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Controlling aqueous silica nanoparticle synthesis
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in the 10–100 nm range†
Cite this: DOI: 10.1039/c5cc06598d
Delyan R. Hristov, Eugene Mahon and Kenneth A. Dawson*
Received 6th August 2015,
Accepted 5th October 2015
DOI: 10.1039/c5cc06598d
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We describe the control of size and homogeneity in silica nano-
particle dispersions, prepared by a two-phase arginine catalysed
aqueous method, through varying the upper organic solvent phase.
The final particle dispersion characteristics can be controlled by
varying features including solvent type and interfacial area, related
to the rate of monomer transfer at the TEOS/water interface.
Highly controlled and good quality silica nanoparticle synthesis
remains of considerable interest both practically and for scien-
tific exploration.1 Controlled synthetic methods for silica nano-
particles have been widely investigated. Silica particle formation
was demonstrated initially by way of controlled hydrolysis of
silicon alkoxides dissolved in alcohols2 with mechanistic under-
standing subsequently developed.3–8 Alongside, processes of
amorphous silica formation in aqueous conditions in nature
were elucidated at a chemical level.9–11 Naturally produced
diatom biosilica was found to be modulated through zwitter-
ionic peptide and polyamine species, leading to the investiga-
tion of a range of synthetic polyamines.12–16 Reduction of these
observations lead to simple synthetic protocols employing
basic amino acids: lysine,17 arginine18 and quaternary amines19
which have enabled highly monodisperse particle synthesis in the
10–40 nm range. Multi-step processes based on controlled regrowth
have also been proposed recently for extending the size range of
such highly monodisperse particles outside this range.18,20
Particle size has been controlled by synthetic parameters
including stirring conditions,21 temperature,22 pH,23 reaction
time,21 precursor concentration22 including the possibility of
multistep regrowth procedures to give larger sizes.24 Here we
increase the ‘‘one-step’’ size range by using solvent variation as a
novel control method. In accord with other recent reports25 we
show that, hydrolysis dependant transfer to the aqueous phase is
a fundamental control mechanism which can be influenced by
Center for BioNano Interactions, School of Chemsitry and Chemical Biology,
University College Dublin, Belfield, Dublin 4, Ireland.
E-mail: Kenneth.A.Dawson@cbni.ucd.ie
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5cc06598d
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organic phase type, interfacial surface area and TEOS concen-
tration. Silica nanoparticles produced by this method have
advantages over those produced in alcohols in terms of increased
stability against dissolution.26 We have noted recently that nano-
silica produced by aqueous methods shows a greater resistance
than those typically produced in ammonia–alcohol systems to
hydrolytic dissolution in biological conditions and can thus
enable the synthesis of biological probes of increased usefulness.
Also a fine level of size control in the range 10–120 nm, or from
the dimension of larger proteins to those of viral capsid assem-
blies, is considered desirable for investigating synthetic nanoscale
biology.27 Hence for the preparation of biologically optimised
nanoprobes we looked for a way to expand the simple one-step
amino acid catalysed approach beyond the typical 10–40 nm range
in a single step by controlling monomer transfer rate.
Previous studies, using similar methodologies, have described
dispersion growth behaviour as following classical La Mer nuclea-
tion principles for supersaturated solutions.21,22,25,28 In light of
these reports, we investigated the use of varied polar solvents;
C2 (ethanol), C3 (isopropanol), C4 (1-butanol), C6 (1-hexanol)
alcohols and cyclohexane, in order to control interfacial transfer
rates through solvation and interfacial interactions, and thus
hydrolysed monomer generation rate in the aqueous phase.
Nucleation and growth characteristics are largely controlled
by the rate of TEOS hydrolysis due to the partition coefficient
(which is Po/w = 103.2 for the tetraethyl form and becomes
Po/w = 10 4 in the hydrolysed silicic acid form). Thus, solvent
control can be envisioned through mutual solubility properties
for the solvents used as presented in Table S1 (ESI†). Firstly, the
trend of increasing relative polarity, correlating with increased
solvent-in-water miscibility, corresponds to decreased enthalpy
of transfer for TEOS (increasing hydrolysis rate). In addition
the solubility of water-in-solvent at equilibrium follows the
same general trend with solvent relative polarity. Increased
water content in the respective solvent phases will increase
TEOS hydrolysis rate. Lastly, for the case of isopropanol and
ethanol complete miscibility results in a loss of the phase
partitioning effect, resulting in rapid hydrolysis, and high
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Fig. 1 (a) Monomer generation for solvent controlled two phase synthesis
of silica nanoparticles detected by molybdate assay and (b) a compari-
son between the rate constants (in mM per min) obtained by NMR and
molybdate assay.
supersaturation concentration giving higher numbers of finally
smaller particles.
We monitored initial stage silicate and ethanol generation
in the aqueous phase by molybdate assay and 1H NMR respec-
tively (Fig. 1 and Fig. S1, ESI†). The generation of dissolved
silicate species in the aqueous phase was monitored to estimate
the initial transfer rates (Experimental details in ESI†) directly.
It is evident that adding solvents of increased polarity results in
increased rates of soluble silicate generation with the series
following ethanol 4 isopropanol 4 butanol 4 hexanol. These
molybdate assay results are further supported through 1H NMR
studies on ethanol concentration increase (resulting from TEOS
hydrolysis), where the series follows isopropanol 4 butanol 4
hexanol (ethanol could not be studied).
Taking initial monomer concentration, determined for 0 to
30 minutes, it is evident that more polar organic solvents lead to a
faster monomer generation. This results in the attainment of a
higher supersaturation concentration, a higher initial seed number
upon nucleation and thus a larger number of smaller diameter NPs
in the final dispersion upon exhaustion of the precursor. Monitor-
ing light scattering counts by dynamic light scattering (DLS)
allowed us to relate soluble silicate concentration kinetics and
nucleation kinetics (Fig. S2, ESI†). Time to nucleation (Fig. S2,
ESI†), was considered as time to obtaining a significant growing
scattering count rate. It is worth mentioning that particle charac-
terisation results obtained in this experiment are not considered
accurate, rather the technique is used only as a monitor of scatter-
ing behaviour. In the case of ethanol nucleation time of 90 mins is
observed by DLS (Fig. S2b, f and S3, ESI†). For the other solvents
nucleation time was shown to occur at longer times in accordance
with polarity decrease (Fig. S3, ESI†). Time to the termination of
dispersion growth was also measured and determined to be
72 hours for our standard protocol (Fig. S4, ESI†).
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Fig. 2 Tuning of NP size by dilution of TEOS in organic phase (a) DLS and
(b) DCS. Effect of adding increasing TEOS amounts to organic phase
evaluated (c) hydrodynamic diameter (Z-average diameter) by DLS and
(d) weight average diameter by DCS.
Based on these initial observations, concluding that solvent
polarity indeed impacts nucleation and growth characteristics,
we then looked to broaden the scope for size modulation by
investigating the effect of increased parameter variation for this
solvent set. We looked at further controlling monomer transfer
rate by diluting TEOS on the organic/aqueous interface. Diluting
the TEOS by increasing the relative volume of organic solvent used
should further decrease transfer rate leading to lower super-
saturation concentrations and hence increased final particle size.
This hypothesis was confirmed by our observations (Fig. 2a
and b, supporting TEM images and histograms are shown on
Fig. S5a–d, histograms on Fig. S6, and further supported in
Fig. S7a, ESI†). Notably, ethanol remains an exception as, in
contrast to the other solvents which phase separate, it completely
solubilises TEOS in the aqueous phase.
Increasing the TEOS concentration results in increasing the
mean final diameter of the dispersion. We surmise that while
increased TEOS concentration may increase initial seed number,
the increased growth enabled by increased precursor availability
overcomes this (Fig. 2c and d, support TEM in Fig. S5e–i and
histograms in Fig. S6b, ESI†).
Further studies on phase volumes were performed as pre-
sented in Fig. S7b (ESI†) where the effect of increasing the
aqueous phase volume holding all else constant was studied.
Here a smaller final diameter was expected given that the
number of seed nuclei formed should increase with volume.
Surprisingly little variation ensued however, with a balancing
effect possible through nucleation occurring at a lower super-
saturation concentration. Both the dilution effect and precursor
concentration effect experiments are summarized in Tables S2
and S3 (ESI†).
Catalyst (L-arginine) concentration was investigated, where
above a critical catalyst concentration, no substantial effects on
size were observed (Fig. S8, ESI†).
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Fig. 3 Effect of interfacial area on particle size. (a) DLS and DCS for particles
made in the absence organic solvent and (b) with butanol as solvent synthe-
sised at different volume/surface area ratios: 0.12 cm 1, 0.65 cm 1 and 1 cm 1.
(c) TEM images for the butanol synthesised particles shown.
For such phase transfer dependant preparation interfacial
area is obviously fundamental to transfer rate. Thus we studied
the effect of varying this parameter as interfacial area/aqueous
phase volume. As can be expected from our previous results, we
observed that increasing interfacial area relative to volume,
thus increasing transfer rates leads to a final dispersion of
smaller NPs (Fig. 3).
The maximum particle diameter we could obtain, pushing
the investigated parameters toward larger sizes (lower interfacial
area/volume and higher dilution of TEOS in organic phase); was
120 nm in a one-pot synthesis. Due to low transfer rate particle
growth took 160 hours to complete as opposed to the typically
observed 72 hours (Fig. S9, ESI†). However secondary nuclea-
tions do become an issue when pushing for larger diameters see
TEM S9, ESI.†
This important consideration, revealed in these studies,
is that increasing the final diameter by limiting transfer rate
operates in a certain range, outside of which secondary nuclea-
tion occurs. This is a result of lowered silicate consumption, by
lower overall particle surface area, allows the precursor to again
supersaturate as phase transfer continues, and thus nucleate.
This effect is especially apparent when using hexanol or cyclo-
hexane as solvents where on average the distribution is
broader, the reproducibility is reduced and bimodality is often
observed (Fig. S5h, S9 and Tables S2, S3, ESI†). The effect also
manifests as a limitation on using TEOS dilution in the organic
phase as a means of increasing NP diameter (Fig. S5d, ESI†)
and reducing precursor solvation rate though reduced tempera-
ture or dynamic temperature (Fig. S10, ESI†).
All reactions above were performed in closed containers,
and while the temperatures applied (70 1C) are below boiling
(Table S1, ESI†), vapour phase composition, impacting slightly
liquid phase concentrations, would vary with solvent inter-
molecular forces. In our interpretations here, we have considered
variation in vapor phase composition as having a very minor
effect on liquid phase composition.
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Fig. 4 Selected optimal parameters: (a) DCS (b) DLS graphs and (c) table
of the synthesis conditions used to make particles of different size.
Thus we can conclude that size and mondispersity of silica
particles synthesized though a modified two phase method is
dependent on a range of factors. Here we emphasize the use
of organic solvents of varied polarity to increase the range of
options available in controlling the nucleation and growth
characteristics of the mixture. Based on these methods, with
adequate attention, a wide range of sizes (10–120 nm) can be
obtained in a one pot synthesis, with selected combinations
outlined in Fig. 4. A drawback of the approach is the increased
polydispersity and polymodality when slowing transfer rates to
attain larger NP diameters.
With ever increasing interest in model probes to study the
biological impact of nanoscale materials from both toxicological
as well as potential therapeutic intervention viewpoints, this bio-
compatible method provides for simple one step variation in
dispersion characteristics. In addition to enabling fine size
control and demonstrated synthetic reproducibility, it is applic-
able in the preparation of nanoscaffolds in a biologically impor-
tant size range, spanning larger proteins to viruses, with scale
having a central impact on biological behaviour.28
E.M. gratefully acknowledges funding from the Irish Research
Council and Intel Ireland, (Ref no: EPSPD/2012/443). Further
assistance through the QualityNano Research Infrastructure
(Agreement no: 262163) is gratefully acknowledged.
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