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Synthesis and processing of magnetic nanoparticles
Dimitri Stanicki1, Luce Vander Elst1,2, Robert N Muller1,2 and
Sophie Laurent1,2
Inorganic nanomaterials and their unique physical properties
are the center of modern material science due to their potential
technological importance. Among the existing structures,
magnetic iron oxide nanoparticles (MNPs), including magnetite
(Fe3O4) and maghemite (g-Fe2O3), exhibit remarkable magnetic
properties, called ‘superparamagnetism’, making these
nanostructures suitable for a wide range of applications.
Because their physico-chemical properties play an important
role in major applications, our review focuses on the synthesis
approaches giving rise to the best control of size and shape.
Addresses
1
Department of General, Organic and Biomedical Chemistry, NMR and
Molecular Imaging Laboratory, University of Mons, 19 Avenue Maistriau,
7000 Mons, Belgium
2
Center for Microscopy and Molecular Imaging (CMMI), 8 Rue Adrienne
Boland, 6041 Gosselies, Belgium
Corresponding author: Laurent, Sophie (sophie.laurent@umons.ac.be)
Current Opinion in Chemical Engineering 2015, 8:7–14
This review comes from a themed issue on Nanotechnology
Edited by Hong Yang and Hua Chun Zeng
For a complete overview see the Issue and the Editorial
Available online 29th January 2015
http://dx.doi.org/10.1016/j.coche.2015.01.003
2211-3398/# 2015 Elsevier Ltd. All rights reserved.
Introduction
In the last decades, the synthesis of inorganic nanopar-
ticles has been intensively pursued because of their many
technological possibilities. Indeed, the reduction of the
size to the nanometer scale has led to the discovery of
novel and extraordinary properties which found many
applications in various technological fields.
Among existing inorganic nano-systems, magnetic iron
oxide nanoparticles (i.e., magnetite and maghemite) have
emerged as a very promising tool. When reducing the size
from bulk to the nanometer size (<20 nm), iron oxide
material (ferrimagnetic) acquires novel magnetic proper-
ties called ‘superparamagnetism’. When superparamag-
netic objects are submitted to a magnetic field, their
global magnetic moment aligns in the direction of the
field, but when the field decreases to zero, the magnetic
moment of the sample immediately returns to zero. This
non-remanence is due to the return to equilibrium of the
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magnetic moments through Néel relaxation, when the
particles are small enough, or through the diffusive rota-
tion of the particle in the solvent in the case of larger
particles [1].
Among exploited applications of superparamagnetic
nano-systems, we can quote catalysis [2,3–6], high den-
sity magnetic data storage [7], gas sensors [8,9], inks and
toners for xenography [10] or polluting agent removal
[11,12]. Thanks to their magnetic properties and poorly
toxic character [13], magnetic iron oxide nanoparticles
(NPs) have also extensively been used for a large panel of
biomedical applications, especially for magnetic reso-
nance imaging (MRI) [14,15,16]. Some iron oxide-based
systems have already been used clinically [13] for the
detection of hepatic or spleen anomalies, and the devel-
opment of emerging areas such as magnetic hyperthermia
[17,18,19,20], cell tracking [21–23], drug delivery [24],
molecular imaging [25–27] or, more recently, magnetic
particle imaging [28,29] have encouraged researchers to
continue their effort in the development of reliable
procedures to afford nanoparticles exhibiting desired
properties. As an example, to be conveniently used in
bio-related applications, the ideal magnetic supports
should have high magnetic properties, small size and
narrow size distribution, high surface functionality,
well-defined morphology, in addition to nontoxicity
and biocompatibility. These characteristics can be
achieved by the optimization of the preparation process.
Iron oxide nanoparticles synthesis
Because of their great potential in a wide range of
applications, numerous synthetic methods were devel-
oped to produce iron oxide nanoparticles, with good
control of shape, composition, size and size distribution
[13,16,27,30]. The manufacturing of nanoparticles can be
roughly categorized as either ‘top-down’ (reduction of the
size from the bulk material) or ‘bottom-up’ (from molec-
ular reagents to the nanosized structure). Typically, the
bottom-up methods are preferred due to the possibility to
obtain smaller particles, with good control over their size,
shape and size distribution.
Upon all existing methods, iron salts co-precipitation in
aqueous solution probably represents the simplest and
most efficient way to produce magnetic nanoparticles at
the gram-scale. The particles obtained by this method
generally exhibit a mean diameter inferior to 50 nm. In a
typical procedure, an alkaline source (NaOH or NH4OH)
is added to a mixture of ferrous and ferric salts. Stable
Current Opinion in Chemical Engineering 2015, 8:7–14
8 Nanotechnology
suspensions are obtained by washing the flocculate with
acid or basic solutions. Following the experimental con-
ditions (stoichiometry, pH, ionic strength, temperature,
nature of the salts, etc.), the size and the shape of the
particles can be adjusted as previously studied by Jolivet
[31] and Hui [32]. Even if the method is fast, easy to
implement and inexpensive (high yield and low cost of
the precursors), it affords poorly crystalline particles,
characterized by a quite broad size distribution which
consequently requires size sorting procedures to reduce
the polydispersity index of the batches.
Stable magnetite colloids can be produced by performing
the reaction in the presence of polymers, such as dextran
[33], or polyacrylic acid [19]. The use of such process
often leads to the formation of particle clusters embedded
in a polymeric matrix, which can be undesirable for the
desired application. The method is also efficient for the
preparation of nanocomposites. In this way, Kalantari [34]
has recently prepared Fe3O4/talc for environmental
applications by the alkaline co-precipitation of iron(II)/
iron(III) chlorides in a suspension of talc. Similarly,
cellulose/Fe3O4 nanocomposites have been synthesized
for arsenic removal applications [34].
A better control of the size distribution and magnetic
properties can be obtained in the presence of surfactants.
Small sized ferrites (including Fe3O4, CoFe2O4 and
MnFe2O4) [35] were prepared by using alkanolamines
(isopropanolamine and diisopropanolamine) as the alka-
line source and as complexing agents. This allows to
control the particle size during the synthesis process
and to improve the spin rearrangement at the surface
(thinner magnetic ‘dead’ layers) conferring better mag-
netic properties when compared to the classical method.
In a recent report, Van Tendeloo [36] studied the influ-
ence of surfactants (cetyl trimethylammonium bromide
(CTAB), polyvinyl pyrrolidone (PVP) and sodium cho-
late) on the structural and magnetic properties of NPs.
Even if TEM measurements on the various iron oxide
nanoparticle batches did not reveal any surfactant effect
on the morphological properties of NPs, the estimated
average particle and crystallite size distributions appear to
depend on the choice of the surfactant.
Alternatively, leading the reaction in a solvent which can
play a role of surfactant revealed to be highly efficient for
the control of the physico-chemical parameters. Diethy-
leneglycol (DEG) was used as a solvent by Qu and
co-workers [37] for the preparation of small-sized spheri-
cal NPs. More than the chelating properties of DEG
which give a good control of the size distribution,
the possibility to work at high temperature allows to
improve the crystallinity and the magnetic properties
of the particles. A similar protocol has been proposed
by the team of Muller for the preparation of bimodal
particles MRI/optical imaging [23,38].
Current Opinion in Chemical Engineering 2015, 8:7–14
Toward the fine tuning of the IONPs
properties
Even if such particles exhibit a quite good control of the
size distribution when comparing with particles obtained
with the classical route, it can be necessary, following the
intended application, to achieve an optimal control of
the shape, size and size distribution. It is reported that the
production of highly monodispersed NPs (in size and
morphology) can be achieved by the decomposition of
iron organic complexes performed at high temperature.
Because of the high temperature, the nanoparticles are
well crystallized and present high saturation moments.
Generally, the reaction occurs in the presence of surfac-
tants (long hydrocarbon chains), which guarantee the
growth control and a good particle dispersibility in apolar
solvent (n-heptan, chloroform or tetrahydrofuran). The
reaction can be performed either by progressively warm-
ing a mixture of the iron precursor and surfactant(s) in a
high boiling point solvent, or alternatively by injecting a
solution of the iron complex in a hot solution containing
the surfactants (this method is referred as the ‘hot injec-
tion’). Both methods are reported to provide well-defined
NPs.
Historically, Rockenberger and collaborators [39] were
the first to report a non-hydrolytic method for the prepa-
ration of transition metal oxides. To proceed, Fe(III) N-
nitrosophenylhydroxylamine was injected in octylamine
at high temperature to produce 4–10 nm particles. Since
that work, many authors have reported the synthesis of
well-controlled magnetic nanoparticles from different
iron precursors, the most studied being iron(0) penta-
carbonyl, iron(III) acetylacetonate and iron(III) oleate.
The last one represents an interesting option since it can
be easily obtained after reaction between cheap and
innocuous reagents, that is iron(III) chloride and sodium
oleate.
Typically, two main strategies are used to vary the size of
the NPs. The first one is referred the ‘seed mediated
growth’ and implies the addition of iron precursor to pre-
existing nuclei. This strategy has been used by Sun for
the synthesis of various-sized NPs (4 nm, 8 nm, 12 nm
and 16 nm) starting from 4 nm seeds.
Alternatively, the nanoparticle size could be controlled by
varying experimental parameters such as reaction time,
temperature, ligand/precursor ratio [40] as well as the
solvents with different boiling points [41,42]. This meth-
od is also referred as the ‘heating-up’ process. Demortière
et al. [41] employed that strategy for the synthesis of
spherical NPs with average size ranging from 4 to 28 nm.
That study confirmed the solvent-dependent size-control
of this procedure, suggesting that its nature influences the
decomposition rate of the iron(III) precursor, influencing
thus the monomer concentration and consequently the
formation of nuclei.
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 Synthesis and processing of magnetic nanoparticles Stanicki et al. 9

In 2007, Kwon et al. [43] presented a mechanistic ap-
proach of the ‘heating-up’ synthesis of NPs starting from
iron(III) oleate as a precursor. The use of thermogravi-
metry coupled to mass spectrometry (TG-MS) as well as
in situ magnetometry measurements revealed the exis-
tence of intermediate structures at the interface between
the starting material (iron(III) oleate) and the final prod-
uct (MNPs). These species (probably poly iron oxo
clusters) are presumed to be the smallest building blocks
of iron oxide nanocrystals. Extra-experimental data
coupled to a theoretical model underlined the mechanis-
tic similitude between ‘hot-injection’ and ‘heating-up’
processes. More recently [44], MALDI-TOF mass
spectrometry has been used as an original tool to follow
the formation of iron oxide (d < 5 nm) during heating-up
process. By analyzing the relationship between mass,
size of NPs and empirical data, the authors found a
mass-to-size estimation method that enables accurate,
reliable, and fast characterization of ultrasmall iron oxide
NPs. Ex situ measurements showed that the formation of
iron–oxo clusters leads to the nucleation of iron oxide NPs
and that NPs with sizes of only a few nanometers grow
discretely from smaller to larger sizes (Figure 1).
An original approach to follow the NPs formation during
the ‘hot injection’ process has been introduced by Belaı̈d
et al. [45]. In this study, relaxometry, particularly nuclear
magnetic resonance dispersion profiles, has been used to
assess the separation between germination and nucle-
ation steps. These results coupled to XRD measurements
suggested a particle formation by digestive ripening.
Even if the co-precipitation method can be used to
diversify the nano-system’s shape (e.g., Yan [46] has

Figure 1

(a) (b) (c)

250 ºC 250 ºC
30 min 60 min

Monodisperse
Nanocrystals
20 nm 20 nm

250 ºC 250 ºC
250 ºC
60 min 20 min
10 min

Discrete
250 ºC Growth
30 min
20 nm 20 nm
250 ºC
20 min 250 ºC 250 ºC
Intensity

0 min 5 min
250 ºC
10 min
Nucleation
250 ºC
5 min 20 nm 20 nm
95 kDa

250 ºC 200 ºC 230 ºC

0 min

230 ºC Iron-oxo
Clusters
23 kDa
20 nm 20 nm
200 ºC
3.5 kDa 140 ºC 170 ºC
170 ºC

140 ºC Iron-oleate
Complexes
2 4 6 8 10 50 100 150 200 250 300 20 nm 20 nm
Mass (kDa) Mass (kDa)
Current Opinion in Chemical Engineering

(a) Mass spectra of sample aliquots drawn from the reaction solution during heating. For clarity, the spectra in the mass ranges of <10.5 kDa (left)
and >11 kDa (right) have been plotted using different scales. (b) TEM images of the nanoclusters in the sample aliquots. (c) Schemes describing
the formation mechanism proposed on the basis of the ex situ MS measurements. Reproduced with permission from Ref. [44].

www.sciencedirect.com Current Opinion in Chemical Engineering 2015, 8:7–14

10 Nanotechnology
recently reported the gram-scale production of nanowires
and nanosheets formed by the presence of sodium acetate
during co-precipitation of sulfate salts), the method suf-
fers from a lack of control of the shape and size distribu-
tion. A fine shape control [47] can be performed by the
thermal process. Prismatic iron oxide nanostructures
formed by the self-assembly of iron oxide nanoparticles
were prepared using a low thermal decomposition of
[Fe(CON2H4)6](NO3)3 [48]. TG-DTA, FT-IR and ele-
mental analysis indicated the in situ formation of cyanuric
acid during the decomposition of the iron–urea complex
which acts as the ligand for the formation of iron oxide
nanoparticles. Hyeon et al. [49] described the preparation
of cubic MNPs using Fe(acac)3 as precursor in benzyl
ether with oleic acid as a surfactant (290 8C; 30 min). By
reducing the amount of benzyl ether, the reaction allowed
the morphology evolution from the truncated cubes and
truncated octahedra to a perfect cubic shape. According to
the HRTEM analysis, it can be concluded that the fast
growth along the h1 1 1i direction resulted in the forma-
tion of nanocubes. Under high monomer concentration,
the anisotropic growth was due to kinetically controlled
growth. Recently, Guardia [50] described the use of such
nanocubes for hyperthermia treatment. Experimental
parameters such as surfactant/iron complex, the vacuum
step duration or the heating rate were found to be critical
for tuning the particles size. Interestingly, it has been
recently reported that the presence of halogen ions can
favor the formation of cubic nanostructures [51]. In fact,
it has been shown that when chlorine (or bromine) ions
lacked, only spherical nanocrystals were observed. The
halogens played a role in stabilizing {1 0 0} facets of
magnetic iron oxides, but not in regulating the thermo-
lysis kinetics or serving as the surfactant. Interestingly,
chloride ions appeared as a key inducer for the prepara-
tion of octapod nanostructures during the decomposition
of iron oleate in octadecene [52]. A proposed mechanism
of octapod iron oxide nanoparticles was that the chloride
ions were selectively bound to iron ions exposed on the
high-index facets (probably [3 1 1]) of iron oxide during
the particle growth.
Another interesting application of the thermal decompo-
sition process is the possibility to produce size-defined
and highly crystalline hybrid structures. Most of the
examples refer to the synthesis of gold/iron oxide hybrids,
either in a ‘core/shell’ structure or in a ‘dumbbell like’
configuration. Resulting from sequential growth of one of
the element on pre-existing seeds, the formation of one
configuration at the expense of the other can be obtained
by accurately adjusting the experimental parameters such
as the ratio seed/metal salt or the heating rate. For
example in the preparation of iron oxide/gold in a core/
shell configuration described by Wang et al. [53], gold(III)
acetate was reduced onto the surface of pre-formed oleic
acid-capped iron oxide nanoparticles. Landgraf [54] syn-
thesized ‘dumbbell’ hybrids from the heterogeneous
Current Opinion in Chemical Engineering 2015, 8:7–14
nucleation of iron oxide on pre-existing gold nanoparti-
cles (hot injection of iron(III) acetylacetonate). Similar
strategy has been used for the preparation MnO/Fe3O4
nanohybrids (core/shell, dumbbell and flower like) by
reducing at high temperature Mn(II) acetate on existing
iron oxide seeds in the presence of trioctylamine [55,56].
Small nuclei can also be included inside the iron oxide
core. The group of Gao [57] was able to produce hybrid
systems where small gadolinium oxide entities were
embedded inside the iron oxide core. Such nanosystems
(Figure 2) were easily obtained by thermal co-decompo-
sition of a mixture of oleate salts of iron and gadolinium
(10/1) in octadecene in the presence of oleic acid. The
size of the produced nanosystems was 14 nm. In another
study, the same team [58] was able to produce smaller
nanohybrids (2.8 nm, 3.5 nm and 4.8 nm) by using other
metal complexes (i.e., iron(III)acetylacetonate and gado-
linium(III) 2,4-pentanedionate) in the presence of a
mixture of surfactants (oleic acid/oleylamine/1,2-hexade-
canediol). The as-prepared nano-hybrids proved to be
interesting alternatives as T1 contrast agents for MRI,
even at high field (7 T). To explain this, the authors
suggested that the presence of the gadolinium oxide
inside the iron oxide core induced an inner spin-canting
effect. This resulted in a significant decrease of the
transverse relaxivity when comparing with the NPs of
same size (41.14 s1 mM1 versus 58.94 s1 mM1 at
7 T).
Walter et al. [18] recently applied the thermal decompo-
sition of iron(II) stearate to produce different-shaped
(spherical, cubical and octopods; Figure 3) hybrid nano-
particles, displaying a wüstite core coated by a magnetite
Figure 2
(a) (b)
~ 5 nm IO ~ 5 nm GdIO
Spin-oriented layer Spin- canted layer
Gadolinium species
Current Opinion in Chemical Engineering
Schematic illustration of spin phenomena in small-sized (a) iron oxide
and (b) Gd iron oxide nanoparticles. The gadolinium species (Gd2O3
nanoclusters) in Gd iron oxide nanoparticles (<5 nm in diameter)
cause an inner spin-canting effect, while the iron oxide nanoparticles
(<5 nm in diameter) contain a spin-canted surface and spin-oriented
core. Reproduced with permission from Ref. [57].
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 Synthesis and processing of magnetic nanoparticles Stanicki et al. 11
Figure 3
(a)
50 nm
(c)
50 nm
TEM images of NPs: (a) NS19, (b) NC16, (c) NO24, and (d) oxNC16. Dashed lines indicate the Fe1xO core and solid lines indicate the Fe3xO4
shell (insets show HRTEM images).
Reproduced with permission from Ref. [18].
shell for MRI/magnetic hyperthermia purpose. The con-
trol of the shape and composition has been achieved by
varying the ligand nature and the oleate quantities, the
latter parameter inducing the formation of core/shell
structures (FeO/Fe3O4).
Although high-temperature decomposition can produce
highly crystalline and uniform-sized and shaped magnetic
nanoparticles, some limitations are inherent to the tech-
nique:
 it needs relatively expensive (and often toxic)
organometallic compounds as precursors
 altough Hyeon et al. [59] reported ultra-large scale
synthesis (iron oleate, oleic acid and 1-octadecene were
mixed and heated up to 320 8C to produce, in a single
reaction, up to 40 g of monodisperse NPs), the process
needs a high temperature and tedious procedure, which
can limit the large-scale production
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(b)
50 nm
(d)
50 nm
Current Opinion in Chemical Engineering
 finally, the particles produced cannot be directly
transferred in aqueous media as a consequence of
the capping layer surrounding the NPs (mostly oleic
acid). To allow the transfer, an additional step is
required, which consists to either the addition of
amphiphilic ligands such as polymers, alkylammonium
salts or lipids [60–62], or to the exchange of the
hydrophobic layer by a hydrophilic one [63–66]. Such
procedure can imply the use of small charged
molecules (citric acid, tetramethyl ammonium hydrox-
ide or dimercaptosuccinic acid being the most used), or
the intervention of more elaborated systems consisting
of a strong anchoring functional group (dopamine,
carboxylic acid, phosphonate or alkoxysilane) attached
to a polymeric structure (often polyethyleneglycol).
Conclusions
Magnetic iron oxide nanoparticles have been exten-
sively studied in terms of their synthesis approaches,
Current Opinion in Chemical Engineering 2015, 8:7–14
12 Nanotechnology
characterizations, surface modifications, and applica-
tions, especially in the biomedical field. There are many
research published and a lot of significant progresses
have been made in recent years, especially for control of
their properties. This article attempts to highlight the
most popular and efficient synthesis approaches for the
controlled synthesis of magnetic iron oxide nanoparti-
cles. Even if deposition approaches have been cited in
the literature (electro-deposition [67] or chemical gas
phase deposition [68]), the wet-chemical approaches
appeared as the most used processes. Given to most
recent studies, thermal decomposition of organometallic
precursors appears as a reference for the synthesis of
crystalline magnetic nanoparticles with a good control
over the size, the shape and the composition. However,
even if the technique arouse a great interest from the
scientific community, it is important to note that most of
the studies imply the production of hundred milligram-
scale. The transposition to industrial production requires
the development of scale-up challenges ensuring repro-
ducibility and cost-effectiveness, as well as the use of
innocuous reagents. Surface engineered multifunctional
NPs present great interests for the future of disease
diagnosis and therapy. Clinical applications for these
nanosystems are pending the investigation of long-term
toxicity and pharmacokinetic profiles in animals and
humans. These studies will generate important informa-
tion on the behavior of developed NPs in the biological
systems. Another challenge is the blood–brain barrier
crossing to target neurodegenerative diseases.
Acknowledgements
The ARC (research contract AUWB-2010-10/15-UMONS-5), the FNRS,
ENCITE program, the COST TD1004 (Theranostics imaging and therapy:
an action to develop novel nanosized systems for imaging-guided drug
delivery), the Walloon Region (first spin-off program), the UIAP VII
program and the Center for Microscopy and Molecular Imaging (CMMI,
supported by the European Regional Development Fund and Wallonia) are
thanked for their support.
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