NANOMEDICINE

Journal of Controlled Release 147 (2010) 304310

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Journal of Controlled Release

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j c o n r e l

Nanoparticles by spray drying using innovative new technology: The Bchi Nano
Spray Dryer B-90
Xiang Li a, Nicolas Anton a,, Cordin Arpagaus b, Fabrice Belleteix b, Thierry F. Vandamme a
a
Universit de Strasbourg, Facult de Pharmacie, UMR CNRS 7199 Laboratoire de Conception et Application de Molcules Bioactives, quipe de Pharmacie Biogalnique,
74 route du Rhin BP 60024 F-67401 Illkirch Cedex, France
b
Bchi Labortechnik AG, Meierseggstr. 40, Postfach CH-9230 Flawil 1, Switzerland

a r t i c l e

i n f o

Article history:
Received 13 May 2010
Accepted 17 July 2010
Available online 24 July 2010
Keywords:
Spray drying
Bchi
Nanoparticle
Nano-emulsion
Nano-crystals

a b s t r a c t
Spray drying technology is widely known and used to transform liquids (solutions, emulsions, suspension,
slurries, pastes or even melts) into solid powders. Its main applications are found in the food, chemical and
materials industries to enhance ingredient conservation, particle properties, powder handling and storage
etc. However, spray drying can also be used for specic applications in the formulation of pharmaceuticals
for drug delivery (e.g. particles for pulmonary delivery). Bchi is a reference in the development of spray
drying technology, notably for laboratory scale devices. This study presents the Nano Spray Dryer B-90, a
revolutionary new sprayer developed by Bchi, use of which can lower the size of the produced dried
particles by an order of magnitude attaining submicron sizes. In this paper, results are presented with a panel
of ve representative polymeric wall materials (arabic gum, whey protein, polyvinyl alcohol, modied
starch, and maltodextrin) and the potentials to encapsulate nano-emulsions, or to formulate nano-crystals
(e.g. from furosemide) are also shown.
2010 Elsevier B.V. All rights reserved.

1. Introduction
Nanoparticles are commonly described as solid colloidal particles,
ranging in size from 10 nm to 1 m [13]. Nanoparticles used for drug
delivery are designed from macromolecular and/or molecular
assemblies, in which the active principles such as drugs are dissolved,
entrapped, encapsulated, or even adsorbed or attached to the external
interface. Nanoparticles can be categorized into two main groups
based on their morphology: nanospheres, presenting a homogeneous,
matricial structure in which the drugs are uniformly dispersed [4], and
nanocapsules, showing a typical core-shell structure. The formulation
of nanoparticles involves certain challenges: size control and
distribution, morphology, the therapeutic goal of drug delivery,
biocompatibility of the polymer and compatibility of the physicochemical properties of the drug.
The methods used to produce nanoparticles can be divided into
three main groups [2,5]: (i) physicochemical methods e.g. the
creation of nanoparticles using preformed polymers and inducing
their precipitation by emulsicationsolvent evaporation, diffusion
or reverse salting-out (ii) in situ chemical synthesis methods of
macromolecules, giving rise for instance to polymerization or

Corresponding author. Tel.: +33(0)3 68 85 42 13; fax: +33(0)3 68 85 43 06.

E-mail addresses: xiang.li@etu.unistra.fr (X. Li), nanton@unistra.fr (N. Anton),
arpagaus.c@buchi.com (C. Arpagaus), belleteix.f@buchi.com (F. Belleteix),
thierry.vandamme@pharma.u-strasbg.fr (T.F. Vandamme).
0168-3659/$ see front matter 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jconrel.2010.07.113

interfacial polycondensation reactions [4] (iii) mechanical methods e.g. use of high-energy devices like high pressure homogenizers, soniers [2], or high-energy wet mills [3]. The relative
interest of using nanoparticulate rather than microparticulate
systems in pharmaceutical applications is in their potential to
increase the absorption rate, improve bioavailability, enable target
drug delivery for cancer therapy and intravenous delivery systems
and so forth [3].
This paper will focus on the generation of nanoparticles by
mechanical methods, that is to say, the third of the above-mentioned
methods. The originality of this study lies in its use of new technology
developed by Bchi, the so-called Nano Spray Dryer B-90. This gives
rise to a fundamentally new concept in spray drying technology, that
of producing submicron particles from a solution.
A traditional spray dryer is generally used to transform liquid
substances into powders rapidly and efciently. The speed of the
process and the consequently short drying time enables the drying of
even temperature-sensitive products without degradation [6,7]. This
spray drying process is particularly used to improve product
conservation in dried solid form. With the development of active
compound and emulsion encapsulation used in pharmaceutics,
cosmetics and functional food preparation, this method has also
been used for encapsulation purposes. The powder thus generated is
a matrix system in the form of microparticles (i.e. microspheres [5]),
exhibiting a spherical or hollowed morphology depending on the
nature of the wall material used and the operational drying
conditions such as the inlet temperature, solid concentration, gas

ow rate or feed rate. The powder samples are generally heterogeneous and amorphous. Overall yields of spray drying on a laboratory
scale are limited, reaching around 50% to 70% [8].
The strength of the Bchi Nano Spray Dryer B-90 lies in its
vibration mesh spray technology, creating tiny droplets (before
evaporation) in a size range of a smaller order of magnitude than in
classical spray dryers. This is a revolution in spray drying
technology, making it possible to produce powders in the
submicron size range with very narrow distributions and high
formulation yields [9].
Our aim in this study was to evaluate the potentials and limits of
this new spray dryer. Firstly, by determining particle size, distribution,
homogeneity, morphology, formulation yields and general aspects of
the samples, the inuence of both the wall materials (of polymeric
nature) and the different experimental conditions were investigated.
The second part of the study focused on the encapsulation of a model
lipid dispersion (i.e. a nano-emulsion formulated by a low-energy
method [10]) to generate dry submicron particles. The nal part deals
with the use of the Nano Spray Dryer B-90 to dry pure active
molecules (solubilized in the aqueous or organic phase) in order to
produce nano-crystals. Sample characterization was performed by
scanning electron microscopy (SEM).
2. Experimental section

305

aqueous phase inducing the demixtion of the oil (through spinodal

decomposition) in the form of nanometric emulsion droplets.
Surfactants immediately stabilized the nano-droplets formed.
Vitamin E acetate was chosen as a model oily phase (0.09 g),
mixed with the nonionic surfactant (0.06 g) and then brought into
contact with the aqueous phase (0.35 g), spontaneously generating
nano-emulsions. The surfactant oil weight ratio (SOR) was set at
40%. 1 wt.% of wall material aqueous solution was separately
prepared and mixed with the nano-emulsion, in order to obtain a
ratio of 1 : 4 between the nano-emulsion and the wall material (dry
compounds). The size distribution and polydispersity of nanoemulsions were assessed by dynamic light scattering using a
Malvern Nano ZS instrument (Malvern, Orsay, France). The
HeliumNeon laser (4 mW) operated at 633 nm with the scatter
angle xed at 173, and the temperature was maintained at 25C.
The polydispersity index (noted PDI) appears merely as a
mathematical denition, accounting for the relative error between
curve t and experimental values. The PDI discloses the quality of
the dispersion, from values lower than 0.1 for suitable measurements and good quality of the colloidal suspensions, to values close
to 1 for poor quality samples, which in concrete terms, either do not
present droplets sizes in the colloidal range, or exhibit a very high
polydispersity. Measurements were performed in triplicate, before
and after performing the spray drying process (ltered on 0.45 m
in this latter case).

2.1. Materials
The so-called wall materials used in this work refer to support
materials for the spray drying process. The following materials were
successively used: arabic gum (kindly provided by CNI Colloides
Naturels International, Rouen, France), whey protein (kindly provided
by DAVISCO Foods international Inc., USA), polyvinyl alcohol (PVA,
from Sigma, Saint-Louis, USA), and Cleargum CO 03psy226 and
Glucidex IT 12psy226 (which are, respectively, modied starch and
maltodextrin with DE 12, kindly donated by Roquette Frres, France).
Nonionic surfactants from BASF (Ludwigshafen, Germany) were
kindly provided by Laserson (Etampes, France), and used as received.
They are Cremophor ELP from BASF (announced by BASF as puried
and compatible with the parenteral administration, with HLB around
1214), which are polyoxiethylated-35 castor oil. Furosemide, an
active and hydrophobic model molecule for the formulation of nanocrystals, was kindly provided by Solmag (Garbagnate, Italy). Vitamin E
acetate, sodium chloride, and acetone were purchased from Sigma,
and ultrapure water was obtained using the MilliQpsy226 ltration
system (Millipore, Saint-Quentin-en-Yvelines, France).

2.2.3. Spray drying of pure low molecular weight materials

In order to formulate nano-crystals, different compounds (hydrophilic or not) were tested and spray dried to obtain nanoparticles of
pure active ingredients. Sodium chloride nano-crystals were formulated from aqueous solutions at 0.1 wt.% and 1 wt.% concentrations.
Furosemide was spray dried at 1.25 wt.% concentration in pure
acetone. In this case the Nano Spray Dryer B-90 apparatus was
connected to a cooling unit, the Inert Loop B-295, for safe operation of
solvents in a closed-mode conguration. Nitrogen was used as an
inert gas to prevent an explosive gas mixture. The O2 concentration in
the closed loop was kept below 4 vol.%.
2.3. The new Bchi technology: the Nano Spray Dryer B-90
The Nano Spray Dryer B-90 is based on a new spray drying
concept. A complete diagram of the apparatus is illustrated in Fig. 1.
The drying gas enters the apparatus from the top, heating up to the
setting inlet temperature, then ows through the drying chamber,
exiting the spray dryer at the bottom outlet, and is ne ltered before

2.2. Sample preparation

2.2.1. Wall material solutions
The different wall material solutions were prepared in ultrapure
water a day prior to performing the experiments (to ensure suitable
polymer swelling), and at three different concentrations: 0.1 wt.%,
1 wt.% and 10 wt.%.
2.2.2. Nano-emulsion formulation
Lipid nano-emulsions were chosen as lipid model suspensions,
with controllable size and polydispersity. The chosen size range of
nano-emulsions was a few orders of magnitude smaller than the
sprayed droplets and dried particles, that is, smaller than 100 nm.
Nano-emulsions were formulated according to the low-energy
emulsication process published elsewhere [10]. Briey, the nanoemulsion droplets are generated by bringing into contacts two
phases: (i) one is composed of oil plus the hydrophilic surfactant
totally miscible; and (ii) the second phase is the aqueous one which
can be for instance pure water or buffer. Once these two phases are
mixed, the hydrophilic species are immediately solubilized by the

Fig. 1. Schematic of the Nano Spray Dryer B-90.

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X. Li et al. / Journal of Controlled Release 147 (2010) 304310

leaving the instrument. The inlet temperature, Tin, and outlet

temperature, Tout, are respectively measured just after the heating
and just before the ne ltering. The liquid sample was fed to the
spray head by a pump. As illustrated in the gure, the generation of
droplets was based on a piezoelectric driven actuator, vibrating a thin,
perforated, and stainless steel membrane in a small spray cap. The
membrane (spray mesh) features an array of precise, micron-sized
holes (4.0, 5.5 or 7.0 m). The actuator is driven at around 60 kHz,
causing the membrane to vibrate, ejecting millions of precisely sized
droplets per second with a very narrow distribution. These extremely
ne droplets are dried into solid particles which are collected by
electrostatic charging and are deected to the collecting electrode.
Finally the resulting powder is collected using a rubber spatula. The
operating conditions for the experiments were kept constant at:
Tin = 100C, feed rates range from 3 to 25 mL/h (depending on the
solution viscosity, composition, etc.), the drying gas ow rate = 100 L/
min, and the spray mesh used in this study was the membrane with
4.0 m sized holes.
2.4. Scanning electron microscope (SEM) and size distribution
The size and structure of spray dried nanoparticles were evaluated
using a scanning electron microscope Philips XL20 (University of
Strasbourg, Plateforme de Microscopie lectronique, Institut de Gntique et de Biologie Molculaire et Cellulaire). The specimens were
coated with platinum/gold and examined at 20 kV. The particle size
distributions were disclosed from the SEM micrographs using a
software-assisted method that we developed, whereby only the
particle number and their diameter are collected from the raw
images (even for these SEM pictures on which the particles appeared
as agglomerated, sticked to the carbon support and metalized).
Even if particles form aggregates, our method, by isolating each
particle from the rest and dening its surface area, allows individual
identication, thus disclosing the particle size distribution. A lognormal extrapolation was applied, with a probability density
function
p
of the form f x; ; = explnx2 = 2 2 = x 2 (where
and are the mean and standard deviation), thus allowing a
quantitative comparison of the SEM pictures, and hence between the
spray dried samples.
3. Results and discussion
3.1. Formulation with pure wall materials
This section deals with the impact of the formulation parameters
on the resulting properties of the spray dried powders, i.e., the
particle size, polydispersity and morphology, which are determined
directly from the raw SEM pictures. These so-called formulation
parameters are (i) the nature of the wall materials, (ii) the precise
location of powder collection on the cylindrical collecting electrode
and (iii) the concentration of the wall material solutions before
spray drying.
As mentioned in Section 2.1, a representative range of ve
different wall materials were spray dried; arabic gum, whey
protein, polyvinyl alcohol, modied starch and maltodextrin. Fig. 2
reports SEM micrographs of spray dried powders made from 1 wt.
% of wall material solution. The particle size distributions next to
the photographs were directly derived from the SEM
pictures. Table 1 summarizes the quantitative values of the size
peaks and SD, as well as the formulation yields. The inuence of
the sample collection locations in the cylinder-shaped electrode is
also highlighted: samples collected from the bottom half of the
collecting cylinder (the lower 50% indicated in Fig. 1) are labeled
subscript 1 and those from the top half (the top 50% indicated in
Fig. 1) are labeled subscript 2. The reason for this comparison lies
in the basic law of electrostatic physics, which should inuence

the magnitude of the active electrostatic forces on the particles in

function of their size. This could result in the segregation of
potential particle size along the cylinder length, and therefore in
variations in particle size distribution along the cylinder electrode.
The spray dried samples were generally powdery and fragile.
The SEM pictures appeared homogeneous, presenting sphericalshaped particles, regardless of the wall materials and collecting
locations. Furthermore, the peak maxima were clearly below 1 m.
For modied starch, the peak was actually below 500 nm, which, for
a spray drying technique is a noteworthy result. Along with the
neness of the distribution, this is a very novel result for such
technology.
Besides these homogeneous global results, signicant differences between the maxima and size distribution standard
deviations of the samples are highlighted by the quantitative
approach reported in Table 1. The comparison demonstrates three
main points: (i) the values of the peak size and SD of the bottom
part (for reference, this part should normally have smaller
particles and a narrower distribution than the top part) (ii)
variation of the particle size between the top and the bottom part,
and (iii) variation of the SD between the top and the bottom part.
The samples of arabic gum (a1) and (a2) showed similar maxima
of 565 and 581 nm respectively. The difference was more apparent
in the peak widths, with a standard deviation of 287 nm for the
bottom part and 363 nm for the top part of the collecting cylinder.
This result indicates that bigger particles are more rapidly trapped
by the high voltage collection system than smaller ones, resulting
in a particle segregation effect over the cylinder length. This
phenomenon is further intensied by the surface charge density of
the macromolecules, as conrmed by the second example with
maltodextrin, a neutral sugar, in which no difference was noted
between the two parts of the cylinder. Indeed, there was no
signicant difference between the two collection parts; neither for
the maxima (657 and 629 nm) nor for the SD values (459 and
435 nm). Polyvinyl alcohol (c) showed a similar trend to
maltodextrin, with a very slight rise of both size maxima (from
673 to 729 nm) and peak width (from 386 to 425 nm), and (d)
show the results for modied starch, a clearly charged molecule
[11]. Here the segregation effect between the two collection parts
was signicantly enhanced. This result corroborates the proposed
particle separation idea, given that the maxima increased from
457 to 617 nm and the SD from 289 to 396 nm.
The next series of experiments were designed to evaluate the
effect of the solid concentration in the sample solution on the spray
dried particle size distributions. Representative cases were found for
arabic gum and whey protein solutions at 0.1, 1 and 10 wt.%
concentrations. The results are presented in Fig. 3 and include the
quantitative values of the size maxima and SD. The formulation yields
are reported in Table 2.
At 0.1 wt.%, outstandingly small particle sizes were achieved: the
peaks shifted to lower values of 353 and 421 nm with standard
deviations of 107 and 144 nm for arabic gum and whey protein
respectively. When the sample concentration was increased to 1 wt.%,
the size and polydispersity also increased (see Table 2). Further
increase of the concentration to 10 wt.% resulted in an enlargement of
the peak width, while the peak location remained roughly unchanged.
Nevertheless it resulted in severe changes to the general powder
morphology (see Fig. 3).
These experiments with pure wall materials illustrate the
promising potentials of the Bchi Nano Spray Dryer B-90. The
generation of spray dried particles is greatly facilitated, with high
fabrication yields and very narrow size distributions, with peaks
well below 1 m. Size and distribution depend on the nature of the
wall materials, the powder collection location (also inuenced and
enhanced by the applied material), and mainly on the sample
concentration.

307

Fig. 2. SEM micrographs of pure wall materials spray dried particles, the concentration for all samples before spray drying was xed at 1%. (a) arabic gum, (b) maltodextrin, (c)
polyvinyl alcohol, and (d) modied starch. The subscripts 1 indicates that the samples were collected from the bottom part of the cylinder, and subscripts 2, from the top part. The
respective size distribution is reported for each one of the samples (see Table 1). The scale bars are 10 m.

3.2. Encapsulation of nano-emulsions

Low-energy nano-emulsions, i.e. simply formed by spontaneous
emulsication, were chosen as a model to investigate the potential of
the Nano Spray Dryer B-90 for lipid encapsulation. The oil-in-water
nano-emulsion formulation procedure was followed, as described in
2.2.2 The nano-emulsion thus obtained was then mixed with 1 wt.%
wall material aqueous solution (at the weight ratio of 1 : 4). In order to

Table 1
Size distribution: values of maxima (curve peaks) and standard deviation of the
samples presented in Fig. 2. Formulation yields and representative experimental data
are also presented: dried initial mass (mini), collected mass (mcoll), inlet temperature
(Tin) and outlet temperature (Tout).
Wall materials

Peak SD
Yield
(nm) (nm) (%)

(a1)
(a2)
(b1)
(b2)
(c1)
(c2)
(d1)
(d2)

565
581
657
629
673
729
457
617

Arabic gum (bottom)

Arabic gum (top)
Maltodextrin (bottom)
Maltodextrin (top)
Polyvinyl alcohol (bottom)
Polyvinyl alcohol (top)
Modied starch (bottom)
Modied starch (top)

287
363
459
435
386
425
289
396

g74.7
g43.0
g80.9
g94.5

mini/mcoll
(mg)

Tin/Tout
(C)

188.8/141.0 100/4358
541.0/232.8 100/4158
357.2/288.9 100/4257
229.6/216.9 100/4358

facilitate encapsulation with the new spray drying process, the lipid
nano-droplets were specically formulated, with a size well below
100 nm (84.9 nm, PDI = 0.117). The nano-emulsion sizes were
measured before and after spray drying following a redispersion in a
volume of water equivalent to that removed (results presented in
Table 3). The emulsion/wall material ratio was adjusted in order to
obtain suitable powdery samples after spray drying. The SEM results
are reported in Fig. 4, and the quantitative values of the size maxima
and SD are summarized in Table 4.
According to the data obtained, the Nano Spray Dryer B-90 is
obviously able to encapsulate emulsions smaller than 100 nm into
separated (i.e. not aggregated) submicron solid particles. In
addition, re-dissolving the spray dried powder in water resulted
in a redispersion of the encapsulated nano-emulsions without any
signicant degradation and/or size increase. This result demonstrates the capacity of this spray drying process to preserve the
integrity of nano-structured systems, a fundamental prerequisite
for research in nano-medicine and nano-pharmaceutics. It is also
worth noting the importance of the nature of the wall materials
used. For instance, when using arabic gum, the PDI dramatically
increased (from 0.117 to 0.511). This is attributed to the specic
surface active features of the arabic gum and its afnities with the
oily components of the emulsion, which can induce droplet
occulation and destruction.

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Fig. 3. Inuence of the sample concentration on the powder size distribution. (a) arabic gum, and (b) whey protein. The subscripts 1, 2 and 3 respectively indicate the three different
concentrations of the aqueous solution before spray drying: 0.1, 1 and 10 wt.%. The samples were collected at the top part of the collecting cylinder. The respective size distribution is
reported for each one of the samples (see Table 2). The scale bars are 10 m.

Comparing the SEM pictures (Fig. 4, and Table 4) of encapsulated

lipid emulsion to those obtained with pure wall materials (Fig. 2,
Table 1) under identical experimental conditions (i.e. WM concentration xed at 1 wt.% collected in the top part of the electrode), we
noted that encapsulated lipid nano-emulsions showed a slight
increase in peak size along with a slight decrease in peak width, this
however shows a non-negligible impact of the presence of the oil
droplets on the generation of the dried particles. With an emulsion/
wall material ratio of 1 : 4, the composition of the particles was
estimated to contain 80% of hydrosoluble wall material, 12% of oil or
active lipophilic compound (vitamin E acetate in this study), and 8% of
nonionic surfactant. We can conclude that the presence of surface
active compounds such as lipid nano-droplets and nonionic surfac-

Table 2
Size distribution: values of maxima (curve peaks) and standard deviation of the
samples presented in Fig. 3. Formulation yields and representative experimental data
are also presented: dried initial mass (mini), collected mass (mcoll), inlet temperature
(Tin) and outlet temperature (Tout).
Wall materials
(a1)

0.1 wt.%

(a2)

1 wt.%

(a3)

10 wt.%

(b1)

0.1 wt.%

(b2)

1 wt.%

(b3)

10 wt.%

Arabic
gum
Arabic
gum
Arabic
gum
Whey
protein
Whey
protein
Whey
protein

Peak
(nm)

SD
(nm)

Yield
(%)

353

107

70.2

60.3/42.3

100/4260

581

363

74.7

188.8/141.0

100/4358

549

545

54.0

365.4/197.3

100/4158

421

144

50.8

54.5/27.7

100/4156

593

374

76.0

416.1/316.0

100/3858

537

618

89.4

mini/ mcoll
(mg)

1053.5/941.5

Tin/Tout
(C)

100/4760

tants do not have a signicant impact on the particle fabrication

process. The powders obtained exhibited size distributions with
maxima still below the 1 m scale and with a relatively narrow size
distribution (compared to the results in Tables 1 and 2).
3.3. Nano-crystals produced by spray drying
The fabrication of spray dried submicron particles made from
solutions using pure active ingredients, i.e. without so-called wall
materials (excipients), is a challenge and is still in abeyance. It is
however of prime interest in pharmaceutic and cosmetic formulation. The main advantage of nano-sized API crystals for drug
delivery systems is the enhanced physicochemical properties of
drug dispersion at the nanometric scale. Two model substances
were tested in this study. The rst was simply hydrosoluble salt,
NaCl, and the second was furosemide, a low molecular weight active

Table 3
Nano-emulsion size distribution, before mixing with wall materials (WM), mixed with
WM before spray drying, and after spray drying when the dried particles are
resolubilized in the same water volume.
Wall materials

Nano-emulsion
+ WM

Nano-emulsion
+ WM

Before spray
drying

After spray
drying

PDI

dh (nm)

PDI

dh (nm)

PDI

0:117

95.49
91.49
83.49
88.54

0.155
0.229
0.088
0.261

105.9
161.5
140.6
110.3

0.511
0.243
0.167
0.268

Raw nanoemulsion
dh (nm)
Arabic gum
Modied starch
Maltodextrin
Whey protein

84:86

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Fig. 4. Encapsulation of low-energy nano-emulsions by spray drying. (a) arabic gum; (b) modied starch; (c) maltodextrin; and (d) whey protein. Wall material concentrations of
the aqueous solution before spray drying: 1 wt.%; Nano-emulsion and the wall material (dry compounds) weight ratio xed at 1 : 4 (see details in the text). The respective size
distribution is reported for each one of the samples (see Table 4). The scale bars are 10 m.

molecule with poor solubility in water, used as a diuretic drug to

treat congestive heart failure and edema. The results are presented
in Fig. 5, and the values of the size maxima and SD are summarized
in Table 5.
Spray drying a pure species be it hydrophilic or lipophilic
with a low molecular weight, results in homogeneous and
powdery samples. In the case of sodium chloride, similar results
as in Fig. 3, were achieved; the size distribution was in keeping
with the sample concentration, and the narrow peaks shifted from
517 to 993 nm by increasing the solid concentration from 0.1 to
1 wt.%. As previously observed when increasing the WM concentration (Fig. 3 and Table 2), this is typically due to an increase of
the substance amount within each droplet formed before drying.
The furosemide powder size measured 1.24 m using a 1.25 wt.%
concentration, which was still considered to be a noteworthy
result. The SEM photograph of furosemide (b) shows the
formation of nanometric needle-like crystals (see insert in
Fig. 5, two of these crystals, indicated by the arrows, were
evaluated at a thickness of 66.9 and 152.0 nm) forming only part
of the predominant sphere-shaped crystals constituting the
particles. This means that the evaporation of discrete droplets
totally controls furosemide crystallization, overriding the free
needle-like crystallization of the product.
Here again, this novel spray drying technology shows signicant
potential in formulating nano-materials and this time without the
application of wall materials. Avoiding the use of excipients is a
considerable advantage in the vast domain of pharmaceutical formulation. In addition to diluting the samples, wall materials can induce
adverse effects. The spray drying experiment described above could
constitute an optimized and efcient method of API formulation.

Table 4
Size distribution: values of maxima (curve peaks) and standard deviation of the
samples presented in Fig. 4.
Wall materials
(a)
(b)
(c)
(d)

Arabic gum
Modied starch
Maltodextrin
Whey protein

Peak (nm)

SD (nm)

709
625
773
801

253
275
352
301

Fig. 5. Powder of pure low molecular weight molecules of (a) a model of water soluble
salt (sodium chloride), and (b) of a model of poorly soluble drug (furosemide). (a1) and
(a2) respectively refer to concentrations of 0.1 and 1 wt.%, and the concentration of
furosemide in (b) is 1.25 wt.%. The star indicates the correspondence with an enlarged
detail in picture (b). The respective size distribution is reported for each one of the
samples (see Table 5). The scale bars are 10 m.

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Table 5
Size distribution: values of maxima (curve peaks) and standard deviation of the
samples presented in Fig. 5.
Materials
(a1)
(a2)
(b)

0.1 wt.%
1 wt.%
1.25 wt.%

Sodium chloride
Sodium chloride
Furosemide

Peak (nm)

SD (nm)

Yield (%)

517
993
1245

182
256
482

81.1
85.4
69.3

Acknowledgments
We are very grateful to Bchi for making it possible to carry out
this study with the Nano Spray Dryer B-90. Many thanks for their
excellent technical support.

References
4. Conclusion
The Bchi Nano Spray Dryer B-90 appears to provide very
satisfactory results for the formulation of submicron particles, with
relatively high yields (70% to 90%) for small sample amounts (50 mg
to 500 mg). Five representative polymeric wall materials (arabic
gum, whey protein, polyvinyl alcohol, modied starch and maltodextrin) were spray dried and the resulting size distributions were
shown to be mainly below the 1 m scale, attaining sizes as low as
~ 350 nm with a standard deviation of ~100 nm for arabic gum
(0.1 wt.% solid concentration), which is a very noteworthy result for
spray drying technology. The size and standard deviation depend on
the nature of the wall material used, the collection location of the
powder samples on the collecting electrode (depending on the
chemical structure and intrinsic molecule charge) and mainly on the
concentration of the spray dried solution. The preliminary results of
encapsulated nano-emulsions and formulated nano-crystals using
this novel spray drying technology appear to be of extreme interest
for API formulation and offer promising perspectives for new
pharmaceutical applications using spray drying.

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