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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
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
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).
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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.
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
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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308
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.
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
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
309
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.
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.