b)
β-galactosidase (Enzyme catalyzing Trehalose Water 80 36–53 100–110 1.0–5.0 500 60–94 n.a. n.a. Bürki et al. (2011)
hydrolysis of saccharides)
Insulin-like growth factor I (Anabolic Trehalose, Silk-fibroin, Water 70 n.a. 115–130 0.3–3.2 n.a. n.a. 74 93 Schultz et al. (2015)
peptide) Polysorbate
Ketoprofen lysinate (Anti-inflammatory Leucine Water, 60–110 n.a. 100 2.4–6.6 n.a. 21–90 n.a. n.a. Aquino et al. (2014)
to treat cystic fibrosis) Isopropyl-
alcohol
Levofloxacin (Antibiotic to treat lung Chitosan, L-leucine Water 120 n.a. 133 2.5–4.6 525 51–79 77–93 n.a. Merchant et al. (2014)
infections)
Methotrexate (Lung cancer) Carbopol (Poly(acrylic Water 85–115 30–50 n.a. 6.8 n.a. 77 89 n.a. Harsha et al. (2015a)
acid))
Phospholipid dispersions (Liposome) Trehalose, Egg, Lecitin Water 60–120 44–47 90–140 0.7–9.1 4’000–50’000 70 n.a. n.a. Brinkmann-Trettenes et al.
(2014)
Pyrazinamide (Anti-tuberculosis) L-leucine Water Ethanol 90–115 n.a. 100 2.8–3.8 n.a. n.a. n.a. n.a. Kaewjan and Srichana (2016)
Resveratrol (Pulmonary arterial Poly(ε-caprolactone), Acetone, 55 n.a. 110 (N2, 1.0–5.0 300 71–88 31 99 Dimer et al. (2015b)
hypertension) Sodium deoxycholate, Water CO2)
Trehalose
Sildenafil (Pulmonary arterial PLGA Acetone 45 25–30 100 (N2, 4.0–11.0 400–1’600 n.a. n.a. n.a. Beck-Broichsitter et al.
hypertension) CO2) (2015a)
(continued on next page)
International Journal of Pharmaceutics 546 (2018) 194–214
C. Arpagaus et al. International Journal of Pharmaceutics 546 (2018) 194–214

better absorption rates and higher bioavailability (Lee et al., 2011;

Behara et al. (2014a,b,c), Son

Martena et al., 2012a; Rascioni et al., 2016), and encourage future

Arpagaus et al. (2010b)

developments in this research field. Nanocapsules, with their reduced

Behara et al. (2014b)

size and large specific surface area provide pronounced improvement in

Yang et al. (2015)

et al. (2013a,b)
controlled drug release and bioavailability (Sithole et al., 2017). This
enables the generation of target drug delivery systems (Arpagaus, 2011;
References

Harsha et al., 2015a; Li et al., 2010). Under optimized conditions, un-

iquely high product yields of about 76–96% can be achieved to process
small sample amounts in the range of 10 mg–2.5 g. Variations in the
yield may occur due to particle depositions around the spray cap
Encap-sulation
efficiency (%)

(Amsalem et al., 2017; Brinkmann-Trettenes et al., 2014; Schmid et al.,

2011) and the chamber walls (Brinkmann-Trettenes et al., 2014; Bürki
et al., 2011; Lee et al., 2011), nozzle blockage (Schmid, 2011; Schmid
n.a.
n.a.

n.a.
n.a.

et al., 2011), or due to losses during the manual collection of the

loadi-

powder with a rubber spatula (Al-Dhubiab, 2013; Harsha et al., 2017).

Drug

12.5

n.a.
(%)

30

30
ng

However, the ability to process small sample amounts makes a nano

spray dryer very suitable for testing valuable biological materials such
yield (%)

as for example monoclonal antibodies, recombinant proteins, or siRNA-

Product

50–60

50–60

based therapeutics (Amsalem et al., 2017; Heng et al., 2011; Schmid,

n.a.
70

2011; Schoubben et al., 2014). Moreover, nano spray drying enables

the encapsulation of drugs in polymers with a high efficiency of over
95% and adjustable drug loading, as shown by several studies in the
amount (mg)
Solid sample

next titles.
2’000
n.a.

n.a.
n.a.

4.1. Pulmonary (lung)

Particle size

A major advantage of nano spray drying is the optimization of the

particle size and morphology for pulmonary drug delivery, as demon-
0.5–3.0
0.5–4.0

0.5–4.0
(µm)

strated by many studies listed in Table 3. There has been significant

0.9

research activity in the formulation of dry powder aerosols for the

treatment of lung diseases, such as:
Drying gas
(L/min)

• asthma with salbutamol (Arpagaus et al., 2010b; Behara et al.,

130
120

120
n.a.

2014a,b,c; Faulhammer et al., 2018, 2015; Littringer et al., 2013;

Pinto et al., 2017; Son et al., 2013a; Yang et al., 2015; Zellnitz et al.,
T out (°C)

2015a,b, 2014), terbutaline (Behara et al., 2014b), or fluticasone

52–56
40–45

n.a.

(Arpagaus et al., 2010b)

40

• inflammation by dexamethasone (Schafroth et al., 2012),

•
T in (°C)

pulmonary arterial hypertension with resveratrol (Dimer et al.,

70–85

2015b) or sildenafil (Beck-Broichsitter et al., 2015a),

120

n.a.

•
70

cystic fibrosis with ketoprofen (Aquino et al., 2014) or azithromycin

(Hindle et al., 2015),
• lung cancer with methotrexate (Harsha et al., 2015a),
•
Ethanol

Ethanol
Solvent

tuberculosis with capreomycin (Schoubben et al., 2015, 2014,

Water,

Water,
Water

n.a.

2013a, b), ethambutol (Ahmad et al., 2014), or pyrazinamide

(Kaewjan and Srichana, 2016), and
• bacterial infections with amoxicillin (Nguyen et al., 2017), cipro-
floxacin (Farkas et al., 2015; Lee et al., 2013; Longest et al., 2015),
Mannitol, L-leucine,

Mannitol, L-leucine,

gatifloxacin (Lee et al., 2013), clarithromycin (Dimer et al., 2015a),

Lactose, Leucine

or levofloxacin (Merchant et al., 2014).

Poloxamer

Poloxamer
Type of drug, application, wall material (excipient)

The selection of a suitable matrix excipient is essential for the en-

Lactose

capsulation of drugs by nano spray drying to achieve the desired de-

composition of the particles and the drug release in the lungs. Mannitol,
chitosan, leucine, lactose, and trehalose are widely used due to their
high aqueous solubility and low toxicity. The hygroscopic excipient
mannitol is especially advantageous for the treatment of bacterial in-
Salbutamol (Albuterol) (Asthma)

fections in cystic fibrosis (Hindle et al., 2015; Torge et al., 2017).

Terbutaline sulfate (Asthma)
Salbutamol sulfate (Asthma)

Salbutamol sulfate (Asthma)

Chitosan offers several advantages for mucosal delivery, such as low

toxicity and good biodegradability as well as antibacterial activity
Table 3 (continued)

(Cerchiara et al., 2015; Dimer et al., 2015a; Merchant et al., 2014; Ngan
et al., 2014; Nguyen et al., 2017; Rampino et al., 2013). Leucine is a
very popular dispersion enhancer to increase the flowability of nano
spray dried particles, as shown in various pulmonary drug delivery
studies (Aquino et al., 2014; Behara et al., 2014a, 2014b, 2014c; Dimer
et al., 2015a; Feng et al., 2011; Guo and Li, 2013; Kaewjan and

202
 Table 4
C. Arpagaus et al.

Different studies on nano spray dried drug delivery applications by oral (gastrointestinal) route (Drug loading (%) = Amount of drug in particles/Mass of particles; Encapsulation efficiency (%) = Amount of drug in
particles/Initial drug amount; n.a. = not available; – = not relevant).
Type of drug, application, wall material (excipient) Solvent T in (°C) T out (°C) Drying gas Particle size Solid sample Product Drug Encap-sulation References
(L/min) (µm) amount (mg) yield (%) loading (%) efficiency (%)

Dexamethasone (Steroid, anti-inflammatory) with poloxamer and Ethanol Acetone 55 n.a. 110 0.4–1.2 500 4–74 – Durli et al. (2014)
surfactants Propanol
Furosemide (Diuretic to treat congestive heart failure and edema) Acetone 100 n.a. 100 (N2/ 0.7–1.7 n.a. 69 Li et al. (2010)
CO2)
Griseofulvin (Antifungal) Methanol, 70 40–45 120 (N2) 3.4–6.5 n.a. n.a. Schmid (2011),
Acetone Schmid et al. (2011)
Indomethacin (Anti-inflammatory, reducing pain and fever) Water, Ethanol 50 n.a. 90 0.6 n.a. n.a. Martena et al.
(2012b)
Nimesulide (Anti-inflammatory, reducing pain and fever) Ammonia 90 n.a. 85 0.2–2.5 n.a. ∼90 Rascioni et al. (2016)
Mecigestone (Steroidal progestin, hormone therapy, treatment of DCM 40 34 135 (N2/ < 10 500 n.a. Nazarov et al. (2016)
gynecological disorders) CO2)
Nicergoline (Blood pressure regulation, blood vessels dilating) Water, Ethanol 50 n.a. 90 0.5–1.6 ∼1’000 91–93 Martena et al.
(2012a)
Dextrans (Model to regulate release Silica particles formed via sol–gel Water 120 58 120 ∼2 n.a. n.a. n.a. n.a. Wang and Friess
kinetics) processing (2017)
Acyclovir (Antiviral and antiherpes Hyaluronic acid, poly(acrylic Water, DCM 85 n.a. n.a. < 0.5 n.a. 75 22 85 Sithole et al. (2017)
agent) acid), hydroxypropyl-cyclodextrin
Amoxicillin (Antibacterial, stomach Gelatine, Carbopol Water 80–120 n.a. n.a. 0.1–0.8 500 64–93 89–93 n.a. Harsha (2013, 2012)
infections, Helicobacter pylori)

203
Curcumin (Antioxidant) loaded solid Compritol ATO 888, Sodium Water 100 n.a. 120 0.5–1.0 n.a. n.a. n.a. n.a. Wang et al. (2016c)
lipid nanoparticles (SLNs) caseinate (Emulsifier), Pectin
(Stabilizer)
Curcumin (food additive, skincare, Stearic acid, Sodium caseinate, Water 100 n.a. 120 0.5–1.0 n.a. n.a. n.a. n.a. Xue et al. (2017b)
natural dye) loaded SLNs Pectin
Curcumin in egg yolk low density Pectin Water 70–120 50–60 120 0.5–1.5 n.a. n.a. n.a. n.a. Zhou et al. (2016)
lipoprotein nanogels
Curcumin in cross-linked egg yolk low Pectin, Carboxymethyl cellulose Water 100 n.a. 120 ∼1 n.a. n.a. n.a. n.a. Zhou et al. (2018)
density lipoprotein nanogels (CMC)
Dexketoprofen Trometamol (Anti- Kollidon (polyvinyl Methanol 120 54 n.a. 0.1–0.7 1’000 n.a. n.a. 36–51 Öztürk et al. (2017,
inflammatory, analgesic delivery) polypyrrolidone), Eudragit 2015)
Eugenol oil nanoemulsion Gum arabic, Lecithin Water, Ethanol 100 n.a. 100–110 0.2–0.5 n.a. n.a. n.a. n.a. Hu et al. (2016)
(Antimicrobial)
Metformin hydrochloride Carbopol Water 100 35 100–110 0.2–0.4 500 74 89 n.a. Harsha (2015)
(Antidiabetic, mucoadhesive)
Nanosuspensions of crosslinked Poly(vinyl alcohol) (PVA) Water 100 n.a. 100 0.1–0.3 n.a. n.a. n.a. n.a. Moshe et al. (2017)
polymeric micelles (Lipophilic
drugs)
Nanoemulsion of peppermint oil Sodium caseinate, Propylene Water 100 n.a. 120 1.0–2.0 n.a. n.a. n.a. n.a. Wang et al. (2016d)
(Antimicrobial), vitamins, glycol, Pectin
minerals, amino acids
Selegiline (Parkinson's disease, Gelatin Water 120 27 100–110 0.1–0.2 n.a. 86–93 98 97–99 Al-Dhubiab (2013)
depression)
Sitagliptin (Antidiabetic, Carbopol Water 80–120 n.a. n.a. 2.0–8.0 500–2’000 64–92 73 n.a. Harsha et al. (2013b)
mucoadhesive)
(continued on next page)
International Journal of Pharmaceutics 546 (2018) 194–214
C. Arpagaus et al. International Journal of Pharmaceutics 546 (2018) 194–214

Srichana, 2016; Merchant et al., 2014; Schoubben et al., 2014, 2013a,

Harsha et al. (2015b,

Wang et al. (2016b)
Wang et al. (2016a)
Xue et al. (2017a)
2013b, 2015; Son et al., 2013a; Yang et al., 2015). The ideal aero-

Cerchiara et al.

Harsha (2015),
dynamic particle diameter for efficient delivery into the deep lung is
about 1–5 µm, which allows penetration and deposition in the alveolar
References

2013a)
regions. Too large particles deposit in the throat and excessively small

(2015)
particles are exhaled. Compared to oral administration, the high bioa-
vailability in the lungs enables a reduction of drug doses, which leads to
a decrease in systemic side effects and benefits patient compliance
Encap-sulation
efficiency (%)

(Kaewjan and Srichana, 2016).

To improve the flowability and the dosing accuracy of nano spray
68–76

dried drug particles in dry powder inhalers, glass beads in the size range
n.a.

n.a.

n.a.

n.a.

of 400–600 µm (Zellnitz et al., 2015b, 2014) or coarse lactose

loading (%)

(60–240 µm) (Faulhammer et al., 2018, 2015) and mannitol (160 µm)
(Pinto et al., 2017) powders are often used as larger carrier particles.
52–64

71–89
Drug

During inhalation, the smaller drug particles separate from the carrier
n.a.

n.a.

n.a.

particles and are deposited in the alveoli (Arpagaus et al., 2010b).

Another recently proposed strategy to achieve almost complete
yield (%)

pulmonary deposition utilizes the hygroscopic growth of inhaled par-

Product

74–88

71–96

ticles in the airways. Nano spray dried powders made of albuterol,

n.a.

n.a.

n.a.

mannitol, L-leucine and poloxamer with an aerodynamic diameter of

about 1.5 μm are considered optimal for delivering a high drug payload
amount (mg)
Solid sample

(Son et al., 2013a,b). Inside the humid airways, the particles take up
100 - 2′000

water and become larger. With this approach, fine particle fractions
(< 5 μm) of 95% are reached. Other studies with asthma drug terbu-
400
n.a.

n.a.

n.a.

taline sulfate (Behara et al., 2014b), antibiotics such as ciprofloxacin

(Farkas et al., 2015; Longest et al., 2015), and anti-inflammatory azi-
Particle size

1.0–10.0

thromycin (Hindle et al., 2015) further demonstrate the feasibility of

0.5–0.8

3.0–5.0

0.4–0.5

0.1–0.6

this enhanced excipient-growth approach.

(µm)

4.2. Oral (gastrointestinal)

Drying gas

100–110
(L/min)

In view of the increasing number of poorly water-soluble drugs,

120

120

120

n.a.

optimizing oral bioavailability remains a major challenge for the

pharmaceutical industry. The formulation of poorly soluble active
T out (°C)

pharmaceutical ingredients as nanosized amorphous solids or en-

27–35
n.a.

n.a.

n.a.

capsulated in a water-soluble polymer matrix has become preferred

40

approaches in recent years.

T in (°C)

Several studies have been conducted to generate nano spray dried

100

100

100

120

oral dosage forms for immediate and sustained drug release, as shown
80

in Table 4. Nano spray drying is suitable for the direct conversion of

pure, poorly water-soluble drugs into dry submicron powders from
organic solutions without wall materials, as shown for example in the
case of diuretic furosemide (Li et al., 2010), pain reducing nimesulide
Solvent

Water

Water

Water

Water

Water

(Rascioni et al., 2016), blood vessels dilating nicergoline (Martena

et al., 2012a), fever reducing indomethacin (Martena et al., 2012b),
anti-inflammatory dexamethasone (Durli et al., 2014), or steroidal
Stearic acid, Sodium Caseinate,

Pectin, Gum Arabic, Alginate,

hormone mecigestone (Nazarov et al., 2016). By nano spray drying,

Compritol ATO 888, Sodium

Rascioni et al. (2016) decreased the particles of nimesulide from 2.9 to

1.4 µm and the degree of crystallinity to 67%. Martena et al. (2012b)
Gelatine, Carbopol

reduced the mean particle diameter of indometacin from 9.2 to 0.6 µm

Caseinate, Pectin

with a crystallinity degree of about 45%, which led to an increase in

Type of drug, application, wall material (excipient)

drug dissolution. The nano spray dried mecigestone particles prepared

Chitosan

by Nazarov et al. (2016) were 7.5 times more bioavailable after oral
Pectin

CMC

administration to laboratory white rats than the starting 200 μm sized

crystalline drug. Durli et al. (2014) showed for dexamethasone dis-
Solid lipid nanoparticles (SLNs) layer-

solved in organic solution that the addition of surfactants allowed an

Vancomycin (Antibiotic, colon drug

increase in process yield during the nano economy drying process.

Solid lipid nanoparticles (SLNs)

Solid lipid nanoparticles (SLNs)

Particle analysis revealed that more than 90% of the nano spray dried
polysaccharide coated

Vildagliptin (Antidiabetic,

particles were submicron.

The wall materials used for the oral administration of encapsulated
Table 4 (continued)

by-layer coated

mucoadhesive)

pharmaceuticals prepared by means of nano spray drying are mainly

water-soluble polymers, such as gelatin, chitosan, compritol, sodium
delivery)

caseinate, pectin, carbopol, carboxymethyl cellulose, gum arabic, algi-

nate, Kollidon and Eudragit. The selection of a suitable wall material for
nanoencapsulation is based on similar factors as for microencapsulation
(Gharsallaoui et al., 2007). The relevant criteria are manifold, including

204
C. Arpagaus et al.
compatibility with the encapsulated active ingredient, suitable release
properties, high encapsulation efficiency, mechanical strength, storage
stability, easy emulsification, water solubility and edibility.
Nano spray drying has also been utilized as a process to dry pre-
formed nanoparticles, namely, solid lipid nanoparticles (SLNs) (Wang
et al., 2016a,b,c, Xue et al., 2017a, 2017b), nanoemulsions (Hu et al.,
2016; Wang et al., 2016d), nanogels (Zhou et al., 2018, 2016), self-
assembled polymeric micelles (Moshe et al., 2017), lipid-polymer hy-
brid nanoparticles (Sithole et al., 2017), or silica particles formed via
sol–gel processing (Wang and Friess, 2017). In most cases, the pre-
formed nanoparticles were mixed with additional excipients and dis-
persing agents prior to nano spray drying to fabricate fine powders.
SLNs are regarded as promising nanoscale delivery systems for
highly lipophilic drugs with limited bioavailability and biological effi-
cacy. SLNs offer a high loading capacity in their lipid core compared to
other colloidal delivery systems. Several studies have shown that SLNs
can be successfully formulated using nano spray drying technology.
Wang et al. (2016a) prepared pectin (a polysaccharide from citrus peel)
coated SLNs made of Compritol ATO 888 (glyceryl behenate) and so-
dium caseinate (milk protein). The nano spray dried SLNs powders
were in the range of 1–3 µm and showed excellent stability. Wang et al.
(2016b) coated SLNs made from Compritol 888 ATO with various
natural polysaccharides by nano spray drying. Wang et al. (2016c)
further tested the feasibility of cross-linking the polymeric double layer
made of sodium caseinate and pectin for oral delivery of curcumin, a
lipophilic bioactive studied as a model drug and nutrient. The cross-
linking significantly improved the physico-chemical properties of the
SLNs, resulting in higher encapsulation efficiency and loading capacity,
better stability and slower release profile in simulated gastrointestinal
conditions. The cross-linking further helped forming homogenous nano
spray dried powders of 0.5–1 µm size. Encapsulation of curcumin in
SLNs also significantly improved its antioxidant activity in aqueous
condition compared to free curcumin. Wang et al. (2016d) applied this
encapsulation technology to develop powder formulations of instant
functional drinks from a pectin-casein with incorporated peppermint oil
as a potential antimicrobial agent. The formulation allowed the si-
multaneous encapsulation of hydrophilic and hydrophobic vitamins as
well as mineral salts and showed a prolonged shelf life. Xue et al.
(2017a) fabricated submicron SLNs by homogenizing melted stearic
acid directly in an aqueous phase containing sodium caseinate and
pectin. After nano spray drying, the obtained dry SLN powders could be
effectively redispersed in water without variation of dimension, shape
and morphology. In another study, Xue et al. (2017b) encapsulated
curcumin in SLNs and produced nano spray dried powders of 0.5–1 μm
size with uniform distribution and no visible aggregation. The pre-
sented manufacturing method of nanoparticles is solvent-free and
promises to encapsulate heat-sensitive lipophilic drugs that are stable in
SLNs for oral administration. Hu et al. (2016) produced spherical dry
powders (200–500 nm) from eugenol oil nanoemulsions with natural
lecithin and gum arabic. Ethanol was used as a co-surfactant, which
improved the morphology and homogeneity of powders during nano
spray drying. The excellent redispersibility of the nanoemulsion pow-
ders and the strong antimicrobial effect was seen as an incentive for
other potential applications of nanoemulsions with other ingredients.
Nanogels made of egg yolk low density lipoprotein and poly-
saccharide are also being explored as oral application systems with
promising encapsulation and release potentials. Zhou et al. (2016) re-
ported on a pH- and heat-induced method for the fabrication of such
nanogels with a diameter of only 58 nm as nutrient delivery systems.
The nano spray dried powders produced from the nanogels exhibited an
average particle size of about 1 µm and could be redispersed in water
and maintained the nanoscale size. Encapsulation of curcumin into the
nanogels was effectively achieved. The nanogels showed a pH-depen-
dent controlled release profile in gastric and intestinal conditions, de-
monstrating potential as oral delivery systems for lipophilic nutrients
and drugs. Furthermore, Zhou et al. (2018) chemically cross-linked
205
International Journal of Pharmaceutics 546 (2018) 194–214
protein-pectin and protein-carboxymethyl cellulose nanogels in order to
improve the gastrointestinal stability.
Self- assembled polymeric micelles are also very popular and a va-
luable nanotechnology platform for encapsulation and administration
of lipophilic drugs, especially for oral mucosal administration. Moshe
et al. (2017) demonstrated the feasibility of nano spray drying for the
production of stable powders from cross-linked micelles of poly(vinyl
alcohol)-g-poly(N-isopropyl acrylamide) in a size range of 100–250 nm,
which could be redispersed in water in any desired concentration at the
time of administration. The production method was described as very
versatile and could open up new horizons in the application of poly-
meric micelles and other self-organized polymeric nanomaterials in
diagnostics and therapies.
Sithole et al. (2017) encapsulated the antiherpes drug acyclovir in
hybrid biopolymeric nanoparticles, which were prepared from cross-
linking hyaluronic acid with poly(acrylic acid). The spray dried nano-
particles were smaller than 500 nm in average and the solubility of
acyclovir could be improved by 30% compared to the conventional
formulation, consequentially enhancing its bioavailability as an oral
drug delivery system.
Silica-based sol–gel materials are another promising delivery form
for controlled drug release purpose. Its main advantage is that drugs
can be entrapped in a porous glass network without the formation of
covalent bonds between the active ingredient and the matrix. Wang and
Friess (2017) used nano spray drying to produce water-soluble silica gel
carrier particles based on a new silicate-based precursor. Dextrans of
different molecular weights (1, 5 and 60 kDa) were incorporated as
model compounds to regulate the release kinetics. A sustained release
over 35 days could be achieved for 60 kDa dextran.
4.3. Intravenous (blood circulation)
Site-specific drug delivery is very important to prevent undesired
side effects. Thereby, the particle size plays a crucial role in target drug
distribution, as shown in Table 5. In this context, Harsha et al. (2014)
prepared 5–15 µm sized gelatin microspheres containing the anticancer
drug carboplatin using nano spray drying for treating lung cancer. After
intravenous injection to albino mice, the drug concentration in the
lungs was significantly higher than in any other tissues e.g. liver,
spleen, or in the blood. It was stated that the particles could be used not
only for sustained drug release, but also for targeted delivery of ther-
apeutic agents to specific organs in the body. The development of new
cancer chemotherapeutics is a constant need. In this application area,
Anzar et al. (2018) explored the nano spray drying method for the
encapsulation of simvastatin in PLGA. Simvastatin, which is typically
used to lower cholesterol levels, has been investigated for the effective
treatment of breast cancer. The process parameters were optimized to
obtain particles of about 260 nm. In vitro cytotoxicity studies revealed
an enhanced anticancer activity with increasing drug concentration and
exposure time. Overall, the nanoparticles were found to be appropriate
for the treatment of solid tumor, e.g. breast cancer via intravenous
administration. Recently, Harsha et al. (2017) encapsulated salbutamol
in albumin microspheres. After fast intravenous injection in rabbits, the
particles with about 8 µm mean size were widely deposit in the pul-
monary capillaries of the lungs. The systemic administration of opti-
mally sized particles is seen as an efficient alternative to currently used
inhalation-based delivery to the lung. In another application, Panda
et al. (2014) co-entrapped the antipsychotic drugs clozapine and ris-
peridone in 250 nm PLGA nanoparticles by nano spray drying and ob-
served sustained drug release profiles in vitro over several days. The
drugs were evenly dispersed within the PLGA particles without any
crystalline content. The prepared particles could be used as an in-
jectable formulation to cross the blood–brain barrier for the treatment
of psychotic disorders, such as Schizophrenia. Last but not least, small
interfering RNAs (siRNAs) are promising therapeutics for the treatment
of a wide variety of genetic disorders and for the silencing of
 Table 5
Published studies on nano spray dried drug delivery applications by different routes other than pulmonary and oral routes (Drug loading (%) = Amount of drug in particles/Mass of particles; Encapsulation efficiency
(%) = Amount of drug in particles/Initial drug amount; n.a. = not available; – = not relevant).
C. Arpagaus et al.

Type of drug, application, wall material (excipient) Solvent T in (°C) T out (°C) Drying gas Particle size Solid sample Product Drug Encap-sulation References
(L/min) (µm) amount (mg) yield (%) loading (%) efficiency (%)

Intravenous (injection) route

Carboplatin (Drug targeting lung Gelatin Water 85–115 30–50 n.a. 5–15 n.a. 88 72 n.a. Harsha et al. (2014)
cancer passively after intravenous
injection)
Clozapine and risperidone PLGA, Polyvinylalcohol (PVA) DCM Water 60–80 31–38 112–118 (N2) 0.2–0.4 100 48–64 6–13 89–98 Panda et al. (2014)
(Antipsychotic drugs to treat
Schizophrenia)
Salbutamol sulphate (Asthma, Bovine serum albumin (BSA) Water 80–120 20 90–95 1.2–10.0 n.a. 86 n.a. 72 Harsha et al. (2017)
targeting lungs passively after
intravenous injection)
Simvastatin (Breast cancer) PLGA, PVA DCM, Water n.a. n.a. n.a. 0.1–0.7 115 n.a. 9 63 Anzar et al. (2018)
siRNA-loaded human serum albumin PLGA, PEG-PLGA DCM, Chloroform, 50 < 39 118–121 0.3–1.0 150–200 30–60 <1 n.a. Amsalem et al.
nanoparticles (Silencing gene Acetonnitrile (N2/CO2) (2017)
expression)

Topical (skin or wound) route

Amoxicillin (Antibacterial to inhibit Chitosan Water, Acetic acid 120 80 130 0.1–0.4 n.a. 60–63 82 n.a. Ngan et al. (2014)
bacterial growth)
Dexamethasone (Anti-inflammatory Poly(ε-caprolactone), Acetone Water 55 n.a. 110 0.4–2.3 100 72–90 47 94 Beber et al. (2014)
drug to treat skin diseases) Deoxycholate
Econazole nitrate (Antifungal drug) Hydroxypropyl-β- Ethanol 95 45 115 0.1–0.3 n.a. 78–87 48–55 n.a. Maged et al. (2017)
cyclodextrin, Stabilizer Tween

206
Gentamicin sulfate (Antibacterial drug Alginate, Pectin Water 90 n.a. 100 0.3–1.0 n.a. 65–91 23–28 70–83 De Cicco et al.
for wound dressing) (2014)
Soy bean isoflavones (Skin cancer Hypromellose acetate Water, Ethanol 60 29 100 0.3–1.3 n.a. 60–88 n.a. 62–86 Del Gaudio et al.
treatment, anti-ageing agent, succinate (2017)
chemopreventive)
Soy bean isoflavone extract CMC Water n.a. n.a. n.a. ∼0.65 n.a. n.a. n.a. 78–89 Del Gaudio et al.
(2016)

Ophtalmic (eye) route

Dexamethasone (Anti-inflammatory steroid, eye drop solutions to cure Ethanol 50 35 100 (N2/ 0.4–2.2 10–125 n.a. – Baba and Nishida
ophthalmic disorders) CO2) (2013)
Fluorometholone (Anti-inflammatory steroid, eye drop solutions to cure Ethanol 50 35 100 (N2/ 0.4–1.2 10–125 n.a. Baba and Nishida
ophthalmic disorders) CO2) (2013)
Calpain inhibitors (Drugs to cure Alzheimer’s and Parkinson’s diseases) Ethanol 50–100 35 100–150 0.1–1.3 n.a. n.a. Baba and Nishida
(N2/CO2) (2012)
Dirithromycin (Ocular bacterial Kollidon SR (Polyvinyl Methanol 90 30–40 n.a. 0.3–0.5 n.a. n.a. n.a. 25–44 (Basran, 2017)
infections) alcohol and polyviniyl
pyrolidone)
Intravesical (bladder) route
Thiolated glycol chitosan conjugates N-acetylcysteine, Glutathione, Water, Acetonitrile 40 30–32 100 (N2/ 0.2–1.4 n.a. 15–25 36–73 64–100 Denora et al. (2016)
(Mucoadhesive, local bladder Glycol, Chitosan CO2)
diseases)

Intraperitoneal route
Paclitaxel (Anticancer therapy, Low molecular weight poly(3- Chloroform 61 n.a. 120 (N2/ 0.7–3.7 2’500 n.a. 13 n.a. Bonartsev et al.
cytostatic) hydroxybutyrate) CO2) (2017), Zernov et al.
(2017)

Cerebral (brain) route

Nimodipine (Dilatation regulator in PLGA DCM 45 n.a. 120 0.7–3.7 n.a. n.a. 10–40 93–98 Bege et al. (2013)
brain arterioles)
International Journal of Pharmaceutics 546 (2018) 194–214
C. Arpagaus et al.
transcription during gene expression. Amsalem et al. (2017) loaded
solid cross-linked human serum albumin primary nanoparticles
(∼100 nm) with siRNA, and encapsulated them in PLGA or a mixture of
PEG and PLGA by nano spray drying. The drying temperature was
around 50 °C to prevent damage to the heat-sensitive siRNA. The pre-
pared solid nano-in-nanoparticles had a median size of about
580–770 nm and exhibited stable spherical shape with a unique inner
morphology. Freeze-fracture SEM revealed many encapsulated siRNA-
loaded nanoparticles embedded within a PLGA polymeric fiber matrix
surrounded by a dense polymeric wall. The structural integrity and the
gene silencing activity of the double encapsulated siRNA were fully
preserved after encapsulation. The nanoscale powder form enabled
systemic administration, e. g. by intravenous injection, and thus the
controlled release of siRNA-based therapeutics and other sensitive nu-
cleic acids.
4.4. Topically (skin or wounds)
In addition to oral, pulmonary, and intravenous administration
pathways, researchers have also produced nanocapsulated drugs
through nano spray drying that can be applied to the skin or wounds
during surgery (Table 5). De Cicco et al. (2014) loaded alginate-pectin
nanopowders with 25% antibacterial gentamicin. This formulation
turns into a gel when administered locally on a wound. The produced
particles with a 4.0 µm spray mesh ranged between 310 and 405 nm. All
formulations were obtained with good production yield ranging from
65 to 91%. Sustained drug release was obtained, achieving a total drug
permeation period of 3–6 days. Ngan et al. (2014) prepared amoxicillin
loaded chitosan nanoparticles by nano spray drying with improved
antibacterial activity. With a highly diluted chitosan solution of 0.025%
(w/v) and a 4.0 µm spray mesh the particle sizes could be adjusted by
the molecular weight of the chitosan in a range of 95–336 nm. The
antibacterial activity against Staphylococcus aureus bacteria was two
times more effective than that of pure amoxicillin. The study demon-
strated that the prepared nanoparticles strongly inhibited bacterial
growth. Beber et al. (2014) dried submicron polymeric particles con-
taining anti-inflammatory dexamethasone and prepared oil-in-water
emulsion creams for local administration to the skin. By optimizing the
powder properties, the creams showed controlled drug release kinetics
and a significant increase in retention of drug in the epidermis com-
pared to formulations containing free drug. Maged et al. (2017) for-
mulated cyclodextrin nanoparticles incorporating antifungal econazole,
which is used to treat skin infections. The nano spray dried particles
ranged between 185 and 325 nm and revealed high yields of 79–85%
and drug loadings of about 50%. Del Gaudio et al. (2017) produced
hypromellose acetate succinate particles loaded with a soy isoflavones
extract by nano spray drying. Particles in submicronic range (mean size
around 550 nm) and narrow size distribution with high encapsulation
efficiency (up to 86%) were obtained with enhanced skin penetration
performance. In a previous study, Del Gaudio et al. (2016) stabilized
the isoflavone extract in carboxymethyl cellulose and enhanced its af-
finity with aqueous media. The permeation through biological mem-
branes increased up to 4.5 times compared to raw soy isoflavone ex-
tract. In a nutshell, the nano spray dried formulations were able to
increase the bioavailability of soy isoflavones and could be used as
topical delivery systems for skin cancer treatment or as anti-ageing
agent enclosed in cosmeceutical products.
4.5. Ophthalmic (eye)
Colloidal drug delivery systems play an important role in the en-
hancement of the ocular bioavailability of active pharmaceutical in-
gredients, especially for topical instillations. In this application field,
Basran (2017) incorporated the antibacterial agent dirithromycin into
Kollidon-based polymeric nanoparticles (0.3–0.5 µm) by nano spray
drying. The encapsulation enabled to extend the release up to 6 h with
207
International Journal of Pharmaceutics 546 (2018) 194–214
enhanced therapeutic efficacy of the prepared mucoadhesive formula-
tions suitable for the efficient treatment of severe ocular bacterial in-
fections. Baba and Nishida (2012) prepared calpain inhibitor steroid
nanocrystals using nano spray drying. The particle size was controlled
by means of selecting the spray mesh sizes and the concentration of the
ethanol-dissolved drug solution. The average particle sizes were 378,
527, and 813 nm in comparison to the spray mesh sizes of 4.0, 5.5, and
7.0 μm. It was stated that the formed calpain inhibitors might be a
promising drug for curing intractable diseases such as Alzheimer’s
disease and Parkinson’s disease. In a subsequent study, Baba and
Nishida (2013) prepared submicron steroid nanocrystals of fluor-
ometholone and dexamethasone with the potential use as eye drop
solutions the treatment of ophthalmic disorders. More details have been
provided in Table 5.
4.6. Intraperitoneal
In cancer therapy, paclitaxel is one of the most widely applied an-
titumor cytostatics. Zernov et al. (2017) encapsulated paclitaxel in low
molecular weight poly(3-hydroxybutyrate) by nano spray drying (see
Table 5). The synthesized particles had a mean diameter of 2.7 µm and
a regular spherical shape with a smooth surface. The crystallinity of the
polymeric microparticles was about 65%. The study of Bonartsev et al.
(2017) demonstrated a significant antitumor activity of the paclitaxel
loaded microparticles both in vitro on murine hepatoma cells and in vivo
by intraperitoneal administration against transplanted tumor models in
mice, i.e. murine Lewis lung carcinoma and xenografts of human breast
cancer. The sustained release of paclitaxel over 2 months makes the
developed biodegradable particles suitable for application in long-term
anticancer therapy.
4.7. Intravesical (bladder)
Mucoadhesive drug delivery systems offer the advantages of ex-
tending the residence time at the site of interest. Denora et al. (2016)
nano spray dried mucoadhesives conjugates of N-acetylcysteine- and
glutathione-glycol chitosan polymer for intravesical drug delivery (see
Table 5). In particular, nano spray drying provided spherical particles
with an average size of 0.8 µm suitable for vesical administration by a
catheter. The prepared particles exhibited good mucoadhesive proper-
ties in a wide range of urine pH (5.0–7.0) and are seen as effective
formulation for intravesical drug delivery and treatment of local
bladder diseases. The drug residence time in the bladder could be in-
creased, and subsequently the efficacy of therapy. In this perspective,
further studies are in progress.
4.8. Cerebral (brain)
Nimodipine is a substance that regulates the dilatation of blood
vessels, particularly the cerebral vasculature in the brain. Originally it
was developed for the treatment of high blood pressure. Bege et al.
(2013) encapsulated nimodipine in PLGA particles by nano spray
drying. The drying conditions are shown in Table 5. The particles
ranged from 1.9 to 2.4 µm and were suspended in a fibrin sealant as an
in situ depot system for treatments related to brain surgery. The fibrin
glue is biodegradable and stable in the cerebrospinal fluid inside the
brain and the spine. The PLGA particles were also colored with en-
capsulated fluorescent coumarin dye to visualize the homogeneity of
the suspended drug particles in the adhesive. Nimodipine loads of
10–40% and high encapsulation efficiency could be achieved, which
make the depot forming device promising for the local treatment of
vasospasm after subarachnoid haemorrhage (bleeding).
5. Characterization and analysis of nano spray dried drugs
Characterization of nano spray dried drugs is very important to
C. Arpagaus et al. International Journal of Pharmaceutics 546 (2018) 194–214

provide in-depth information about their quantitative and qualitative
parameters, so that these nanocarriers can be formulated appropriately
for different applications and administration routes. Properties such as
morphology, particle size and size distribution, surface properties and
physicochemical attributes can be analyzed in nanoencapsulated drugs
obtained from a nano spray drier (Faridi Esfanjani et al., 2017). These
properties affect the storage, stability, functional characteristics, release
and bioavailability of the final pharmaceutical products (Jafari et al.,
2017a). On the other hand, a deep knowledge in this area could help
researchers to better design a drug delivery system without any side
effects and with minimum doses for controlled and target delivery. In
this section, a brief overview of common and most important analytical
methods for the characterization of nano spray dried drugs will be
provided.
5.1. Morphology of powder particles
One of the important properties of nano spray dried powders is their
morphology, which plays an important role on the functional and re-
lease characteristics of nanoencapsulated products (Jafari and
Esfanjani, 2017). Analyzing the morphology of powder nanoparticles
can provide useful information about their structure, shape, and size
through capturing high quality images by advanced microscopic ana-
lysis like Electron Microscopy, including Scanning Electron Microscopy
(SEM), Field Emission SEM (FESEM), and Transmission Electron Mi-
croscopy (TEM); Atomic Force Microscopy (AFM); and Confocal Laser
Scanning Microscopy (CLSM). Explaining the principles of these tech-
niques is outside the scope of this paper and readers are referred to
study specialized literature in this field. High-resolution images at a
magnification of ×103–×106 and a resolution smaller than 1 nm can be
obtained by Electron Microscopy techniques from nano spray dried
powders as shown in Fig. 5.
By applying AFM, it is possible to visualize nano spray dried par-
ticles in three dimensions (Ghasemi et al., 2017). This technique pro-
vides useful information about the structure of nanoparticles at the
atomic and molecular level by scanning the surface of samples with a
sharp tip without any contacts. In fact, topography study of these
powder particles is possible through AFM. Finally, CLSM can capture
fluorescent-enriched images of the samples revealing the position of the
core/wall materials and their distribution within the powder particles.
5.2. Size and surface analysis of powder particles
Many parameters of the drug-loaded carriers including stability,
appearance, rheology, release profile, etc., are influenced by their size
(Faridi Esfanjani and Jafari, 2016). The size analysis results of nano
spray dried powder particles can be presented as particle size dis-
tribution (PDS), polydispersity index (PDI), Sauter or Volume mean
diameter, Span, and Z-average (based on intensity, number, or volume
of particles). Also, the size distribution of powder particles can have a
single peak (optimum distribution) or multiple peaks, e.g., two peaks
(bimodal distribution) as a result of secondary droplet breakup or the
generation of satellite droplets during atomization (Al-Dhubiab, 2013;
Harsha et al., 2013a; Littringer et al., 2013; Rampino et al., 2013).
There are different analytical instruments to measure the size of nano
spray dried particles, including Statical Light Scattering (SLS), Dynamic
Light Scattering (DLS), Gravitational Settling and Centrifugation, and
Laser-Induced Breakdown Detection (LIBD).
Due to engagement of different ionic materials such as phospholi-
pids, phenolic compounds, proteins, polysaccharides, etc. in na-
noencapsulated powders produced by nano spray drying, there are
some electric charges at the surface of these nanocarrier particles,
which could strongly affect the stability, release rate, bioavailability,
and physicochemical properties of the final products (Assadpour and
Jafari, 2017). The most common way to express these surface electric
charges is the measurement of the zeta-potential, which typically could
be in the range of +100 to −100 mV. Briefly (Basran,
2017): ± 0–10 mV (highly unstable), ± 10–20 mV (relatively
stable), ± 20–30 mV (moderately stable), and > ± 30 mV (highly
stable); in other words, those particles with a zeta-potential > +30 mV
or < −30 mV are considered strongly cationic and anionic, respec-
tively with enough stability against attraction forces and minimum

Fig. 5. Examples of the SEM characterization results for nano spray dried powder particles containing: A: Salbutamol sulfate particles (1% (w/w) solid concentration,
nano spray dried at 100 °C); reprinted with permission from Littringer et al. (2013); B: Powders of albuterol sulfate in mannitol, L-leucine and poloxamer 188
(30:48:20:2 mixing ratio, 0.5% (w/w) solid concentration in water–ethanol solution (80:20), nano spray dried at 70 °C); reprinted with permission from Son et al.
(2013a,b); C: Aggregated cyclosporin nanoparticles in PLGA (50:50, 15 kDa, scale bar 300 nm) (dissolved in DCM and nano spray dried at 29 °C); reprinted with
permission from Schafroth et al. (2012); D: Uniform trehalose particles prepared with the addition of 0.005% (w/w) polysorbate 20 (0.1% (w/w) solid concentration,
nano spray dried at 120 °C); reprinted with permission from Schmid et al. (2011); E: Particles of β-galactosidase encapsulated in trehalose (1:2 (w/w) mixing ratio,
5% (w/w) solid concentration, nano spray dried at 80 °C); reprinted with permission from Bürki et al. (2011); F: Bovine serum albumin particles prepared with 0.05%
(w/v) Tween 80 (0.5% (w/w) solid concentration, nano spray dried at 120 °C); reprinted with permission from Lee et al. (2011).

208
C. Arpagaus et al.
aggregation due to strongly repulsive forces. It is possible to measure
the zeta-potential through some lab instruments, including electro-
phoresis, laser Doppler velocimetry, and zeta sizer (Malvern, UK).
Another important characteristic is the surface composition analysis
of powder particles produced by nano spray drying, which can be
achieved by X-ray photoelectron spectroscopy (XPS). By this technique,
it is feasible to determine what elements/compounds are existent at the
surface layer (a few nm information depth) of dried powder particles, so
that an in-depth analysis of the particle surfaces could help researchers
to evaluate the successfulness of process and predict the behavior of
these nanocarriers in real situations. Jafari et al. (2008a) identified the
unloaded fish oils in nano-encapsulated powders by analysing the sur-
face composition through XPS. The relative atomic concentration (%) of
carbon, oxygen, and nitrogen in the surface layer of the powder sample
was explored. As a consequence, the percent composition (relative
coverage) of the different components, such as fish oil in the surface
layer of powder prepared from whey protein concentrate (WPC) and
maltodextrin was calculated by using the relation in a matrix formula
as:
CE = αCS + βCP + γ CO
OE = αOS + βOP + γ OO
NE = α NS + β NP + γ NO
where C, O, and N are the relative atomic concentrations of carbon,
oxygen and nitrogen in encapsulated powder (CE, OE and NE), mal-
todextrin (CS, OS and NS), protein, i.e., WPC (CP, OP and NP), and fish
oil (CO, OO, NO); which are values obtained from the areas of the C 1s, O
1s, and N 1s at the XPS peaks (Fig. 6). For instance, spray dried powder
particles made with whey protein concentrate and maltodextrin in the
proportion of 1:3 and containing 20% nanodroplets of fish oil had a
surface elemental composition of 26% carbon, 4.5% nitrogen, and
69.5% oxygen. It was calculated that these powder particles have a
surface oil coverage of about 15 to 35% based on the initial emulsifi-
cation technique and the emulsion droplet size for the spray dryer feed
(Jafari et al., 2008a).
5.3. Physicochemical analysis of nano spray dried powders
Beside morphological, size, and surface analysis of powder particles,
it is important to measure some other properties such as formation of
chemical bonds, crystalline and amorphous nature, thermal properties,
magnetic characteristics, etc. in nanocarriers loaded with bioactive
compounds (Jafari et al., 2017a). Characterization of crystalline or
amorphous powders and crystallographic structures of particles con-
taining various drugs can be performed by X-ray diffraction (XRD)
(Fontana et al., 2014; Merchant et al., 2014; Panda et al., 2014;
Rascioni et al., 2016).
Another useful technique is Differential Scanning Calorimetry
(DSC), which can provide some details about thermal properties of
powder particles including glass transition temperature (Tg), heat ca-
pacity (Cp), melting point (Tm), and recrystallization time of nano-
carriers (Baba and Nishida, 2013; Martena et al., 2012a; Son et al.,
2013a). On the other hand, identification of different materials and
compounds within the powder and their chemical interactions is
achieved through Fourier Transform Infrared Spectroscopy (FTIR)
(Basran, 2017; Cerchiara et al., 2015; Fontana et al., 2014; Merchant
et al., 2014; Wang et al., 2016c). Finally, the data obtained by Nuclear
Magnetic Resonance (NMR) can reflect simultaneously the chemical
nature and the molecular mobility of individual components (Ahmad
et al., 2014; Basran, 2017; Merchant et al., 2014; Öztürk et al., 2017).
209
International Journal of Pharmaceutics 546 (2018) 194–214
6. Bioavailability and release of nano spray dried drugs
6.1. Entrance of nano spray dried drugs into the blood stream
There are many routes for the administration of drugs such as pul-
monary, oral, topical, and injection procedures. In general, spray dried
nanoparticles containing encapsulated drugs are in the form of pow-
ders, which are converted into pills for oral consumption by the pa-
tients. After oral administration, the entry of nano spray dried drugs
into systematic circulation is restricted by several hurdles including
acidic conditions of the stomach, brush border membrane and proteases
in the gut lumen, metabolism by the liver enzymes, and tightly-bound
intestinal epithelial cells (Jafari and McClements, 2017). Nano spray
dried particles loaded with drugs can pass the intestinal epithelium by
diffusing through the cells (transcellular route) (Harsha, 2015; Harsha
et al., 2013a). In fact, nanocarriers produced by nano spray drying can
have a higher bioavailability; i.e., higher availability of the drugs for
the human body.
Nano spray dried drugs that are consumed via the oral route for
reaching the target tissue must adhere to the mucus and cross the
mucosal layer as the first barrier (Jafari et al., 2017b). This layer, which
covers the epithelium, is retarding the transport of drugs by inhibiting
the direct adhesion to the epithelial cells. The nanoencapsulated drugs
should be able to enter the blood stream to trigger the targeted release.
Viscoelasticity is a key factor for the mucus layer, because based on this
parameter, there are two types of loosely and firmly adherent mucus
layers. pH also varies throughout the gut; in the stomach, the pH of the
mucus is about 1–2 on the luminal surface to nearly neutral (pH = 7) at
the epithelial surface. This pH will be partially neutralized in the
duodenum and steadily increases through the rest of the gastro-
intestinal tract, so that the pH reaches 7–8 in the colon and rectum
(Jafari et al., 2017a). It should also be noted that the mucus layer has a
hydrophobic nature due to presence of lipids, glucolipids, and cer-
amides. Nano spray dried drugs need to be mucoadhesive to pass
through this layer and then, penetrate and move from the epithelial
cells into the blood stream. There are many theories and mechanisms
for this process, which however, is outside the scope of this paper.
6.2. Release of drugs from nano spray dried particles
Another important factor for nano spray dried drugs is the release
rate and process within the body; many release mechanisms have been
developed to achieve both temporal and sustained controlled release of
nanocarriers (Assadpour et al., 2017). These release theories can be
classified into partitioning, dissolution, osmosis, diffusion, swelling,
and erosion processes. There are some analytical techniques including
Fig. 6. An example of surface composition analysis of powder particles loaded
with nanoencapsulated bioactives and produced by spray drying; reprinted with
permission from Jafari et al. (2008a,b).
 C. Arpagaus et al.

Table 6
Common mathematical models for the analysis of drug release from nano spray dried particles (reprinted with permission from Jafari et al., 2017b).
Type of model Model Equation Model parameters

Zero-Order C = C 0 − K0 t • CC ==Amount of drug release or dissolved

0
• K = Zero Initial amount of drug in solution
0
• t = time order rate constant
•
First Order Kinetic Log C = Log C0 − Kt/2.303 0
• CK ==Initial concentration of drug
First order constant
• t = time
•
Higuchi C = [D (2qt − Cs) Cst]1/2 • CD == total amount of drug release per unit area of the matrix
• qt =diffusion coefficient for the drug in the matrix
• C = total amount of drug in a unit volume of matrix
s
• t = timedimensional solubility of drug in the polymer matrix
• Ct
Korsemeyer-Peppas* Ct
= kt n C∞
• = fraction of drug release at time t
C∞
• kn == rate constant
• release exponent
Hixson-Crowell 1 1 t of drug released in time t
Ct3 −Ct3 = KHC t
• CC =amount
0 amount of drug in the tablet
• K =initial
HC

210
• =rate constant for Hixson-Crowell equation
Weibull −(t − T ) ⎤ b of dissolved drug as a function of time t
C = C0 [1−exp ⎡
a
• CC0==amount of drug being released.
⎣ ⎦ • T = lagtotaltimeamount
measured as a result of dissolution process parameters
• a = scale parameter
• b = shape of dissolution that describes the time dependence
• curve.

Hopfenberg n M is the amount of drug in time t

Mt k0 . t t
= 1− 1−
M∞ C0 . a
( ) • M is the total amount ofdissolved
∞ drug dissolved when the pharmaceutical dosage form is exhausted
• k is the erosion rate constant
o
• C is the initial concentration of drug in the matrix
o
• a is the initial radius for a sphere or cylinder or the half thickness for a slab
• n is 1, 2 and 3 for a slab, cylinder and sphere respectively
•
Baker–Lonsdale 2 is the drug release amount at time t M∞ is the amount of drug released at an infinite time
3 Mt 3 Mt • Mt
f = 1− 1− = kt
2 ( M∞ ) M∞ • K is the release constant which corresponds to the slope of the graph when plotted as [d(Mt/M∞)]/dt with respect to the root of time inverse
Release exponent (n) Nutrient transport mechanism Rate as a function of time

n = 0.5 Fickian diffusion t −0.5

0.5 < n < 1 Non Fickian diffusion t n−1
n=1 Case II transport Zero order release
n Higher than 1 Super Case II transport t n−1

* n values and related release mechanisms.

International Journal of Pharmaceutics 546 (2018) 194–214
C. Arpagaus et al.
destructive and non-destructive methods to measure the release of
drugs from nanoencapsulation systems, so that it can be predicted what
happens to encapsulated drugs when administered into the human
body.
Characteristics of the nano spray dried drugs such as size, shape,
surface charge, wall composition, molecular weight, etc. play a major
role on the release and bioavailability of drugs. For example, prolonged
circulation and accumulation in the targeted tissue and enhanced dif-
fusion in the tissue can be obtained by applying carriers with a particle
size of 20–100 nm. Beck-Broichsitter et al. (2015a) reported for ex-
ample that smaller particles exhibit a higher speed of active compound
release compared to larger ones, due to the difference in exposed sur-
face area, as evidenced by sildenafil-loaded polymeric particles. Re-
garding the influence of molecular weight, it has been shown that the
release kinetics of active compounds encapsulated in PLGA polymers
with a low molecular weight are faster compared to those with a high
molecular weight, due to the higher hydrolysis and degradation rate
(Panda et al., 2014). Also, a PLGA polymer with low molecular weight
can provide sustained release for four to six weeks (Schafroth et al.,
2012). Release profiles typically exhibit two phases. In the first burst
phase, about 10–30% of the active compound is released due to free
binding at the surface of the particles (Harsha et al., 2015b, 2013a). The
rest of the active compound is released in a second phase for a longer
duration, known as sustained release (Harsha, 2015, 2013; Harsha
et al., 2013a).
Al-Dhubiab (2013) developed selegiline loaded gelatin nanospheres
(∼100 nm) by nano spray drying and evaluated the drug release in
vitro. The encapsulation provided a controlled release of the drug over a
period of 10 h. The prepared nanospheres were considered as an effi-
cient oral formulation of selegiline for the treatment of Parkinson's
disease. In vivo studies need to be carried out to substantiate these
findings. Harsha et al. (2015a,b, 2013a) encapsulated the antidiabetic
drugs vildagliptin and metformin in gelatin and carbopol for mu-
coadhesive oral administration with sustained release. Spherical parti-
cles in the range of 0.1–0.6 µm with smooth surface were obtained by
nano spray drying with up to 90% drug loading and high product
yields. Complete drug release could be delayed by up to 12 h. The same
research group also designed nano spray dried oral dosage forms of
amoxicillin in gelatin nanoparticles to treat Helicobacter pylori infection
in stomach (Harsha, 2013, 2012) or antidiabetic sitagliptin in mu-
coadhesive carbapol microspheres (Harsha et al., 2013b). Öztürk et al.
(2017, 2015) loaded dexketoprofen in Kollidon and Eudragit nano-
particles (0.7–0.7 µm) by nano spray drying and extended the drug
release and the analgesic efficacy following oral application to mice.
Cerchiara et al. (2015) encapsulated the antibiotic vancomycin in
chitosan particles to treat serious colon infections. The nanoparticles
showed prolonged in vitro drug release at low pH, similar to the gastric
environment. In addition, the particles showed a uniform bactericidal
activity.
Considering the modeling of release data and its kinetics for nano
spray dried particles loaded with drugs, there are common mathema-
tical and experimental models which may lead to the accurate predic-
tion in terms of delivery performance and design of nanoparticles. In
fact, these models describe the concentration of the released drug as a
function of time. The most applied models have been summarized in
Table 6 along with their relevant parameters and predicted release
mechanisms.
7. Conclusions and further remarks
The number of publications in the field of nano spray drying for
pharmaceuticals has increased rapidly since the market introduction of
the Nano Spray Dryer B-90 in 2009 by Büchi Labortechnik AG
(Switzerland). More than 160 papers have been identified and reviewed
in this paper. Compared to conventional spray drying processes, nano
spray drying relies on a vibrating mesh technology to produce an
211
International Journal of Pharmaceutics 546 (2018) 194–214
ultrafine spray and a highly efficient electrostatic powder collector to
extend the size spectrum of separable particles to the nanoscale. The
fabrication of nanoparticles by nano spray drying is relatively simple
and fast, which make the technology suitable for processing smallest
sample amounts ranging from 10 mg to 2.5 g with uniquely high yields
of over 95%. The high yields enable the economical use of valuable
active pharmaceutical ingredients, like pure drugs and drug loaded
polymeric particles. Tiny spray dried particles can be formed down to a
size of only 100 nm with diluted solutions of 0.1–1% (w/v) solids
concentration. The drying process is gentle and contributes to main-
taining the stability and activity of heat-sensitive materials, such as
peptides, proteins, hormones and amino acids. Different particle
morphologies can be created, including dense, hollow and porous
particles with spherical, wrinkled, shrinked or donut shapes. The effects
on the powder properties, like particle size, morphology, yield, pro-
ductivity, encapsulation efficiency, drug loading, release profile and
stability depend on the selected process parameters. The most im-
portant adjustable parameters are the inlet temperature, drying gas
flow rate, spray mesh size, solvent, solids concentration, and selection
of the corresponding excipients, stabilizers and surfactants. Depending
on the application, an optimized set of process parameters can be
found. Nano spray drying has been successfully applied for a wide
variety of pharmaceutical applications, such as increasing the bioa-
vailability of poorly soluble drugs by nanoisation and structural mod-
ification, as well as encapsulation of nanoparticles, nanoemulsions or
nanosuspensions in biocompatible polymeric wall materials for sus-
tained drug release and high bioavailability. High encapsulation effi-
ciencies of over 95% are achieved by adjustable drug loadings. The
prepared drug loaded particles are administered in various ways, in-
cluding pulmonary, oral, intravenous, topically, ophthalmic, in-
traperitoneal, intravesical, or even cerebral, which underlines the ver-
satility of the nano spray drying technology. To further explore the
potentials of nano spray drying technology future research should focus
on the further commercialization of this technology on an industrial
scale. The applications discussed so far are restricted to the laboratory
scale. There is an increasing need for scale-up to pave the way for
translating nano spray dried pharmaceutical products from bench-to-
bedside. The application trends are in the areas of pulmonary drug
delivery, nanotherapeutics, the encapsulation of nanoemulsions with
poorly water-soluble active ingredients and the formulation of nano-
crystals for a higher bioavailability.
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