Advanced Powder Technol., Vol. 17, No. 6, pp.

587– 611 (2006)

© VSP and Society of Powder Technology, Japan 2006.
Also available online - www.brill.nl/apt

Review paper

Preparation of functional nanostructured particles

by spray drying

KIKUO OKUYAMA 1,∗ , MIKRAJUDDIN ABDULLAH 2 ,

I. WULED LENGGORO 1 and FERRY ISKANDAR 1
1 Department of Chemical Engineering, Graduate School of Engineering, Hiroshima University,
Higashi-Hiroshima 739-8527, Japan
2 Department of Physics, Bandung Institute of Technology, Jalan Ganeca 10,
Bandung 40132, Indonesia

Received 16 November 2005; accepted 24 February 2006

Abstract—When particle dimensions are reduced to the order of several nanometers, their physical
and chemical properties deviate significantly from the bulk properties of such materials. Because
of this, there is abundant potential for their use in future technologies including electronic and
optoelectronic, mechanical, chemical, cosmetic, medical, drug, and food technologies. However,
due to their extremely small sizes, the particles suffer from many problems related to their surface and
thermal stability, shape preservation, handling, assembly in devices, etc. It is therefore an important
challenge to solve these problems by developing slightly larger particles (e.g. on the submicrometer
scale) in which the properties generated by the nanoscale material are preserved. One approach to
this is to trap nanoparticles in a micrometer-sized inert matrix. This approach allows the nanoscale
properties to be retained, since nanoparticles are separated from each other in the inert matrix. The
inert matrix also serves as a coating medium that inhibits any chemical changes to the surface of the
nanoparticles. Their larger size allows easy handling or assembly in devices. A promising method for
designing and fabricating these composite structures is a spray method, in which spherical particles
can be produced. In this paper, we review the nanostructural processing (synthesis) of submicrometer-
sized particles by a spray method, which provides a restricted reaction environment (such as pores or
cages) in the matrix for their synthesis and handling. The characterization and potential applications
of these composites are also discussed.

Keywords: Spray drying; nanoparticles; nanotechnology; functionalized nanoparticles.

NOMENCLATURE
A constant (—)
d geometrical diameter (μm)

∗ To whom correspondence should be addressed. E-mail: okuyama@hiroshima-u.ac.jp

588 K. Okuyama et al.

daer mass mean aerodynamic diameter (μm)

D particle diameter (nm)
t time (day)

Greek

α constant (—)
ρ specific gravity of the particles (g/cm3 )

1. INTRODUCTION

Spray drying is an established method that is initiated by atomizing/spraying a sus-

pension of droplets followed by a drying process, resulting in the production of solid
particles [1]. It is an efficient drying method due to the large surface area avail-
able for heat and mass transfer as a result of atomizing the liquid into very small
droplets of the order of tens to hundreds of micrometers [2]. Spray drying is success-
fully used in the pharmaceutical industry to produce products with defined physical
and chemical properties. In food processing technology, spray-drying methods are
widely used in manufacturing (e.g. dried eggs, powdered milk, animal feeds, cake
mixes, citrus juices, corn syrup, creamers, fish concentrates, infant formulas, pota-
toes, shortening, starch derivatives, tomato puree, yeast, and yogurt). In material
processing, spray drying has been used to produce submicrometer- to micrometer-
sized powder particles of metals, semiconductors and oxides with a spherical shape
that are non-agglomerated and nearly monodispersed, with a controlled particle
size [3]. The formation of individually dispersed nanoparticles derived from col-
loidal sols via spray drying at low pressure was recently investigated [4]. Spherical
powders are of practical importance since, in general, they have better rheological
properties than irregular powders [5].
In order to generate droplets, the liquid feed can be atomized by rotary disks,
two-fluid nozzles or ultrasonic nebulizers, depending on the droplet size required.
The droplets are sprayed into a drying chamber heated to a temperature above the
vaporization temperature of the solvent using a carrier. The time required to dry the
droplets depends on the residence time of the droplet in the gas phase, which, in turn,
is determined by the geometry of the chamber, carrier gas flow rates, temperature
and pressure. Powder collection can be achieved using a cyclone, filter bag or
electric field precipitator. Figure 1 shows a schematic diagram of a typical spray-
drying reactor.
Due to its simplicity and rapid processing, spray drying has great potential for
designing materials that are rich in advantageous properties. Here, we present a
review of the applications of the spray-drying method in designing functional ma-
terials and material architectures with dimensions of several micrometers, starting
 Preparation of functional nanoparticles 589

Figure 1. Schematic of spray-drying equipment consisting of an ultrasonic nebulizer to generate

droplets, a dryer for solvents evaporation, a source of carrier gas to carry the droplets into the dryer
and a powder collector. This figure is published in color on http://www.ingenta.com

from nanoparticles (i.e. a bottom-up approach). This approach permits the preser-
vation of nanoscale properties, but with particles on a micrometer scale. This is im-
portant since micrometer-sized particles are easier to handle than nanometer-sized
particles. During the process, the spray temperature is usually not very high and the
residence time of the droplet/particles is very short, so that, after spraying, the inher-
ent properties of the nanoparticles do not change appreciably. For example, when
using water as the dispersing medium, an operating temperature of around 150 ◦ C
is sufficient to completely dry droplets within a few seconds. In addition, although
the air temperature for drying can be relatively high, the actual temperature of the
evaporating droplets is significantly lower, due to cooling, as the result of the latent
heat of vaporization. During spraying, the evaporated moisture forms a skin around
the droplets, which absorbs most of the heat. Generally, the mean temperature of
the droplet is 15–20 ◦ C below the temperature of the surrounding environment [6].
590 K. Okuyama et al.

Thus, spray drying is also advantageous for the production of micrometer-sized low-
melting-point materials such as lipids, which are important for producing particles
used in drug delivery.

2. SYNTHESIS OF POROUS PARTICLES BY SPRAY DRYING

Porous materials are of scientific and technological interest because of their poten-
tial applications in separation processes, catalysts, chromatography, controlled drug
release, low dielectric constant fillers, pigments, microelectronics, electro-optics
and other emerging technologies in addition to nanotechnologies [7 –10]. A va-
riety of macroporous ceramics, metals, semiconductors and polymers with well-
defined pore sizes in the submicrometer range have been successfully synthesized
using self-assembled templates of a colloid as well as self-assembled templates of
an emulsion [11, 12]. The above methods for preparing ordered porous materials
have, thus far, resulted in irregular shapes and/or thin-film shapes. However, for
practical applications, ordered porous materials must be in the shape of a usable ob-
ject. It would be desirable, for example, to produce ordered porous materials with a
spherical form [13].

2.1. Aggregation of nanoparticles into micrometer-sized particles

The properties of particles containing interconnected pores depend, in part, on the
pore size. Large pores enable high mass transfer due to convective flow. Smaller
pores are responsible for generating a large surface area and therefore have a high
capacity for molecules that can be adsorbed. Materials with a bimodal pore size,
i.e. micro- and macroporosity or meso- and macroporosity, have been synthesized
by a combination of two or more pore-building processes, such as via zeolite
nanoparticles [14, 15] or supramolecularly templated inorganic aggregates [16, 17]
in combination with colloidal templating.
Lind et al. reported on the production of spherical mesoporous silica particles with
a hierarchical porosity by spray drying [18]. MCM-41- and MCM-48-containing
nanopores are dispersed in water and spray dried to form large spherical particles
(spherical aggregates). The aggregates contain two pore sizes. One pore scale is
found inside the MCM-X (X = 41 or 48) nanoparticles and another pore scale is
found between the MCM-X nanoparticles. An illustration of the aggregate structure
is shown in Fig. 2. The size of the MCM-41 was 400–1000 nm, while that of MCM-
48 was 200–700 nm.
Similarly, the production of micrometer-sized particles using a colloid of silica
nanoparticles as the precursor has been reported [19, 20]. Since the colloid particles
did not contain pores, the micrometer-sized particles produced contained only a
single scale of pore size, i.e. the one attributed to interparticle spacing. The sizes
of the silica particles used ranged down to 5 nm in diameter. Thus, the predicted
pore sizes could be as low as 2.9, 2.2, 1.44 or 1.2 nm, if it is assumed that the
 Preparation of functional nanoparticles 591

Figure 2. Schematic of a powder particle prepared by spray drying MCM-X. The particle has two
scales of pore size. Small pores (nanometer order) are developed in MCM-X particles and larger pores
(on the order of hundreds of nanometers) are found between the MCM-X particles.

nanoparticles had cubic, orthorhombic, tetragonal or rhombohedral arrangements,

respectively. In addition, the spaces between nanoparticles in the aggregates are
interconnected; therefore, this method is effective for producing micrometer-sized
particles containing interconnected pores of the order of a few nanometers.
Figure 3 shows examples of particles produced from various sizes of silica
colloids: (a) 4–6, (b) 20–30, (c) 40–60 and (d) 70–100 nm [20]. The surface areas
(BET method) and pore sizes were measured using automated gas absorption. For
example, the BET surface areas (m2 /g) and pore sizes (nm) for samples prepared
using silica colloids with particle sizes of 20–30 and 70–100 nm were 111.9 and
5.8 and 24.5 m2 /g and 28.0 nm, respectively. These pore sizes are very close to the
predicted values of about 5.8 and 20 nm, respectively, for these two particles.
In an ultrasonic nebulizer, the size of the particles produced can easily be
controlled by adjusting the droplet size (frequency of atomizer) as well as the
concentration of nanoparticles in the precursor. For example, when the atomizer is
operated at 1.7 MHz, the effect of SiO2 precursor concentration on the agglomerate
size is listed in Table 1 [19]. It is clear that the sizes of the produced agglomerates
are similar to the size of MCM-X particles, i.e. several hundreds of nanometers.
Thus, the produced particles could compete with MCM-X particles, since almost
all the structural properties of MCM-X particles are also found in the produced
particles.
Another advantage of the present method is that the synthesis process is rapid,
safe, easy to control with respect to particle size and pore size (by selecting silica
with different nanoparticle sizes), and the size of the agglomerate produced can
easily be further classified by placing, for example, a differential mobility analyzer
(DMA) at the outlet of the drying reactor [19]. Several types of porous particles can
be produced by this method as long as the corresponding nanoparticle colloids are
available.
592 K. Okuyama et al.

Figure 3. Agglomerate silica particles produced by spray drying nanometer-sized silica colloids of
various sizes: (a) 4–6, (b) 20–30, (c) 40–60 and (d) 70–100 nm. (Reprinted with permission from
Ref. [20], © 2001 Kluwer.)

Table 1.
Effect of precursor concentration on the volume mean particle diameter

Concentration of SiO2 Volume particle diameter (μm)

nanoparticles (mol/l)
0.01 0.30
0.1 0.56
1.1 1.02

2.2. Self-assembly of silica and polystyrene latex (PSL) nanoparticles

The production of submicrometer-sized particles composed of silica nanoparticles

and organized macropores using spray drying with a mixture of a silica nanoparticle
colloid and a colloidal suspension of PSL beads as the precursors was reported
[21 –23]. In principle, it is possible to prepare such porous particles using different
oxide materials, providing colloidal oxide nanoparticles are available. An additional
requirement is that the dispersing medium for this colloid should be similar to that
of PSL beads, to avoid unexpected reactions during the mixing process.
 Preparation of functional nanoparticles 593

Figure 4. Schematic of a process for producing silica particles containing ordered pores prepared
by spray drying a mixture of silica and PSL colloids. At the lower part of the reactor (low-
temperature region) only solvent evaporation takes place, resulting in agglomerates composed of silica
and PSL nanoparticles. In the upper part of the reactor (high-temperature zone) PSL nanoparticles
decompose, resulting in silica particles containing pores. This figure is published in color on
http://www.ingenta.com

The precursor for this method is a mixture of a colloid containing several

nanometer-sized silica particles and a colloid containing PSL beads tens to hundreds
of nanometers in size. The droplets are generated using an ultrasonic atomizer and
are directly introduced into a tubular reactor by a carrier gas. The tube is classified
into two heating zones: a low-temperature zone and a high-temperature zone. The
low-temperature zone is located at the inlet and is used to evaporate the droplet, thus
producing compact particles consisting of silica nanoparticles and PSL beads. The
temperature of this zone must be lower than the decomposition temperature of the
PSL beads used. The residence time of the droplet needs to be controlled so that,
after leaving this zone, the solvent has completely evaporated. This control can be
performed by adjusting the flow rate of the carrier gas. The high-temperature zone
is used to decompose the PSL beads so that pores are formed at the positions they
occupied in the composite particles, when leaving the lower-temperature zone. For
the above conditions, this zone can be set to 0.4 m in length for an inner diameter
13 mm with a temperature of 450 ◦ C. Interestingly, during solvent evaporation in
the lower-temperature zone, the PSL beads organize themselves into a hexagonal
structure. As a result, micrometer-sized particles with an organized porous structure
can be produced. Figure 4 illustrates the formation process of particles containing
ordered pores.
Figure 5a shows scanning electron microscopy (SEM) image of a product
prepared using 5-nm silica nanoparticles and PSL colloids containing PSL beads
79 nm in size. The precursor was prepared by mixing 10 ml of silica colloid
(0.05%) with 1 ml of PSL colloid (3.6 × 1013 particle/ml). Figure 5b shows a
magnified view of the particle surface, clearly showing the organization of pores
594 K. Okuyama et al.

Figure 5. SEM images of the morphology of silica powders obtained using 79-nm PSL latex and
4- to 6-nm silica particles. (a) Enlarged view of the surface of a single particle and (b) SEM image
of a collection of particles. (Reprinted with permission from Ref. [21], © 2001 American Chemical
Society.)

in a hexagonal/nearly hexagonal arrangement. The advantage of this method is

that it allows the pore size to be controlled by changing the size of the PSL
beads. Controlling pore size also implies controlling the distance between pores,
since, based on magnified field emission (FE)-SEM images, the pores are intercon-
nected [22].
There are many applications where larger mesoporous particles with a higher
monodispersity are needed or highly beneficial [24]. Several examples include con-
trolled delivery, where monodispersity can ensure uniform delivery rates, biosens-
ing based on flow cytometry [25] where monodisperse spheres with sizes of several
micrometers could serve as ‘cell mimics’, and photonic band gap materials [26]
where high monodispersity, periodicity and control of the dielectric constant are
critical factors.
Indeed, understanding the formation of organized pores in particles during the
spray-drying process, to permit total control of the pore arrangements, is an
important challenge. We recently examined this process using an elementary law of
topology [27]. Although a direct test using experimental data was not performed,
the existence of a ‘stationary state’ in which organized mesoporous particles with
hexagonal close packing can be produced could be qualitatively defined.
The refractive index of particles is typically determined using a laser particle
counter coupled with a pulse height analyzer, which is based on elastic scattering
from a single particle. The response of the instrument can be used to calculate
the refractive index of the particles using the Mie theory of light scattering [28].
A schematic of this experiment is shown in Fig. 6 [29, 30]. When light scattered
through an aperture is collected by a photodetector, the magnitude of the optical
counter signal is proportional to the partial light scattering cross-section, σ , of the
particles [31]. The scattering cross-section is proportional to the response voltage
produced by the pulse height analyzer. Examples of response voltages of porous and
dense particles are shown in Fig. 7, along with both SEM and transmission electron
 Preparation of functional nanoparticles 595

Figure 6. Arrangement of a laser particle counter coupled with a pulse height analyzer for determining
the light scattering of porous particles. (Reprinted with permission from Ref. [29], © 2002 Elsevier.)
The effective dielectric constant of particles can be calculated from light scattering data by fitting the
measured data with the scattering equation based on Mie theory.

microscopy (TEM) images of the particles [29]. The response voltage decreases
with increasing porosity. From the calculation it is found that, for a sample prepared
using 6-nm silica nanoparticles, the effective refractive index is located between
1.147 and 1.194 [29].

2.3. Evaporation-induced self assembly (EISA)

In EISA, a surfactant or amphiphile (e.g. surfactants or block copolymers) in an
inorganic precursor solution undergoes a concentration-driven mesophase transfor-
mation as the solvent evaporates from the droplet [32]. Simultaneously, reactions
596 K. Okuyama et al.

Figure 7. Dependence of response voltage on the porosity of particles. The morphologies of the mea-
sured particles are also shown as SEM images (top) and TEM images (bottom). (Reprinted with per-
mission from Ref. [29], © 2002 Elsevier.) This figure is published in color on http://www.ingenta.com

between the inorganic species occur that eventually solidify the particle and freeze
the mesostructure. Removal of the organic solvent produces mesopore particles
possessing the order introduced by the amphiphile. The mesostructural order can
be controlled by virtue of the choice of amphiphile, solution composition or use of
additives [24, 33].
The process is initiated with a homogeneous solution of soluble silica and
a surfactant prepared in an ethanol/water solvent where the initial surfactant
concentration is much lower than the critical micelle concentration (CMC). When
the drying process occurs in the reactor, alcohol dries more readily than water which
increases the relative surfactant, water and silica concentrations. The concentration
of surfactant then reaches the CMC, micelles are formed and the successive co-
assembly of silica-surfactant micellar species into a liquid-crystalline nanophase is
induced. Lu et al. found that the resulting particles are in generally solid, with
highly ordered hexagonal, cubic or vesicular nanostructures [32].
This method allows the design of porous silica with various pore structures.
For example, using different surfactants: CTAB (CH3 (CH2 )15 N+ (CH3 )3Br− ), a
 Preparation of functional nanoparticles 597

Figure 8. Representative TEM micrographs of mesostructured silica particles. (a) Faceted, calcined
particles with a hexagonal mesophase (d100 = 32.5 nm). (b) Calcined particles showing cubic
mesostructure. (c) Calcined particles showing a vesicular mesophase (d100 = 92). (d) Uncalcined
silica particles showing the ‘growth’ of ordered vesicular domains from the liquid–vapor interface.
The particle interior has a disordered, worm-like mesostructure. (Reprinted with permission from
Ref. [32], © 1999 Macmillan.)

non-ionic surfactant [Brij-56 or CH3 (CH2 )15 (OCH2 CH2 )10 OH; Brij-58 or
CH3 (CH2 )15 (OCH2 CH2 )20 OH] or triblock copolymers [Pluronic-P123, i.e.
(EO)20 (PO)70 (EO)20 ] with an acidic silica sol, Lu et al. were able to produce a
wide variety of pore structures. CTAB produced particles with a highly ordered
hexagonal mesophase over the concentration range of 0.06–0.16 M (Fig. 8a and 8c).
The use of a non-ionic surfactant, e.g. Brij-56 or Brij-58, results mainly in vesic-
ular mesostructures, with a minor presence of cubic and hexagonal mesostructures
(Fig. 8b and 8d). At a higher drying temperature, during which the outer silica shell
solidifies before droplet shrinkage is complete, uniform dimpling of the silica shell
results in order to preserve the solidified shell surface area (Fig. 8c).
598 K. Okuyama et al.

Theoretically, if the drying of a sprayed droplet is sufficiently slow and the solute
within the droplet has adequate time to redistribute by diffusion throughout the
evaporating droplet, relatively dense dried particles are produced. By contrast,
if the drying of the droplet is short and the solute in the droplet does not have
sufficient time to diffuse from the surface to the center of the droplet, it accumulates
near the drying front of the droplet. The surfactant concentration is distributed
radially and the surfactant CMC is first exceeded near the droplet surface, which
might then cause the formation of a shell-like micelle layer inside the solidified
silica shell layer. This is due to the tendency of the surfactant to attract silica.
After the formation of the micelle layer, continuation of the drying process results
in the formation of a second silica layer inside the micelle layer. This process is
illustrated in Fig. 9. At the end of the process, alternating silica and micelle layers
are found. This means that, after the removal of the organic material by post-firing
(calcination), the shell surface is uniformly dimpled.
Based on small-angle X-ray scattering (SAXS) and N2 absorption methods, it has
been observed that the d-spacing and pore size increases with increasing surfactant
volume/molecular mass (CTAB < Brij-56 < P123).

Figure 9. Illustration of the formation of porous silica containing uniform dimpling of the shell
surfaces when Pe  1. (a) Initial droplet in the liquid phase. A shell-like micelle layer inside the
solidified silica shell layer (b). The formation of a second silica layer inside the micelle layer (c) and
the formation of a second micelle layer (d). At the end of the process, alternate silica and micelle
layers are found.
 Preparation of functional nanoparticles 599

3. SPRAY-DRYING MICRO-ENCAPSULATION OF NANOPARTICLES

The majority of drugs and most new drug delivery systems require drug substances
in particulate form, many at the final dosage unit [34]. Important pharmaceuti-
cal issues such as chemical and physical stability and therapeutic and clinical per-
formance are often related to the properties of drug particles such as particle size
and surface properties. Encapsulation of inorganic particles into organic polymers
endows particles with important properties that bare, uncoated particles lack [35].
Polymer coatings on particles enhance their compatibility with organic ingredients,
reduce susceptibility to leaching and protect the particle surface from oxidation [36].
Consequently, encapsulation improves dispersability and chemical stability, and re-
duces toxicity [37].
Encapsulation is the packaging of a specified material (both liquid and solid) with
another material (usually inert material) in the form of capsules [38]. Based on the
resulting size, we can classify three scales of encapsulation, i.e. nanoencapsulation,
in which the product sizes are in the range of 1 nm to 1 μm, microencapsulation, in
which the product sizes are in the range of 1 μm to 1 mm, and macroencapsulation,
in which the product sizes are larger than 1 mm. The purposes of encapsulation
include achieving controlled/remote release, making active materials easier/safer to
handle, compartmentalizing multiple-component systems, protecting sensitive ma-
terials from their environment and turning liquids into powders/solids. Commercial
applications of microcapsules can be found in various formulations such as fertil-
izers, pesticides, toothpaste, shampoo, bath salts, extended relief pharmaceuticals,
carbonless paper, detergents and bleaches, air fresheners, vacuum cleaner bags, fire
retardants, and facial tissues.
Coacervation is the associative phase separation used for microencapsulation [39].
In this process, two oppositely charged polymers are generally used. Oppositely
charged polymers will attract each other and form a concentrated polymer phase
(coacervate), which separates from a very dilute polymer phase [40]. In the
coacervation process for microencapsulation, an insoluble material is dispersed in
the polymer solution before coacervation takes place. The coacervate deposits are
then dispersed on an insoluble core material, thus providing encapsulation.
One of the microencapsulation techniques for producing microspheres is spray
drying. This process has been used to produce drug-loaded microspheres of
poly(lactide) and poly(lactide-co-glycolide) (PLGA) due to its advantages with
respect to the water-in-oil emulsion process [41]. Spray drying allows microspheres
with a small diameter are suitable for drug administration by injection to be
produced, probably in a more convenient way than that for those with larger
diameters which are produced using a solvent evaporation process [42]. Spray
drying is a fast, single-step process that has the potential for the large-scale
encapsulation of fragile drugs. It generally yields microparticles with a narrow size
distribution and is characterized by a high encapsulation efficiency [43].
PLGA micropores are degraded to oligo- and monomers over prolonged periods
of time, slowly releasing the entrapped active component [44]. These microspheres
600 K. Okuyama et al.

also protect the active entities from destructive action by enzymes and the low pH
environment of the stomach [45].
Encapsulation of specific agents for subsequent controlled release is a very
attractive potential application of these particles. The functionality of the particles in
this case is provided by virtue of the engineered transport properties of the particles
and by way of the method of encapsulation or containment. For example, CeCl3
can be encapsulated within a porous silica shell by the EISA method. After removal
of the surfactant, the CeO2 /CeCl3 core is surrounded by a mesoporous silica layer
through which Ce3+ can be released to provide corrosion inhibition [46].
Mesoporous oxide particles are exciling candidates for heterogeneous catalysts
due to the precise control of pore size, and very high pore volume and surface area.
The impregnation of hexachloroplatinic acid followed by reduction in the presence
of water vapor leads to the formation of platinum nanowire within the pores of
hexagonally ordered mesoporous silica [46].

4. MICRON-SIZED CARRIER PARTICLES CONTAINING NANOPARTICLES

FOR DRUG DELIVERY

The pressurized metered dose inhaler (pMDI) was introduced in 1956 to deliver
a conventional formulation of a micronized suspension [47]. Unfortunately, it
is inefficient, with most formulations, depositing no more that 10–15% of the
dose in the lungs, with the majority of the dose being deposited in the oro-
pharynx [48]. Due to a high input energy, disruption in the crystal lattice can
cause physical and chemical instability. Disorder regions in the resulting product
are thermodynamically unstable.
Traditional approaches to formulations for pMDIs have involved formulating
micronized particles with densities in the range of 1.0–1.5 g/cm3 [49]. However,
micronization usually results in a broad particle size distribution, with little control
over other particle attributes such as density and surface energy [50].

4.1. Nanoparticles in a micrometer-sized matrix

More recently, there has been considerable interest in the development of novel
methods for the delivery of peptides and proteins that exhibit poor oral absorption,
and which currently have to be administrated by injection [51]. Pulmonary
delivery offers an acceptable non-invasive alternative to the needle for systemic
administration. Administration of drugs via the pulmonary route is technically
challenging as oropharyngeal deposition may be high and variations in inhalation
technique may affect the quantity of drug delivered to the lungs [52].
Research on applications of nanometer-sized particles as drug release agents is
currently attracting substantial attention. There are many interesting phenomena
related to utilizing nanoparticles for drug delivery in the human body. Particles
with geometric diameters of less than a few hundred nanometers have an even
 Preparation of functional nanoparticles 601

Figure 10. Spray-drying method for producing micrometer-sized particles comprised of nanoparticles
for drug delivery. This figure is published in color on http://www.ingenta.com

longer residence time in the lungs [53]. Once deposited, nanoparticles often remain
in the fluid lining of the lung until dissolution (if they are soluble). In addition,
cellular uptake studies have demonstrated that certain cells such as cancer cells
and epithelial cells are able to take up nanoparticles [54]. In vivo studies have
reported an accumulation of nanoparticles at tumor sites [55]. Such properties make
nanoparticles a very attractive delivery vehicle for the treatment of lung cancer.
If nanoparticles can be delivered to the lungs, their unique properties of avoiding
mucociliary clearance and delivering drugs directly to the target tissue or target cells
might be utilized in the therapeutic treatment of lung-specific diseases, including
lung cancer.
However, a serious current problem in the utilization of nanoparticles for drug
release that makes their use severely limited is their low inertia. The mass median
aerodynamic diameter (MMAD) of nanoparticles is not suitable for purposes of
inhalation [56] and they are predominantly exhaled from the lung after inspira-
tion [57]. The size of many nanoparticles places them in a transitional region,
where neither diffusion nor sedimentation or impaction are effective deposition
mechanisms [58]. Consequently, it would be expected that a large fraction of an
inhaled dose would be exhaled and only a small particle fraction of the particles
would be deposited in the lung. In addition, their small size leads to the formation
of aggregates, making their physical handling in liquid and dry powder form difficult
— a common practical problem that must be overcome before nanoparticles can be
used for oral drug delivery [59]. Because of these limitations, nanoparticles are not
presently being exploited commercially or clinically as vehicles for drug delivery in
the lung [53].
Maximum deposition of a drug in the tracheo-bronchial and deep alveoli regions
for normal inhalation rates can be achieved when powder particles several microm-
eters in diameter with a narrow size distribution are used [56]. In respiratory drug
602 K. Okuyama et al.

delivery, size influences drug deposition patterns and particles of 1–5 μm are re-
quired for deep lung penetration. Therefore, a current challenge is to integrate the
transportation properties of micrometer-sized particles with the attractive properties
of nanoparticles for drug delivery. Towards this objective, Finlay et al. [58] inves-
tigated the feasibility of developing carrier particles to deliver nanoparticles to the
lung by incorporating nanoparticles into microparticle carriers. This approach is
illustrated in Fig. 10. The MMAD of such carriers can be adjusted to give sufficient
lung deposition in the desired upper or lower part of the lung (either the bronchial
region or the alveolar region). After deposition in the lung, the carrier matrix dis-
solves, releasing the nanoparticles. Finlay et al. used gelatin (242 ± 14 nm) and
poly(butylcyanoacrylate) (nano)particles (173 ± 63 nm) with lactose as the matrix.
The size of the powder was determined by confocal laser scanning microscopy (2.5–
2.6 μm), with the MMAD being around 3 μm.

4.2. Large porous particles (LPPs) composed of nanoparticles

Another type of carrier particle for drug delivery is a LPP. This type of particle
is characterized by geometrical sizes larger that 5 μm and mass densities of 0.1
g/cm3 or less. LPPs have recently become popular for use as carriers for drugs
that need to be delivered to the lungs for local and systemic applications [60]. A
principal advantage of LPPs over conventional inhaled therapeutic aerosol particles
is their aerosolization efficiency [61]. In addition, LPPs possess the potential to
avoid alveolar macrophage clearance [62], enabling the sustained releases of a drug
in the lung [63].
Particles for drug delivery that combine the advantages of LPPs and nanoparticles
while avoiding their limitations have been developed. Spray-drying techniques to
form LPPs comprised of nanoparticles that are held together by physical means,
such as van der Waals forces, or within a matrix of additional ingredients such
as biopolymers or phospholipids, have been developed [53]. The products have
the same physical and delivery properties as LPPs, yet, once deposited in the
lungs (or placed in a physiologically similar environment), they dissociate to yield
nanoparticles, with their inherent attractive features for drug delivery.
Figure 11a shows an example of LPPs prepared by spray drying a precursor
containing polystyrene latex particles 170 nm in size. Figure 11b is a magnified
view of the surface of such a particle. The aerodynamic diameter can be calculated
as follows. Assuming the particle shape to be spherical, the relation between mass
mean aerodynamic diameter, daer , and geometrical diameter, d, is given by [64]:
√
daer = d ρ, (1)
with ρ being the specific gravity of the particles. Although the particle size is larger
than 5 μm, since the density is very low, the aerodynamic diameter might also be
low, i.e. acceptable for optimum inhalation. For example, using d ∼ 15 μm and
ρ ∼ 0.1 g/cm3 , a value daer ∼ 4.7 μm is obtained.
 Preparation of functional nanoparticles 603

Figure 11. SEM images of (a) a typical hollow sphere LPP obtained by spray drying a solution of
polystyrene nanoparticles (170 nm) and (b) magnified view of the particle surface in (a). (Reprinted
with permission from Ref. [53], © 2002 National Academy of Science USA.)

Figure 12. Variation in the mass mean aerodynamic diameter (!) and geometrical diameter (F)
of DPPC–DMPE–lactose. (Reprinted with permission from Ref. [53], © 2002 National Academy of
Science USA.)

Figure 12 shows the variation in mass mean diameter and geometrical diameter of
spray-dried DPPC–DMPE–lactose. Compressed air at variable pressure (1–5 bar)
ran a rotary atomizer located above the dryer with a drying air flow rate of 98 kg/h;
the inlet temperature was fixed at 110 ◦ C, the outlet temperature was 46 ◦ C, and the
feed rate of the solution was 70 ml/min.
The Peclet number also controls the formation of large hollow porous nanoparti-
cles (LPNPs). Pe  1 yields relatively dense dried particles. However, if Pe  1,
nanoparticles are trapped at the free surface of the droplet in an energy well result-
ing from the large air–water surface energy, which is greater than the difference be-
tween the particle–air and particle–water surface energies. As the droplet evaporates
and particles accumulate on the free surface, capillary forces draw nanoparticles to-
gether and ultimately van der Waals forces [65] lock them in place. At the end of
the process, the evaporating front becomes a shell with a crust rich in nanoparticles,
604 K. Okuyama et al.

enclosing the remaining solution. As the solution escapes by evaporation from the
shell, the nanoparticles remaining in the drop are pushed onto the inner surface of
the shell.

5. NANOPARTICLES AND BINDERS

5.1. Prolonging the stability of a property

Binders play several roles, including controlling the release of drugs via a coating
process or strengthening brittle materials [66]. Bergna prepared attrition-resistant
porous particles by spray drying slurries of mixtures of micron-sized particles and
discrete nanoparticles [67].
Solid lipid nanoparticles (SLN™ ) [68] are interesting colloidal dry delivery
systems since they have all the advantages of fat emulsions (large-scale product,
no organic solvent, and low systemic toxicity and cytotoxicity) and polymeric
nanoparticles [69]. Aqueous SLN dispersions possess a long-term stability of at
least 3 years. However, prolonged long-term stability can only be achieved when
they are stored as a dry product [70].
On the other hand, a functional nanoparticle such as ZnO emits a broad lumines-
cence emission in the green–yellow region, and, as a result, it is a potential material
for use in advanced displays and light sources. When the particle size is reduced
below 6 nm, a shift in the emission spectrum to shorter wavelengths occurs, due
to the quantum confinement of electrons and holes in the particles. The peak for
the emission spectrum is located in the blue region for particle sizes smaller than
about 3 nm. Very large ZnO particles show an emission spectrum with a peak at a
wavelength of around 550 nm, i.e. a green–yellow color. If ZnO nanoparticles could
be produced in a range of sizes from about 3 to 10 nm, a variety of emission peaks
could be produced.
One simple method for producing ZnO nanoparticles is a hydrolysis method, first
described by Spanhel and Anderson [71]. In this method, a ZnO colloid is produced
in an ethanol solution with an initial particle size (immediately after mixing the
precursors) as small as 3 nm. The particle size then continues to grow, or age, after
synthesis, even when stored at 0 ◦ C. After about 5 days of aging, the particles reach
a size of about 5.5 nm. Monticone et al. reported that the time dependence of the
size of ZnO particles produced by this method can be fitted to the expression:

D = 2At α , (2)

where D is the particle diameter (nm), A = 2.6 ± 0.3 nm day−α , α = 0.33 ± 0.03
and t is the time in days [72]. The visible luminescence of ZnO is also dependent
on particle size. Spanhel and Anderson [71] observed that the luminescence peak at
about 500 nm for fresh colloid shifted to 560 nm after 5 days of aging. The shift in
the luminescence peak results from an increase in the energy band gap opening due
 Preparation of functional nanoparticles 605

to the change in crystalline size, which can be roughly predicted using the Brush
equation [73].
It has been proposed that the visible luminescence is caused by the disintegration
of excitons and an electron then jumps to a state located near the center of the
gap [74]. The increase in band gap on particle size reduction shifts the position
of the luminescence spectra to shorter wavelengths. If the time evolution of the
luminescence spectra of a ZnO colloid prepared by Spanhel and Anderson’s method
is observed, it can be seen that the fresh colloid emits a nearly blue color, which then
changes to green and finally reaches a yellow–green color. This definitive change
is very interesting. When the size of particles in a ZnO colloid could be stopped
at various aging times, ZnO particles that produce a variety of colors ranging from
nearly blue to nearly yellow could be produced.
For preparing ZnO composites that emit stable colors, ZnO nanoparticles in a
fresh ZnO colloid prepared by the Spanhel and Anderson method [71] were trapped
in a matrix made of silica nanoparticles [75]. Initially, the ZnO colloid and silica
colloid were mixed and then quickly spray dried. Depending on the aging time of
the colloid, the color of the powder can be varied. Figure 13 shows the effect of
aging time on the luminescence spectra of ZnO composite [75]. For comparison,
the inset in Fig. 13 shows the evolution of the luminescence spectra of a ZnO colloid
prepared by the Spanhel and Anderson method; from fresh colloid to colloid aged
for 1 week. The luminescence peak located around 500 nm for the fresh colloid
shifted to around 560 nm after 1 week of aging. The present method, therefore, is a
simple one for producing ZnO nanoparticles that emit a specified color.

Figure 13. (a) Dependence of PL spectra for samples prepared at SiO2 concentrations of (A) 4 and
(B) 0.4 mol/l, using a 254-nm Xe laser source measured after aging for various times: as prepared,
aged more than 10 days and aged more than 30 days. The inset shows the PL spectra of the ZnO
colloid (0.1 M); solid line: fresh colloid and dashed line: colloid aged for 1 week. (Reprinted with
permission from Ref. [75], © 2001 American Institute of Physics.)
606 K. Okuyama et al.

5.2. Controlling quantum properties

Since the color of ZnO colloids changes with time, the production of composites that
emit different colors by trapping ZnO colloids of different ages in a silica matrix
remains a challenge. A composite using ZnO colloid was prepared according to
the Spanhel and Anderson method and, instead of silica colloid, tetraethoxysilane
(TEOS) was used as the precursor of the silica [76]. Initially, a ZnO colloid was
prepared using the standard Spanhel and Anderson method [71]. As the precursors
for producing submicrometer-sized silica particles containing nanoparticles of ZnO,
the ZnO colloid, aged for different times, was mixed with TEOS at specified weight
fractions.
The luminescence spectra of samples prepared under various conditions are shown
in Fig. 14. The sample obtained by simply spray drying a ZnO colloid aged for 0 h
has a luminescence spectrum that peaks at around 523 nm. The addition of 1 g of
TEOS to a ZnO colloid aged for 0 h before spraying shifted the luminescence peak
to around 460 nm and the intensity increased as well. Samples prepared using a ZnO
colloid aged for 12 h or 1 week, each of which had been mixed with 1 g of TEOS,
had luminescence peaks that were very close to that of the ZnO colloid aged for
0 h without TEOS. The peak positions for the samples prepared using ZnO colloids
aged for 12 h and 1 week were located at around 516 and 529 nm, respectively. This
approach appears to be promising for controlling the ‘color’ of ZnO composites.
Another advantage of dispersing nanoparticles in a silica matrix is the presence of
surface silanol groups that can easily react with alcohol and silane coupling agents
[77] to produce a dispersion which is not only stable in non-aqueous solvents, but
also provides an ideal anchorage for the covalent bonding of specific ligands [36].

Figure 14. Luminescence emission of ZnO/SiO2 particle composites prepared using (a) a ZnO colloid
aged for 0 h without the addition of TEOS, (b) a ZnO colloid aged for 0 h (100 ml) with the addition
of 1 g of TEOS, (c) a ZnO colloid aged for 12 h (100 ml) with the addition of 1 g of TEOS and (d) a
ZnO colloid aged for 1 week (100 ml) with the addition of 1 g of TEOS. (Reprinted with permission
from Ref. [76], © 2004 Elsevier.)
 Preparation of functional nanoparticles 607

5.3. Function improvement

Fe–Cu particles can be used as a catalyst in a Fisher–Tropsch (FT) synthesis,
a reaction in which coal or natural gas is converted to liquid fuels. For coal
conversion, Fe catalysts are preferred since they can operate at the lower H2 /CO
ratio in coal-derived syngas. The preferred reactor type is a slurry-phase bubble
column that requires spherical catalyst agglomerates 50–70 μm in diameter.
Fe–Cu particles can be made by simple precipitation. For example, Pham et al.
prepared Fe–Cu particles by the precipitation method and found the size of the
precipitated particles was around 80 nm. Aging the precipitate led to agglomeration
of sizes below 5 μm, which may not be acceptable for the slurry in a FT reactor. The
addition of SiO2 binder results in particles larger than 5 μm (median size 8 μm),
which are still smaller than desired for the FT process. Calcining the precipitate
before spraying can lead to larger agglomerates. For example, calcining at 300 ◦ C
led to a median diameter of 23 μm, but the shape was not spherical [65].

6. CONCLUSION

Nanometer-sized materials that exhibit exotic properties can be used in elec-

tronic/optoelectronic, medicinal, environmental and material processing technolo-
gies, etc. However, there are still several problems associated with these tiny mate-
rials that must be solved before they can be brought into large-scale industrial use.
Some examples of these are difficulties in handling and instability (changes over
time). The spray-drying method, which has been used for decades in food technolo-
gies, has great potential for improving nanoparticle usability. For example, to solve
the handling problems associated with nanoparticles, the spray-drying method can
be used to produce a submicrometer-sized powder composed of nanoparticles, in
which the nanoscale properties of the particles are preserved. Unexpected chemical
reactions that may occur on the surface of nanoparticles, in particular those induced
by a high surface area which allows chemical reactions to proceed readily, can be
depressed by spray-dry coating of nanoparticles with inert materials. This results
in the long-term stability of nanoparticle properties: chemical, optical, size, etc. In
catalyst technology, particles having very high porosity (very large surface area) are
required for developing efficient catalysts. The spray drying of a colloid mixture
of silica nanoparticles and polystyrene latex nanoparticles permits the production
of particles with porosities as high as 0.81. For electronic/optoelectronic technolo-
gies, this highly porous material exhibits a very low dielectric constant, as low as
1.2, which has great potential for developing ultrahigh memory devices. One major
trend for future medical technology is the use of nanoparticles in treating diseased
tissues in the human body such as cancerous tumors, where nanoparticles are in-
troduced into the body through an inhalation process. Their low inertia problem,
which results in most of the nanoparticles being exhaled from the lung after inhala-
tion, can be overcome by developing micrometer-sized powders from nanoparticles
608 K. Okuyama et al.

using the spray-drying method. These could be in the form of large porous particles
that microencapsulate nanoparticles.

Acknowledgements
Japan Society for the Promotion of Science (JSPS) Postdoctoral Fellowships for
M. A. and F. I. are gratefully acknowledged. This work was supported by the Grant-
in-Aids from the Ministry of Education, Culture, Sports, Science and Technology
through the JSPS (K. O. and I. W. L.), and by the NEDO’s Nanotechnology Particle
Project based on a fund provided by the Ministry of Economy, Trade and Industry,
Japan.

REFERENCES
1. K. Masters, Spray Drying Handbook. Wiley, New York (1991).
2. M. Fareed, A new approach to modeling of single droplet drying, Chem. Eng. Sci. 58, 2985–2993
(2003).
3. K. Okuyama and I. W. Lenggoro, Preparation of nanoparticles via spray route, Chem. Eng. Sci.
58, 537–547 (2003).
4. W. N. Wang, I. W. Lenggoro and K. Okuyama, Dispersion and aggregation of nanoparticle
derived from colloidal droplets under low-pressure conditions, J. Colloid Interface Sci. 288,
423–431 (2005).
5. P. Luo and T. G. Nieh, Synthesis of ultrafine hydroxyapatite particles by a spray dry method,
Mater. Sci. Eng. C 3, 75–78 (1995).
6. J. Broadhead, S. K. Edmond Rouan and C. T. Rhodes, The deposition of spray-dried beta-
galactosidase from dry powder inhaler devices, Drug Dev. Ind. Pharm. 18, 1169–1206 (1992).
7. M. E. Davis, Ordered porous materials for emerging applications, Nature 417, 813–821 (2002).
8. F. Schüth and W. Schmidt, Microporous and mesoporous materials, Adv. Mater. 14, 629–638
(2002).
9. O. D. Velev and A. M. Lenhoff, Colloidal crystals as templates for porous materials, Curr. Opin.
Colloid Interface Sci. 5, 56–63 (2000).
10. A. Stein, Sphere templating methods for periodic porous solids, Microporous Mesoporous Mat.
44-45, 227–239 (2001).
11. O. D. Velev, T. A. Jede, R. F. Lobo and A. M. Lenhoff, Porous silica via colloidal crystallization,
Nature 389, 447–448 (1997).
12. A. Imhof and D. J. Pine, Ordered macroporous materials by emulsion templating, Nature 389,
948–951 (1997).
13. J. Kim, O. Wilhelm and S. E. Pratsinis, Packaging of sol-gel-made porous nanostructured titania
particles by spray drying, J. Am. Ceram. Soc. 84, 2802–2808 (2001).
14. B. T. Holland, L. Abrams and A. Stein, Dual templating of macroporous silicates with zeolitic
microporous frameworks, J. Am. Chem. Soc. 121, 4308–4309 (1999).
15. K. H. Rhodes, S. A. Davis, F. Caruso, B. Zhang and S. Mann, Hierarchical assembly of zeolite
nanoparticles into ordered macroporous monoliths using core–shell building blocks, Chem.
Mater. 12, 2832–2834 (2000).
16. M. Antonietti, B. Berton, C. Göltner and H.-P. Hentze, Synthesis of mesoporous silica with
large pores and bimodal pore size distribution by templating of polymer lattices, Adv. Mater. 10,
154–159 (1998).
17. J. S. Yin and Z. L. Wang, Plasmon energy shift in mesoporous and double length-scale ordered
nanoporous silica, Appl. Phys. Lett. 74, 2629–2631 (1999).
 Preparation of functional nanoparticles 609

18. A. Lind, F. C. Hohenesche, J.-H. Smått, M. Lindén and K. K Unger, Spherical silica agglom-
erates possessing hierarchical porosity prepared by spray drying of MCM-41 and MCM-48
nanospheres, Microporous Mesoporous Mat. 66, 219–227 (2003).
19. F. Iskandar, I. W. Lenggoro, T.-O. Kim, N. Nakao, M. Shimada and K. Okuyama, Fabrication and
characterization of SiO2 particles generated by spray methods for standards aerosol, J. Chem.
Eng. Jpn. 34, 1285–1292 (2001).
20. F. Iskandar, I. W. Lenggoro, B. Xia and K. Okuyama, Functional nanostructured silica powders
derived from colloidal suspensions by sol spraying, J. Nanoparticle Res. 3, 263–270 (2001).
21. F. Iskandar, Mikrajuddin and K. Okuyama, In situ production of spherical silica particles
containing self-organized mesopores, Nano Lett. 1, 231–234 (2001); see also: Highlights of
the recent literature, materials science: spraying nanoporous silica, Science 292, 1611 (2001).
22. F. Iskandar, Mikrajuddin and K. Okuyama, Controllability of pore size and porosity of self-
organized porous silica particles, Nano Lett. 2, 389–392 (2002).
23. F. Iskandar, Mikrajuddin and K. Okuyama, Ordered nanoporous particles, in: Encyclopedia of
Nanoscience and Nanotechnology, H. S. Nalwa (Ed.), Vol. 8, pp. 259–270. American Scientific
Publishers, CA (2004).
24. G. V. R. Rao, G. P. Lòpez, J. Bravo, H. N. Pham, A. K. Datye, H. Xu and T. L. Ward,
Monodisperse mesoporous silica microspheres formed by evaporation-induced self assembly
of surfactant templates in aerosols, Adv. Mater. 14, 1301–1304 (2002).
25. T. Buranda, G. M. Jones, J. P. Nolan, J. Keij, G. P. Lopez and L. A. Sklar, Ligand receptor
dynamics at streptavidin-coated particle surfaces: a flow cytometric and spectrofluorimetric
study, J. Phys. Chem. B. 103, 3399–3410 (1999).
26. C. Kresge, M. Leonowichz, W. Roth, C. Vartuli and J. Beck, Ordered mesoporous molecular
sieves synthesized by a liquid-crystal template mechanism, Nature 359, 710–712 (1992).
27. L. Gradoń, S. Janeczko, M. Abdullah, F. Iskandar and K. Okuyama, Self-organization kinetics
of mesoporous nanostructured particles, AIChE J. 50, 2583–2593 (2004).
28. C. F. Bohren and D. R. Huffman, Absorption and Scattering of Light by Small Particles. Wiley,
New York (1983).
29. H. Chang and K. Okuyama, Optical properties of dense and porous spheroids consisting of
primary silica nanoparticles, J. Aerosol Sci. 33, 1701–1720 (2002).
30. F. Iskandar, H. Chang, and K. Okuyama, Preparation of microencapsulated powders by an
aerosol spray method and their optical properties. Advanced Powder Technol. 14, 349–367
(2003).
31. J. Heyder and J. Gebhard, Optimization of response functions of light scattering instruments for
size evaluation of aerosol particles, Appl. Opt. 18, 705–711 (1979).
32. Y. Lu, H. Fan, A. Stump, T. L. Ward, T. Rieker and C. J. Brinker, Aerosol-assisted self-assembly
of mesostructured spherical nanoparticles, Nature 398, 223–226 (1999).
33. M. T. Bore, S. B. Rathod, T. L. Ward and A. K. Datye, Hexagonal mesostructure in powders
produced by evaporation-induced self-assembly of aerosols from aqueous tetraethoxysilane
solutions, Langmuir 19, 256–264 (2003).
34. P. York, Supercritical fluids ease drug delivery, Manufact. Chem. 71, 26–29 (2000).
35. R. F. Ziolo, E. P. Giannelis, B. A. Weinstein, M. P. O’Horo, B. N. Ganguly, V. Mehrotra,
M. W. Russell and D. R. Huffman, Matrix-mediated synthesis of nanocrystalline γ -Fe2 O3 : a
new optically transparent magnetic material, Science 257, 219–223 (1992).
36. P. Tartaj, M. de Puerto Morales, S. V. Verdaguer, T. G. Carrenõ and C. J. Serna, The preparation
of magnetic nanoparticles for applications in biomedicine, J. Phys. D 36, R1820-R197 (2003).
37. E. Bourgeat-Lami and J. J. Lang, Encapsulation of inorganic particles by dispersion polymeriza-
tion in polar media: 1. silica nanoparticles encapsulated by polystyrene, J. Colloid Interface Sci.
197, 293–308 (1998).
38. M. N. A. Hawlader, M. S. Uddin and M. M. Khin, Microencapsulated PCM thermal-energy
storage system, Appl. Energy 74, 195–202 (2003).
610 K. Okuyama et al.

39. P. Deasy, Microencapsulation and related drug process, Drugs Pharmac. Sci. 20, 1–361 (1984).
40. A. Millqvist-Fureby, M. Malmsten and B. Bergenståhl, An aqueous polymer two-phase system
as carrier in the spray-drying of biological, J. Colloid Inteface Sci. 225, 54–61 (2000).
41. F. Pavanetto, I. Genta, P. Giunchedi and B. Conti, Evaluation of spray-drying as a method for
polylactide and polylactide-co-glycolyde microsphere preparation, J. Microencapsul. 10, 487–
497 (1993).
42. D. Kobayashi, S. Tsubuku, H. Yamanaka, M. Asano, M. Miyajima and M. Yoshida, In vivo
characteristics of injectable poly(DL-lactic acid) microspheres for long-acting drug delivery,
Drug Dev. Ind. Pharm. 24, 819–825 (1998).
43. P. Giunchedi, H. O. Alpar and U. Conte, PDLLA microspheres containing steroids: spray-
drying, o/w and w/o/w emulsifications as preparation methods, J. Microencapsul. 15, 185–195
(1998).
44. C. Thomasin, G. Corradin, Y. Men, H. P. Merkle and B. Gender, Tetanus toxoid and synthetic
malaria antigen containing poly(lactide)/poly(lactide-co-glycolide) microspheres: importance of
polymer degradation and antigen release for immune response. J. Control. Release 41, 131–145
(1996).
45. Ch. B. Felder, N. Vorlaender, B. Gander, H. P. Mekle and H. U. Bertschinger, Microencapsulated
enterotoxigenic Escherichia coli and detached fimbriae for peroral vaccination of pigs, Vaccine
19, 706–715 (2001).
46. T. Ward, A. Datye, G. Lòpez, J. Brinker and F. van Swoll, Nanostructural Engineering of
Complex Functional Particles. National Science Foundation, Arlington, VA (2003).
47. Y. Kawashima, T. Serigano, T. Hino, H. Yamamoto and H. Takeuchi, A new powder design
method to improve inhalation efficiency of pranlukast hydrate dry powder aerosols by surface
modification with hydroxypropylmethylcellulose phthalate nanospheres, Pharmacol. Res. 15,
1748–1752 (1998).
48. R. Melchar, M. F. Biddischombe, V. H. F. Mak, M. D. Short and S. G. Spiro, Lung deposition
patterns of directly labelled salbutamol in normal subjects and in patients with reversible airflow
obstruction, Thorax 48, 506–511 (1993).
49. S. P. Newman, K. P. Steed, G. Hooper, J. I. Jones and F. C. Upchurch, Improved targeting of
beclomethasone diproprionate (250 g metered dose inhaler) to the lungs of asthmatics with the
Spacehaler™ , Respir. Med. 93, 424–431 (1999).
50. P. H. Hirst, G. R. Pitcairn, J. G. Weers, T. E. Tarara, A. R. Clark, L. A. Dellamary, G. Hall,
J. Shorr and S. P. Newman, In vivo lung deposition of hollow porous particles from a pressurized
metered dose inhaler, Pharmacol. Res. 19, 258–264 (2002).
51. A. L. Adjei and P. K. Gupta, Inhalation Delivery of Therapeutic Peptides and Proteins. Marcel
Dekker, New York (1997).
52. L. Gradoń, T. Sosnowski, K. Okuyama, and F. Iskandar, Interaction of nanostructured particles
with the lung surfactant, in: Nanostructured Materials and Their Applications, W. W. Szyman-
ski, P. E. Wanger, M. Itoh and T. Ohachi (Eds), pp. 145–156. Facultas, Vienna (2004).
53. N. Tsapis, B. Bennett, B. Jackson, D. A. Weitz and D. A. Edwards, Trojan particles. Low porous
carriers of nanoparticles for drug delivery, Proc. Nat. Acad. Sci. USA 99, 12001–12005 (2002).
54. R. Ghirardelli, F. Bonasoro, C. Porta and D. Cremaschi, Identification of particular epithelial
areas and cells that transport polypeptide-coated nanoparticles in the nasal respiratory mucosa
of the rabbit, Biochim. Biophys. Acta Biomembr. 1416, 39–47 (1999).
55. I. Brigger, C. Dumernet and P. Convreur, Nanoparticles in cancer therapy and diagnosis, Adv.
Drug Deliv. Rev. 54, 631–651 (2002).
56. W. H. Finlay, The Mechanics of Inhalated Pharmaceutical Aerosol: An Introduction, Academic
Press, New York (2001).
57. J. Heyder, J. Gebhard, G. Rudolf, C. Schiller and W. Stahlhofen, Deposition of particles in the
human respiratory tract in the size range 0.005–15 μm, J. Aerosol Sci. 17, 811–825 (1986).
 Preparation of functional nanoparticles 611

58. J. O.-H. Sham, Y. Zhang, W. H. Finlay, W. H. Roa and R. Löberberg, Formulation and
characterization of spray-dried powders containing nanoparticles for aerosol delivery to the lung,
Int. J. Pharm. 269, 457–467 (2004).
59. M. Kabbaj, N. C. Phillips, Anticancer activity of mycobacterial DNA: effect of formulation as
chitosan nanoparticles, J. Drug. Targeting 9, 317–328 (2001).
60. D. A. Edwards, J. Haness, G. Caponetti, J. Hrkach, A. BenJebria, M.L. Eskew, J. Mintzes,
D. Deaver, N. Lotan and R. Langer, Large porous particles for pulmonary drug delivery, Science
276, 1868–1871 (1997).
61. D. L. French, D. A. Edwards and R. W. Niven, The influence of formulation on emission,
deaggregation and deposition of dry powders for inhalation, J. Aerosol Sci. 27, 769–783 (1996).
62. T. R. Sosnowski, L. Gradoń, F. Iskandar and K. Okuyama, Interaction of deposited aerosol
particles with the alveolar liquid layer, in: Optimization of Aerosol Drug Delivery, L. Gradoń
and J. Marijnissen (Eds), pp. 205–216. Kluwer, Dordrecht (2003).
63. R. Vanbever, A. BenJebria, J. Mitzes, R. Langer and D. A. Edwards, Sustained release of insulin
from insoluble inhaled particles, Drug Dev. Res. 48, 178–185 (1999).
64. I. Gonda, Physico-chemical principles in aerosol delivery, in: Topics in Pharmaceutical
Sciences, D. J. A. Crommelin and K. K. Midha (Eds), pp. 95–115. Medpharm Scientific, Stuttgart
(1991).
65. O. D. Velev, K. Furusawa and K. Nagayama, Assembly of latex particles by using emulsion
droplets as templates: 1. Microstructured hollow spheres, Langmuir 12, 2374–2384 (1996).
66. H. N. Pham, A. Viergutz, R. J. Gormley and A. K. Datye, Improving the attrition resistance of
slurry phase heterogeneous catalysts, Powder Technol. 110, 196–203 (2000).
67. H. E. Bergna, Attrition resistant porous particles produced by spray drying, in: Proc. 196th Natl.
Mtg. of ACS. ACS, Washington, DC (1989), Ch. 7.
68. R. H. Müller and J. S. Lucks, Arzneistofftrager aus festen Lipidteilchen (Feste Lipidnanospharen
(SLN)), Eur. Patent EP 0 605 497 B1 (1996).
69. C. Schwarz, W. Mehnert, J. S. Lucks and R. H. Müller, Solid lipid nanoparticles (SLN) for
controlled drug delivery: I. Production, characterization and sterilization, J. Control. Release 30,
83–96 (1994).
70. C. Freitas and R. H. Müller, Spray-drying of solid lipid nanoparticles (SLNTM), Eur. J. Pharm.
Biopharm. 46, 145–151 (1998).
71. L. Spanhel and M. A. Anderson, Semiconductor clusters in the sol-gel process: quantized
aggregation, gelation and crystal growth in concentrated ZnO colloids, J. Am. Chem. Soc. 113,
2826–2833 (1991).
72. S. Monticone, R. Tufeu and A. V. Kanaev, Complex nature of the UV and visible fluorescence
of Colloidal ZnO nanoparticles, J. Phys. Chem. B. 102, 2854–2862 (1998).
73. L. Brus, Electronic wave-functions in semiconductor clusters — experiment and theory, J. Phys.
Chem. 90, 2555–2560 (1986).
74. M. Abdullah, T. Morimoto and K. Okuyama, Generating blue and red luminescence from
ZnO/polyethylene glycol nanocomposites prepared by in-situ method, Adv. Funct. Mater. 13,
800–804 (2003).
75. Mikrajuddin, F. Iskandar, F. G. Shi and K. Okuyama. Stable photoluminescence of zinc oxide
quantum dots in silica nanoparticles matrix prepared by the combined sol-gel and spray drying
method. J. Appl. Phys. 89, 6431–6434 (2001).
76. M. Abdullah, S. Shibamoto and K. Okuyama, Synthesis of ZnO/SiO2 nanocomposite emitting
specified luminescence color. Opt. Mater. 26, 95–100 (2004).
77. A. Ulman, Formation and structure of self-assembled monolayers, Chem. Rev. 96, 1533–1554
(1996).