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Evaluation of scale-up strategies for the batch synthesis of dense and hollow mesoporous silica microspheres
Accepted Manuscript Evaluation of scale-up strategies for the batch synthesis of dense and hollow mesoporous silica microspheres Marek Šoltys, Martin Balouch, Ond ej Kašpar, Miloslav Lhotka, Pavel Ulbrich, Aleš Zadražil, Pavel Kova ík, František Št pánek PII: DOI: Reference:
S1385-8947(17)31934-4 https://doi.org/10.1016/j.cej.2017.11.026 CEJ 17997
To appear in:
Chemical Engineering Journal
Received Date: Revised Date: Accepted Date:
10 August 2017 2 November 2017 3 November 2017
Please cite this article as: M. Šoltys, M. Balouch, O. ej Kašpar, M. Lhotka, P. Ulbrich, A. Zadražil, P. Kova ík, F. Št pánek, Evaluation of scale-up strategies for the batch synthesis of dense and hollow mesoporous silica microspheres, Chemical Engineering Journal (2017), doi: https://doi.org/10.1016/j.cej.2017.11.026
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Evaluation of scale-up strategies for the batch synthesis of dense and hollow mesoporous silica microspheres
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Marek Šoltys , Martin Balouch , Ondř ej ej Kašpar Kašpar , Miloslav Lhotka , Pavel Ulbrich , Aleš Zadražil , 4
Pavel Kovač ík ík , František Ště pánek pánek
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1,*
Department of Chemical Engineering, University of Chemistry and Technology, Prague, Technická 5,
166 28 Prague 6, Czech Republic 2
Department of Inorganic Technology, University of Chemistry and Technology, Prague, Technická 5,
166 28 Prague 6, Czech Republic 3
Department of Biochemistry and Microbiology, University of Chemistry and Technology, Prague,
Technická 5, 166 28 Prague 6, Czech Republic 4
Zentiva, k.s., U Kabelovny 130, 102 00 Praha 10, Czech Republic
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Corresponding author. Tel.: +420 220 443 236; E-mail: [email protected]
Abstract Despite the wide application interest in mesoporous silica micro- and nano-particles and a number of synthesis routes reported in the literature, the question of chemical engineering scale-up of the synthetic routes has rarely been addressed. The present work reports the results of an experimental and computational study of batch scale-up by a factor of 40x in the specific case of two types of dense and hollow mesoporous silica microparticles produced by the hydrolysis of tetraethoxysilane (TEOS) using a CTAB surfactant template. Volume and concentration based scale-up approaches have been investigated and systematically compared using a similarity index that included parameters related to the particle size distribution (d10, d50, d90) and pore structure (mean pore diameter, specific surface area, total pore volume, sorption hysteresis loop). The particle size distribution was found to be dependent mainly on the hydrodynamic conditions, expressed by the homogenization time, while the pore structure and the overall yield of the process were found to depend mainly on the CTAB/TEOS ratio.
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Overall, successful scale-up criteria in both volume and concentration based approaches have been identified.
Keywords: scale-up; mesoporous silica; nanoparticles; core-shell; batch reactor; mixing.
1 Introduction
Structured mesoporous SiO2 micro- and nano-particles represent a class of materials with diverse applications such as catalyst supports [1–3], stimuli-responsive adsorbents [4], components of mixed matrix membranes [5] or structured micro- and nano-reactors such as chemical robots or artificial cells [6–8], carriers for targeted drug delivery [9] or a platform for theranostics. Since the possibility of loading active pharmaceutical ingredients (APIs) into the silica mesopores has been demonstrated [10], a number of studies describing the use of mesoporous silica particles in drug delivery have appeared [11], including in-vivo studies [11–17]. Although the majority of these studies are still in the early pre-clinical stages where only 10's-100's mg quantities of the materials are typically used, it can be anticipated that the need for a reproducible manufacture of scaled-up quantities of mesoporous silica nano- and micro-spheres will arise as research into silica-based drug carriers progresses to further stages.
In the pharmaceutical industry, two main silica grades are currently available as Pharmacopeia-listed excipients. One is Aerosil®, a fumed non-porous silica produced by flame pyrolysis and commonly used as a glidant in pharmaceutical formulations [18]. The other one is Syloid®, a micronized mesoporous silica marketed by Grace company in several sub-grades with different specific surface area and particle size [19]. The main use of Syloid® in pharmaceutical formulations is still as a glidant and anti-caking agent. However, other beneficial properties such as moisture binding (including liquid-solid formulations), stabilization of API form (amorphisation), or improved tablet disintegration have been pointed out.
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On an industrial scale, silica particles are manufactured either by the gas-phase pyrolysis route [20] from SiCl4 precursor (like Aerosil) or by the liquid-phase precipitation method from silicic acid [21,22], which typically involves also additional particle size modification steps. However, these two methods do not offer as high flexibility in varying the particle morphology and internal pore structure as other liquid-phase methods, such as the microemulsion, Stöber or biomimetic methods [23]. Although a relatively large number of various template-based particle synthesis protocols can be found in the literature, there is a notable absence of works that investigate scale-up approaches for these methods [23]. To the best of our knowledge, the present work is the first that deals with the subject of experimental scale-up of a process for the production of mesoporous silica particles with a hollow core structure.
The present work reports a systematic comparison of scale-up approaches for the production of mesoporous silica microspheres by a microemulsion route [24], which has been previously shown on the laboratory scale to provide material with interesting application properties [25]. The process was shown to provide mesoporous particles with a mean diameter ranging from 400 to 700 nm, pore size in the range 2-3 nm and the particles can be prepared either with a hollow or a dense core morphology. However, typical yields were in the order of 0.1 g of SiO2 particles per batch. For drug delivery studies and pharmaceutical formulation development, larger quantities of silica particles fabricated per batch are required.
Two different scale-up approaches were investigated in the present work. The first one was focused on the overall reactor scale – increasing the batch volume from 40 ml to 1580 ml. The second one was focused on the silica precursor concentration in the reactor, attempting to obtain higher particle yield while keeping the batch volume constant. The experimental conditions – in particular mixing – that are required for successful scale-up, have been identified.
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2 Experimental methods
2.1 Materials
Tetraethyl orthosilicate (TEOS, 98%), cetyltrimethylammonium bromide (CTAB), and ammonium hydroxide solution (28-30%) were purchased from Sigma-Aldrich. Ethanol for UV (99.8%) was purchased from Penta. All chemicals were used as received. Demineralized water (Aqual 25, 0.07 µS/cm) S/cm) was was used used for for all all reactions reactions and and treatment treatment processes. processes.
2.2 Synthesis of hollow and dense silica particles
The production of mesoporous silica particles described by Teng et al. [24] is based on a soft templating route (Fig. 1) where TEOS serves as both template and the silica precursor. CTAB surfactant is used for the stabilization of the emulsion in the ethanol:water (10:17 v:v) mixture. The silica hydrolysis and polycondensation is initialized by ammonium hydroxide. The original small-scale synthesis proceeds as follows: 25.5 ml of water is mixed with 15.0 ml of ethanol under vigorous stirring (25x4 mm stirring rod, 600 rpm, 100 ml glass flask), followed by the addition of 0.5 ml of TEOS. Next, varying amounts of CTAB are added (0.08 g for hollow-core structure – sample marked as RegH or 0.16 g for solid-core structure – sample marked as RegD) followed by the addition of 0.5 ml of ammonium hydroxide. During the process, the pH rises from pH 7 (water-ethanol mixture) to pH 8 (addition of TEOS), and eventually to pH 10 (addition of ammonia) where it remains until the end of the synthesis. The mixture is kept under vigorous stirring at room temperature for three hours. The resulting dispersion is then centrifuged, washed with water and calcined at 200 °C for 6 h and then at 600 °C for 6 h. A typical yield is 0.1 g of SiO2 particles. The silica particles obtained in this way were used as a reference for those synthesized during scale-up experiments.
2.3 Volume based scale-up
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The original synthesis (see Section 2.2) was scaled up using a 2 liter PTFE beaker equipped with baffles and a larger stirrer to ensure sufficient stirring and a fast homogenization time of the entire reaction volume. In the scale-up synthesis, the amount of each component was increased 40x in order to maintain the same concentrations of all reagents as in the small-scale synthesis. The synthesis proceeded as follows: 1000 ml of water was mixed with 590 ml of ethanol and the solution was sonicated for 30 seconds using the needle sonicator (Bandelin SONOPULS HD 3100) to remove dissolved gas, then 19.6 ml of TEOS was added while stirring (350 rpm, 80 x 9 mm stirring rod unless stated otherwise) followed by the addition of varying amounts of CTAB (3.2 g for hollow-core and 6.4 g for solid-core structure). The reaction was initiated by the addition of 19.6 ml of ammonium hydroxide and the mixture was stirred for 3 hours at room temperature. The resulting dispersion was filtered using pressure filtration (membrane filter Nuclepore, pore size 200 nm, diameter 134 mm) and washed with water and ethanol. The collected particles were dried at 90 °C overnight, then disrupted into a fine powder using a mortar and pestle and finally calcined at 600 °C for 6 hours.
To investigate the effect of stirring on the properties of the silica particles upon scale-up, the reaction was carried out also with a smaller stirring rod (50 x 7 mm) at 250 and 650 rpm (with and without baffles), while all other experimental conditions remained unchanged. The full set of experimental conditions investigated during volume-based scale-up is summarized in Table 1, along with the sample codes. The sample codes are structured so as to contain information about the experimental conditions. In the volumetric scale-up the sample codes start with the prefix Vx, followed by the stirrer diameter and the stirring speed in rpm, the multiple of CTAB concentration used compared to the default synthesis conditions, and lastly a + or – symbol to indicate whether baffles were used or not. For example the code Vx8/350C1+ denotes a sample from the volumetric scale-up (Vx) prepared using a stirring rod 8 cm in diameter running at 350 rpm (8/350) where the amount of CTAB was equal to that in the original laboratory synthesis (C1), and finally the + sign indicates that baffles were installed in the reaction vessel. Samples originating from the default laboratory-scale synthesis (before scaleup) are denoted “RegH” and “RegD” for the hollow and dense silica particles, respectively, and their synthesis conditions are specified on the first two lines of Table 1. These samples serve as reference materials for judging the success of individual scale-up conditions.
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Since the experiments were conducted using a magnetic stirrer and there was a change in the vessel geometry (from a round-bottom flask in the small-scale experiments to a beaker in the scaled-up experiments), the reaction mixture homogenization time was evaluated in order to compare the stirring conditions between the individual set-ups. A detailed description of the procedure used for the homogenization time determination can be found in Supplementary Information 1. The final values of the homogenization time as well as the corresponding Reynolds numbers for mixing are summarized in Table 1. Please note that due to the low concentrations of TEOS in the reaction mixture, the Reynolds number calculations are based on the properties (density and viscosity) of a binary system water-ethanol.
2.4 Concentration based scale-up
In the second scale-up approach, the aim was to increase the quantity of the final SiO2 particles obtained per batch by increasing the reactant concentrations. The original synthesis (see Section 2.2) was modified by increasing the reagent concentrations in the synthesis mixture (the total reaction volume was slightly increased due to higher amount of TEOS or CTAB used). In this case, the quantities of the template (CTAB) and the silica precursor (TEOS) were increased either individually or simultaneously in order to investigate the effect on the resulting particle morphology. The synthesis was carried out in a 200 ml teflon beaker using a 25x4 mm stirring rod at 800 rpm (homogenization time 2.5 s), otherwise the procedure was identical to that used in the volume-based scale-up. The parameters and sample codes of the concentration-based scale-up experiments are summarized in Table 2. As in the case of volumetric scale-up, the sample codes are constructed so as to contain information about the experimental conditions. In the case of concentration scale-up, the samples start with the prefix Cx, followed by the multiples of TEOS and CTAB concentration used compared to the RegH synthesis. For example the sample code CxT3C1 denotes a concentration scale-up (Cx) sample where the concentration of TEOS was three times higher (T3) compared to the RegH synthesis while the CTAB concentration remained the same (C1).
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2.5 Particle characterization
Transmission Electron Microscopy (TEM) was used to observe the structure of the silica particles and to confirm the size of the primary particles. A suspension of particles was deposited onto carboncoated copper grids for 5-10 minutes. Excess of solution was removed and the grids were dried by Whatman filtration paper. The samples were observed by JEOL JEM-1010 transmission electron microscope at acceleration voltage of 80 kV. Micrographs were taken by SIS Megaview III digital camera (Soft Imaging Systems) and analyzed by AnalySIS 2.0 software. Scanning Electron Microscopy (SEM) was used to observe the external particle morphology. A sample of dry particles was attached to an SEM stud by a double-sided carbon tape, sputter-coated by gold, and observed by the Jeol JCM-5700 SEM at an acceleration voltage of 20 kV using the secondary electron (SEI) detector.
The particle size distribution was evaluated by static light scattering (SLS) using Horiba Partica LA950V2 in the wet dispersion mode (the dispersion medium was demineralised water), using batch measurement cuvette. The refractive index for silica particles (1.45) was selected for calculating the particle size distribution from the scattering pattern. The pore size and area distribution were measured by the nitrogen sorption method (ASAP 2020, Micromeritics, USA). Samples were degassed at 300 °C for 400 minutes prior to measurement. The equilibration time in between the measurement steps was 10 seconds.
2.6 Scale-up success criteria
In order to objectively evaluate the success of scale-up, we define a set of particle properties that should be preserved when transferring the synthesis from the original small scale to the larger scale. These include parameters related to the particle size distribution (e.g. dv,10, dv,50, dv,90) and those related to the particle internal structure (e.g. presence of a hollow core, specific surface area, hysteresis loop). The "similarity index" SI is then defined as a weighted sum of the relative differences in each parameter evaluated from the original particles and from particles after scale-up:
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N
SI = ∑ w i i=1
x i − x i,0 x i,0
(1)
where wi are the weights (satisfying the condition ∑i wi = 1), xi,0 and xi are the values of the i-th property before and after scale-up, respectively. In our specific case, N = 7 and the parameters of interest are dv,10, dv,50, dv,90, the mean pore diameter, specific surface area, total pore volume and the area of the hysteresis loop (difference in the area under the adsorption and desorption curves in the nitrogen sorption measurements). Their weights were chosen differently for the hollow (RegH) and dense (RegD) core syntheses. For detailed information about the weights see the Supplementary information 2. Samples with the lowest SI are the most similar to the reference sample. As will be discussed below, an important aspect of this multi-parameter scale-up criterion is that not all particle properties can be preserved simultaneously during scale-up, and therefore the choice of the weights should reflect the relative importance of each parameter from the final application point of view. For example, if the particle flow properties are critical, then the parameters related to size distribution are more important than those related to the internal particle structure, and vice versa if the most important application property is the sorption capacity of the particles, as would be the case in pharmaceutical formulation applications. In the case of an ideal scale-up that would exactly preserve all particle attributes, the SI would be equal to 0. We will use the term “successful” scale-up to denote such scaleup conditions that will minimise the SI value (SI < 1.0), even if the SI value is not strictly 0. Likewise, scale-up conditions that lead to very large deviations from the reference material in one or more parameters (i.e., values of SI >> 1.0) will be deemed “unsuccessful”.
Apart from the similarity index, the conversion of the reactant (TEOS) achieved during the synthesis is also an important measure of success. According to the stoichiometry of the TEOS hydrolysis to SiO2, the reaction conversion was defined as
X=
mSiO2 M w,TEOS mTEOS M w,SiO2
(2)
where mSiO2 is the final mass of recovered silica particles (after drying and calcining), mTEOS is the initial mass of TEOS used for the synthesis, and Mw,i are the molar weights of the substances.
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2.7 CFD analysis
The quality of stirring of the reaction mixture during scale-up was characterised by the mixing time, which is defined as the time required for a tracer compound introduced from a point source to be fully dispersed in the entire volume of the vessel. Experimentally, the homogenisation time was determined by image analysis as described in Supplementary Information 1. Computationally, the homogenisation time was evaluated by the post-processing of velocity profiles obtained by Computational Fluid Dynamics (CFD). The flow was modelled using the Rotating Machinery, Fluid Flow physics module of the COMSOL Multiphysics® software, which solves the Navier-Stokes equations on geometries with rotating impellers. The transport of a mass-less tracer was modelled using the transport of diluted species physics. For all simulations the k-ε turbulence turbulence model model of of incompressible incompressible flow flow has has been been employed. The 3D geometry of the magnetic stirrer and baffles was approximated by infinitesimally thin 2D walls, which prevents convergence issues and significantly reduces the computation time. The comparison of a fully described 3D model and simplified geometry showed no significant difference regarding the velocity gradients or shear rate. The physical parameters for a 37% (v/v) aqueous -3
ethanol solution at 20°C were set as follows: density 951.5 kg.m ; dynamic viscosity 2.46 mPa.s; surface tension 33.5 mN.m-1.
The initial conditions were obtained by a frozen rotor study, where the effect of the impeller rotation was accounted for by the Coriolis and centrifugal forces. The time-dependent evolution of the fluid flow was then calculated for 10 s with a time resolution 0.01 s. Deformation of the free surface by baffles, walls and the flow current were solved by the moving mesh (ALE). The pseudo-stationary flow was reached in the first two seconds (11 to 26 full revolutions for 350 rpm to 800 rpm, respectively). The homogenization time was determined by coupling the results of a turbulent flow time-dependent study (2-10 s) with equations describing the transport of diluted species by diffusion and convection. A model substance of initial concentration c0 = 1 mol.m-3 (Dc = 10-9 m2.s-1) was placed at t0 = 0 s in the upper third of the vessel. The homogenization time was determined in the same
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fashion as for physical experiments with a tracer, i.e. by calculating the mean square deviation over time for 4 different control locations by the ImageJ software.
3 Results and discussion
3.1 Particle size and morphology
3.1.1 Original particles
The silica particles prepared at the 40 ml scale according to the original synthesis (Section 2.2) with 0.08 g of CTAB (sample RegH) had a uniform spherical shape with a core-shell structure. The size distribution (Fig. 2a) showed that the primary particles are the most populous fraction with a mode at 600 nm. A wider peak ranging from 1 to 10 µm in diameter based on the static light scattering (SLS) measurements is, however, also present (Fig. 2a). The TEM images show only the primary particles of 600 nm in diameter with a hollow-core structure (Fig. 3a). There were no larger particles or aggregates observed during the TEM imaging, which suggests the larger structures indicated by SLS are probably temporary clusters of several primary particles that exist in the liquid state. This is also confirmed by SEM (Fig. 3a), which shows individual smooth spherical particles of uniform size. The shell thickness of the particles is 48 ± 5 nm, evaluated using image analysis from the TEM micrographs. The yield of the RegH silica nanoparticles was 0.1 g per batch (77 % of theoretical yield based on reaction stoichiometry).
The silica particles prepared using 0.16 g of CTAB (sample RegD) had a uniform spherical shape with a dense core. The size of the primary particles was slightly smaller with a mode around 400 nm. The secondary peak was clearly separated (unlike with RegH) and was ranging between 2 and 40 µm (Fig. 2c). Both TEM and SEM images showed again only the primary particles (Fig. 3c). The yield of the RegD silica nanoparticles was 0.12 g per batch (conversion 90 %). Both particle types had a
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developed disordered mesoporous structure with a mean pore diameter around 3 nm, which will be further discussed in Section 3.2.1.
The mechanism of hollow-core silica particle formation was elaborated in detail in refs [24] and [26], and is shown schematically in Fig. 1. Let us briefly mention that CTAB is assumed to act both as a template for the mesopores (warm-like micelles), and as a surfactant to stabilise the TEOS droplets (spherical micelles). At low CTAB concentrations, hollow core particles are formed as the hydrolysis is initiated from the external surface of TEOS droplets and the reactant from the core is gradually depleted. At higher CTAB concentrations, the warm-like micelles form space-filling aggregates, resulting in porous silica particles without a hollow core.
3.1.2 Volume based scale-up
The particles prepared on a large scale (1580 ml volume) using the 80 x 9 mm stirring rod at 350 rpm in a beaker equipped with baffles (samples Vx8/350C1+ and Vx8/350C2+) had a very similar morphology to the particles prepared in the original synthesis and these scale-up conditions were considered successful. The shape, inner structure, size and morphology were comparable under both TEM and SEM (Fig. 3). The synthesis of hollow particles (Vx8/350C1+) yielded a somewhat larger amount of aggregates than the original synthesis (indicated by the rise of the secondary peak in Fig. 2a). On the contrary, the synthesis of the dense particles (Vx8/350C2+) behaved in the opposite way, yielding a smaller amount of aggregates (Fig. 2c). The TEOS conversion of the scaled up syntheses dropped only slightly to 72 % (Vx8/350C1+) and 85 % (Vx8/350C2+), respectively. The total mass yields were about 40 times higher, being 4.0 g and 5.0 g per batch, respectively, when compared to the original small-scale synthesis.
The scaled-up syntheses conducted using a smaller diameter (5 mm) stirrer, irrespective of the rpm and the presence or absence of baffles in the reaction vessel, all provided particles with a deviating morphology and were considered unsuccessful. Although the primary particles still retained their
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spherical shape, a notable coalescence has occurred, resulting in the presence of very large aggregates of over 10 µm (Fig. 2b) and sometimes even non-spherical, macroscopic silica chunks. The TEM micrographs of all particles including those obtained during unsuccessful scale-up are summarized in Supplementary Information 3. As will be discussed below, this can be attributed to poor stirring conditions, manifested by large homogenization times (Table 1). No major effect of the stirring conditions on the yield was observed. However, in addition to poor particle size distribution, the hollow structure of the particles that were supposed to be hollow was lost (also indicated by the nitrogen sorption isotherms, discussed in Section 3.2). It was attempted to counter this behaviour by slightly lowering the concentration of CTAB to 4 mM in the sample Vx5/650C0.8+. The hollow structure was regained, but the extent of particle coalescence increased rapidly and the conversion rate dropped to 62 %.
3.1.3 Concentration based scale-up
Although the absolute mass of silica particles per batch was significantly increased during the volumetric scale-up (from 0.1 g to 4.0 g per batch), the mass yield of silica particles in relation to the overall volume is still relatively low (approx. 2.5 g of SiO2 per 1000 ml). Hence, the possibility of increasing the total yield by increasing the silica precursor (TEOS) concentration in the synthesis mixture was investigated.
Initially, both TEOS and CTAB concentrations were increased proportionally by a factor of 1.5, 2, 3 and 4 (as specified in Table 2). In the case of smaller concentration increases (samples CxT1.5C1.5 and CxT2C2) the particles formed aggregates, as is visible from the size distributions (Fig. 4a). Interestingly, when the concentrations were higher (CxT3C3 and CxT4C4), the aggregates almost completely disappeared and smaller primary particles with a mode diameter around 300 nm were formed (Fig. 4b). From the size distribution point of view, the scale-up in these two cases can be considered successful. In terms of particle morphology, particles with a new rattle-like structure were obtained in the case of sample CxT1.5C1.5 (Fig. 5a), and a mixture of hollow and dense particles was
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obtained in the case of sample CxT2C2 (Fig. 5b). The high-concentration samples (CxT3C3 and CxT4C4) both provided nearly identical, dense spherical particles (Fig. 5c). The conversion was around 70% in both cases, meaning that the mass yield was improved by a factor of 2.9 and 3.8, respectively, compared to the volume based scale-up, to 7.1 and 9.4 g per 1000 ml, respectively.
In a separate set of experiments, only the concentration of the silica precursor (TEOS) was increased while keeping the template concentration (CTAB) unchanged. The TEOS concentration was increased by a factor of 2 and 3 (samples CxT2C1 and CxT3C1 as specified in Table 2). This resulted in a larger diameter of the primary particles (close to 1 µm), and almost all of them were fused together, forming large aggregates (Fig. 4a). The large extent of aggregation in this case can be attributed to the loss of colloidal stability of the primary particles. Due to insufficient coverage by the CTAB surfactant, the electrostatic repulsions between the particles are reduced relative to attractive van der Waals interactions, which results in the formation of particle aggregates. Particles from sample CxT2C1 retained the original hollow structure (Fig. 5d), while in particles CxT3C1 the hollow structure was lost and only dense particles were formed. TEM micrographs showing the structure of all particles produced under the concentration scale-up conditions are summarised in Supplementary Information 3.
3.2 Particle pore structure
3.2.1 Original particles
As reported in our previous work [25], the original samples RegH and RegD synthesized according to Teng et al. [24] (Section 2.2) yielded atypical nitrogen sorption isotherms measured at 77 K (Fig. 6a and 6c). The formation of the first monolayer can be observed up to the relative pressure 0.1, followed by the second layer, which forms up to the relative pressure 0.2. The steep increase of adsorbed volume in the pressure range from 0.2 to 0.3 can be attributed to condensation in the uniform, open mesopores. The following slow adsorption from relative pressure 0.3 to 0.9 is attributed to adsorption
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on the external surface of the particles, since the pores are already filled. At relative pressure 0.9, there is a steep increase, which is likely due to condensation of nitrogen in the free spaces between the particles. In case of sample RegH, there is a notable hysteresis loop during desorption. This behaviour normally suggests the presence of ink-bottle pores. However, as we discussed in our previous work, in this case it is the result of the hollow-core cavities present inside the particles. In sample RegD (no hollow core as seen in the TEM micrographs, Fig. 3c), no such hysteresis loop is present (Fig. 6c).
The BET specific surface areas of the samples were calculated from the relative pressure p/p0 = 0.050.2 and are listed in Table 3 along with other pore structure parameters evaluated from the nitrogen sorption isotherms. The C constants ranged from 13 to 30, therefore it can be assumed that the samples do not contain micropores, and the linearization of the t-plot passes through zero for calculation of the surface area of mesopores (Table 3) in the interval t = 0.3-0.4. The external surface area was calculated from the t-plot in the range t = 0.5-0.8. The values obtained from the t-plot method were in a satisfactory agreement with the BET values.
3.2.2 Volume based scale-up
The volume based scale-up samples Vx8/350C1+ and Vx8/350C2+, which were considered successful from the particle size distribution point of view (Section 3.1.2), both have qualitatively very similar sorption isotherms (Fig. 6a and 6c) to their RegH and RegD. The BET specific surface areas, the surface areas of mesopores (t-plot), the total pore volume and the mesopore volume (t-plot) were all comparable or only slightly higher than in the case of the RegH and RegD reference materials (Table 3). The sample Vx8/350C1+ containing hollow-core particles also exhibited the same hysteresis behaviour as the RegH sample, confirming the presence of the cavities (Fig. 6a). The sample Vx8/350C2+ had the highest total pore volume and mesopore volume values of all the measured samples (Table 3), but it also must be noted that the volume of the hollow cavities in the sample Vx8/350C1+ is not counted in these values, thus the total available inner volume will be higher in the hollow particles.
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In case of the samples produced at lower-intensity mixing conditions, the isotherms exhibit some notable changes. In case of the synthesis which should provide hollow particles, there is no hysteresis loop present (Fig. 6b), which is in agreement with the TEM images (see Supplementary information 3). A strong hysteresis loop is exhibited only by the sample Vx5/650C0.8+, which was produced using a lower amount of CTAB, and the particles are notably hollow also in the TEM images (see Supplementary information 3). Another notable difference is the missing bend in the isotherm at relative pressure range from 0.05 to 0.3. This could be explained by the slight reduction of the pore diameter from 3 nm to 2 nm and the consequent overlap of regions where the formation of the second adsorbed nitrogen layer and the condensation of nitrogen in the pores occur simultaneously. The specific surface areas (BET) and the specific surface areas of mesopores (t-plot) are generally higher for these samples, compared to particles obtained in the original RegH and RegD syntheses (Table 3). However, the results could be slightly affected by the presence of aggregates discussed in Section 3.1.2. This especially applies for the external surface area (t-plot) calculations.
3.2.3 Concentration based scale-up
The sorption isotherms of particles obtained during concentration based scale-up (Fig. 6d) are in agreement with the morphologies observed by TEM measurements. The two aggregate-free samples (CxT3C3 and CxT4C4) are both without a hysteresis loop, confirming the dense-core structure. Interestingly, their specific surface area (BET) and the specific surface area of mesopores (t-plot) are both notably larger then the specific surface areas of the original RegH and RegD samples (Table 3).
The pore size distribution was determined from the nitrogen sorption isotherms by the BJH and the DFT methods. Both methods confirmed the presence of mesopores in all of the samples with a narrow size distribution and a mean diameter of 2.2 nm (BJH) or 3.2 nm (DFT) for the original RegH and RegD samples and for the final Vx8/350C1+ and Vx8/350C2+ samples. The poorly mixed samples in
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the volumetric scale-up and the final samples of the concentration scale-up (CxT3C3 and CxT4C4) had the pores size distribution slightly shifted to smaller diameters to about 1.9-2.1 nm (BJH).
3.3 Comparison of scale-up approaches
3.3.1 Similarity criteria
Having analysed in detail the size distribution and the internal pore structure of particles prepared under a range of scale-up conditions, it is worthwhile making an overall, multi-criteria comparison. The Similarity Index (SI), defined in Section 2.6, was used as a measure of successful scale-up and evaluated for samples obtained during all the scale-up experiments, using the hollow-core sample RegH as a reference. The final scores are summarised in Fig. 7a (let us recall that the lower the SI value, the better the overall similarity of the SiO2 particle samples). For the hollow core synthesis, the most similar was the sample Vx8/350C1+, closely followed by the sample Vx5/650C0.8+. These samples had not only a satisfactory particle size distribution (in particular, the absence of large aggregates as expressed by dv,50 and dv,90), but also a very similar internal pore structure, including the presence of the hollow core (hysteresis loop). On the other hand, none of the other samples was able to achieve a good match in all the criteria. The results suggest that in case where it is not possible to reach suitable stirring conditions and when the presence of smaller aggregates (under 10 µm) is not an issue, it might be possible to obtain the desired particle morphology by slightly lowering the CTAB concentration in the reaction mixture.
For the dense core synthesis, the weights were adjusted in order to not factor in the hysteresis loop, since for this synthesis it was irrelevant. The most similar sample was the Vx8/350C2+ (Fig. 7b). The samples CxT3C3 and CxT4C4 had higher SI index (indicating poor similarity). In the absence of a hollow core, the main differentiating factor for the particle size distribution. However, it should be noted that a large deviation in the dv,50 and dv,90 values after scale-up does not necessarily mean a "bad"
16
product if this is caused by the absence of any aggregates. Depending on the application needs, this might be a preferable change and such particles could be considered better than the reference particles.
3.3.2 Effect of scale-up parameters on particle aggregation
It was already mentioned (Section 3.1.2) that the stirring quality has a strong influence on the outcome of the SiO2 particle synthesis – affecting both morphology and aggregation of the particles (in the case of irreversible aggregation, the particle clusters could not be broken up even by intense sonication). In order to quantify the extent of aggregation, the particle size distribution curves (Fig. 2 and Fig. 4) were post-processed to evaluate the volume fraction of non-aggregated primary particles, defined as the area under the first mode relative to the area under the entire PSD curve as illustrated in Supplementary Information 4. The homogenization time (determined experimentally as described in Supplementary Information 1) was plotted against the fraction of non-agglomerated primary particles (fprimary) and the two quantities were found to be related (Fig. 7). Longer homogenization times clearly resulted in an increased presence of aggregate presence in the sample. The homogenization time of the sample Vx8/350C1+ (volume 1580 ml), which was also the "winner" in terms of the similarity index, was comparable to the homogenization time of the original RegH synthesis volume (40 ml). The amount of aggregates present in both samples was also comparable (cf Fig. 2a). In the samples produced using less aggressive mixing conditions and therefore longer homogenization times, large aggregates were formed.
This observation was supported also by the CFD analysis of the stirred vessels before and after scaleup for both successful and unsuccessful volumetric scale-up conditions. Examples of calculated velocity profiles and tracer concentrations corresponding to physical experiments are summarised in Fig. 8 for the successful and unsuccessful volumetric scale-up. (Additional velocity profiles for other experiments can be found in Supplementary Information 5). The final homogenisation times evaluated by the post-processing of CFD simulations are given in Table 4. The trends agree well with physical experiments and confirm that in the large vessel used during volume-based scale up, a combination of
17
lower RPM with a larger diameter impeller (conditions Vx8/350C1+) provides a more efficient homogenisation than a combination of higher RPM with a smaller diameter impeller (conditions Vx5/650C1+).
3.3.3 Effect of scale-up parameters on conversion and yield
Apart from the requirement to preserve the particle properties, an important consideration during scale-up is also the overall mass balance (the product yield with respect to the theoretical maximum at a 100% stoichiometric conversion), which would have implications on the process economics. By analysing the mass yield of SiO2 obtained during the scale-up experiments, it was observed that the TEOS/CTAB reagent ratio had a very strong impact on the overall conversion, which is plotted in Fig. 10. The samples with a higher concentration of CTAB provided significantly higher yields, suggesting that TEOS cannot effectively form silica particles without the surfactant pore template used in this synthesis setup. However, since CTAB is lost in the calcining step rather than recycled in the present process, a trade-off between TEOS conversion and CTAB consumption would have to be considered in an economic analysis of the process. Fig. 10 also shows that the stirring conditions did not have a very significant influence on the TEOS conversion compared with the effect of the TEOS/CTAB ratio. The data points clustered around the TEOS/CTAB ratio 10, which correspond to the various mixing conditions investigated during the volumetric scale-up, all fall into a relatively narrow range of conversion between approx. 70-75 %.
The process of silica particle particle formation from TEOS consists of several elementary steps: (i) the actual chemical reaction (hydrolysis and polycondensation of TEOS to form SiO2); (ii) the nucleation and growth of silica particles; (iii) the aggregation of silica particles. The rates of these processes depend on the process conditions and jointly determine the quantity and quality of the final silica product. It can be expected that at constant temperature, the reaction and nucleation rates should mainly depend on the concentration of TEOS (water is at a stoichiometric excess), while the particle growth and aggregation rates should depend mainly on the hydrodynamic conditions and the
18
surfactant (CTAB) concentration. Indeed, the concentration scale-up experiments with the highest TEOS concentrations (CxT3C3 and CxT4C4) resulted in very small particles, presumable due to rapid formation of super-saturation and consequently high driving force for particle nucleation. Volumetric scale-up experiments with poor mixing conditions (e.g. Vx5/650C1-) resulted in very broad, polydisperse particle size distributions compared to well-mixed experiments for otherwise identical composition (e.g. Vx8/350C1+), presumably due to non-homogeneous concentration profiles in the reaction vessel, and therefore a broad variation of local reaction, nucleation and growth rates. Finally, experiments with insufficient surfactant concentration (e.g. CxT2C1 and CxT3C1) enabled significant particle aggregation into macroscopic clusters due to lack of primary particle stabilisation.
4 Conclusions
The scale-up of a process for the soft-templated synthesis of mesoporous silica particles by the hydrolysis of TEOS was investigated experimentally using two different approaches. In a volume based scale-up, the total yield of SiO2 particles was increased almost 40-fold, from 0.10 g (conversion 77 %) to 4.0 g (conversion 72 %) per batch in the case of hollow-core particles and from 0.12 g (conversion 90 %) to 5.0 g (conversion 85 %) in the case of dense-core particles. The stirring conditions during the synthesis (expressed by the batch homogenization time) were identified as the key parameter that determines successful scale-up, enabling both particle size distribution and internal pore structure to be preserved.
With the reagent concentration based scale-up, the total yield was increased 16-fold (4-fold from batch size enlargement and 4-fold from a higher reagent concentration) from 0.10 g (conversion 77 %) to 1.52 g (conversion 71 %) per batch. The particles obtained from the synthesis using a higher concentration of reagents lost their hollow structure, but their pore morphology was retained, the particles had a higher specific surface area and an increased mesopore volume compared to the original synthesis. Moreover, the extent of primary particle aggregation was lower.
19
Although the litre-scale production investigated in this work is still below the typical volumes that would represent a full industrial manufacture, the scaling up from a small laboratory synthesis provided important insights into the parametric dependence of the process and the trade-offs involved. When supported by CFD analysis, the current work provides a solid basis for further scale-up steps in this important yet under-explored area of chemical engineering research.
Acknowledgments We would like to acknowledge support from the Czech Science Foundation (project no. GACR 1705421S). M.S. would like to thank the Specific University Research (projects no. 4/2017 and 43/2017) for financial support. The research was conducted within the infrastructure built up from the support of the Operational Program Prague – Competitiveness (CZ.2.16/3.1.00/24501) and the financing by the CIGA project No.20132007.
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22
Figures
Figure 1: Scheme of the steps involved in the preparation of hollow and dense silica microspheres.
a)
b)
c) Figure 2: Volume-weighted size distributions of particles prepared under different conditions during volume based scale-up. a) Comparison of the original synthesis RegH with the successful scale-up conditions Vx8/350C1+, b) Comparison of the original synthesis RegH with several unsuccessful scale-up conditions, displaying the presence of large aggregates, c) Comparison of the original synthesis RegD with the successful scale-up conditions Vx8/350C2+ and one unsuccessful result displaying the presence of large aggregates.
24
a)
b)
c)
d) Figure 3: TEM and SEM micrographs of particles prepared during successful volume based scale-up, compared with the original reference. a) RegH, b) Vx8/350C1+, c) RegD, d) Vx8/350C2+.
a)
b) Figure 4: Size distributions of particles obtained during concentration based scale-up. a) Comparison of the original RegH synthesis with samples where the TEOS and CTAB concentrations were increased proportionally. b) Comparison of samples where only the TEOS concentration was increased.
26
a)
b)
c)
d)
Figure 5: TEM micrographs of particles obtained during concentration based scale-up. Samples a) CxT1.5C1.5, b) CxT2C2, c) CxT4C4, d) CxT2C1.
a)
b)
c)
d)
Figure 6: Nitrogen sorption isotherms of samples prepared during scale-up, compared with the reference materials. a) Samples RegH and Vx8/350C1+ contain a hysteresis loop due to a hollow-core structure. b) Samples obtained during volume based scale-up of sample RegH, some of which have their hysteresis loop. c) Sample RegD containing a dense core and its counterparts after a volume based scale-up. d) Comparison of samples obtained during concentration based scale-up.
a)
28
b) Figure 7: a) Similarity Index for all of the samples, using the original RegH synthesis as a reference (SI = 0). The most similar samples according to the SI score are Vx8/350C1+ and Vx5/650C0.8+. b) Similarity Index for selected samples when using the original RegD synthesis as a reference.
29
Figure 8: The ratio of the amount of the primary particles divided by the total area of all peaks in the size distribution (fprimary) was plotted against the homogenization time for the samples obtained during the volume based scale-up. Higher ratios (signifying lower amount of aggregates) were achieved with fast enough homogenization times.
a)
b)
30
c)
d)
e)
f) Figure 9: Calculated velocity and concentration profiles in stirred vessels after scale-up. a) Common logarithm of shear rate, b) velocity magnitude for experiment Vx5/650C1+. c) Evolution of tracer concentration for experiment Vx5/650C1+ at t = 0 s, t = 1.6 s and t = 7.2 s (homogenised). d) Common logarithm of shear rate, e) velocity magnitude for experiment Vx8/350C1+. f) Evolution of tracer concentration for experiment Vx8/350C1+ at t = 0 s, t = 1.6 s and t = 3.6 s (homogenised).
31
Figure 10: Dependence of TEOS conversion (based on the final yield of SiO2 particles) on the initial TEOS/CTAB molar ratio in the reaction mixture.
32
Tables Table 1: List of experiments conducted on 1600 ml scale using various stirring speeds and reactor vessel geometry. The reaction vessels was either equipped with flow regulators (marked by + at the end of the sample name) or the flow regulators were removed (marked with – at the end of the sample name). Sample
Water (ml/M)
RegH / Vx2.5/600C1RegD / Vx2.5/600C2Vx5/250C1-
25.5 / 34.1 25.5 / 34.1 1000 / 34 Vx5/650C11000 / 34 Vx5/650C21000 / 34 Vx5/650C1+ 1000 / 34 Vx5/650C0.8+ 1000 / 34 Vx8/350C1+ 1000 / 34 Vx8/350C2+ 1000 / 34
Ethanol TEOS 99.8% (ml/mM) (ml/M) 15 / 6.2 0.5 / 54
15 / 6.2
0.5 / 54
590 / 6.2 590 / 6.2 590 / 6.2 590 / 6.2 590 / 6.2 590 / 6.2 590 / 6.2
19.6 / 54 19.6 / 54 19.6 / 54
19.6 / 54 19.6 / 54 19.6 / 54 19.6 / 54
CTAB (g/mM)
NH3 (ml)
Stirring (mm/rpm) 2.5/600
Homog. Time (s) 1.8
Reynolds number (-) 2 500
0.08 / 5.3 0.16 / 10.6 3.15 / 5.3 3.15 / 5.3 6.3 / 10.6 3.15 / 5.3 2.52 / 4.2 3.15 / 5.3 6.3 / 10.6
0.5
0.5
2.5/600
1.8
2 500
19.6
5.0/250
11.5
4 000
19.6
5.0/650
8.1
10 500
19.6
5.0/650
8.1
10 500
19.6
5.0 /650
5.3
10 500
19.6
5.0/650
5.3
10 500
19.6
8.0/350
2.2
14 500
19.6
8.0/350
2.2
14 500
Table 2: List of the concentration based scale-up experiments with the sample name reflecting the multiples of TEOS and CTAB concentrations used compared to the regular synthesis of hollow silica particles. Sample
Water (ml/M)
RegH / 25.5 / 34.1 CxT1C1 RegD / 25.5 / 34.1 CxT1C2 CxT1.5C1.5 102 / 33.9
Etanol 99.8% (ml/M) 15 / 6.20
TEOS (ml/mM)
CTAB (g/mM)
NH3 (ml)
Stirring (mm/rpm)
0.5 / 54
0.08 / 5.3
0.5
2.5/800
15 / 6.20
0.5 / 54
0.16 / 10.6
0.5
2.5/800
60 / 6.16
3.0 / 81
0.45 / 7.4
2.0
2.5/800
CxT2C2
102 / 33.7
60 / 6.10
4.0 / 107
0.60 / 10.0
2.0
2.5/800
CxT2C1
102 / 33.7
60 / 6.10
4.0 / 107
0.30 / 5.0
2.0
2.5/800
CxT3C1
102 / 33.3
60 / 6.05
6.0 / 159
0.30 / 4.8
2.0
2.5/800
CxT3C3
102 / 33.3
60 / 6.05
6.0 / 159
0.90 / 14.5
2.0
2.5/800
CxT4C4
102 / 32.9
60 / 6.00
8.0 / 210
1.20 / 19.1
2.0
2.5/800
33
Table 3: Summary of pore structure characteristics of all the prepared samples based on nitrogen sorption isotherms. SSA (BET) [m²/g]
SSA of mesopores (t-plot) [m²/g]
External SSA (t-plot) [m²/g]
Total pore volume [cm³/g]
Mesopores volume (t-plot) [cm³/g]
Reg-H
950
863
110
0.705
0.504
Reg-D
1150
1027
177
0.798
0.605
Vx5/250C1-
1250
1150
59
0.585
0.517
Vx5/650C1+
1290
1090
74
0.607
0.531
Vx5/650C0.8+
1360
1030
200
0.816
0.528
Vx5/650C1-
1620
1315
119
0.770
0.650
Vx5/650C2-
1670
1480
100
0.806
0.708
Vx8/350C1+
1040
975
92
0.744
0.631
Vx8/350C2+
1300
1160
105
0.876
0.762
CxT2C1
1275
930
113
0.724
0.562
CxT3C1
1015
960
107
0.574
0.418
CxT1.5C1.5
1410
1130
65
0.661
0.592
CxT2C2
1380
1000
127
0.748
0.562
CxT3C3
1435
1245
77
0.728
0.638
CxT4C4
1370
1105
77
0.702
0.616
Sample
34
Table 4: Summary of CFD simulations based on experimental conditions and used for the evaluation of homogenization time. Calculated Sample code
CFD set-up
Stirring homogenization time (s)
100 ml round-bottom flask, 25x4 mm rod, 600 rpm
RegH / RegD
1.8
25.5 ml water, 15 ml EtOH
35
200 ml beaker, CxT1C1
25x4 mm rod, 800 rpm
2.2
50x7 mm rod, 650 rpm
7.2
80x9 mm rod, 350 rpm
3.6
102 ml water, 60 ml EtOH 2000 ml beaker + flow regulators, Vx5/650C1+ 1000 ml water, 590 ml EtOH 2000 ml beaker + flow regulators, Vx8/350C1+ 1000 ml water, 590 ml EtOH
Highlights First study into scale-up of microemulsion based process for mesoporous silica particles Volume and concentration based scale-up approaches were investigated Conditions for successful scale-up by a factor of 40x were identified Reactor mixing was the most important parameter as confirmed by CFD and experimental analysis
37
S1385-8947(17)31934-4 https://doi.org/10.1016/j.cej.2017.11.026 CEJ 17997
To appear in:
Chemical Engineering Journal
Received Date: Revised Date: Accepted Date:
10 August 2017 2 November 2017 3 November 2017
Please cite this article as: M. Šoltys, M. Balouch, O. ej Kašpar, M. Lhotka, P. Ulbrich, A. Zadražil, P. Kova ík, F. Št pánek, Evaluation of scale-up strategies for the batch synthesis of dense and hollow mesoporous silica microspheres, Chemical Engineering Journal (2017), doi: https://doi.org/10.1016/j.cej.2017.11.026
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Evaluation of scale-up strategies for the batch synthesis of dense and hollow mesoporous silica microspheres
1,4
1
1
2
3
1
Marek Šoltys , Martin Balouch , Ondř ej ej Kašpar Kašpar , Miloslav Lhotka , Pavel Ulbrich , Aleš Zadražil , 4
Pavel Kovač ík ík , František Ště pánek pánek
1
1,*
Department of Chemical Engineering, University of Chemistry and Technology, Prague, Technická 5,
166 28 Prague 6, Czech Republic 2
Department of Inorganic Technology, University of Chemistry and Technology, Prague, Technická 5,
166 28 Prague 6, Czech Republic 3
Department of Biochemistry and Microbiology, University of Chemistry and Technology, Prague,
Technická 5, 166 28 Prague 6, Czech Republic 4
Zentiva, k.s., U Kabelovny 130, 102 00 Praha 10, Czech Republic
*
Corresponding author. Tel.: +420 220 443 236; E-mail: [email protected]
Abstract Despite the wide application interest in mesoporous silica micro- and nano-particles and a number of synthesis routes reported in the literature, the question of chemical engineering scale-up of the synthetic routes has rarely been addressed. The present work reports the results of an experimental and computational study of batch scale-up by a factor of 40x in the specific case of two types of dense and hollow mesoporous silica microparticles produced by the hydrolysis of tetraethoxysilane (TEOS) using a CTAB surfactant template. Volume and concentration based scale-up approaches have been investigated and systematically compared using a similarity index that included parameters related to the particle size distribution (d10, d50, d90) and pore structure (mean pore diameter, specific surface area, total pore volume, sorption hysteresis loop). The particle size distribution was found to be dependent mainly on the hydrodynamic conditions, expressed by the homogenization time, while the pore structure and the overall yield of the process were found to depend mainly on the CTAB/TEOS ratio.
1
Overall, successful scale-up criteria in both volume and concentration based approaches have been identified.
Keywords: scale-up; mesoporous silica; nanoparticles; core-shell; batch reactor; mixing.
1 Introduction
Structured mesoporous SiO2 micro- and nano-particles represent a class of materials with diverse applications such as catalyst supports [1–3], stimuli-responsive adsorbents [4], components of mixed matrix membranes [5] or structured micro- and nano-reactors such as chemical robots or artificial cells [6–8], carriers for targeted drug delivery [9] or a platform for theranostics. Since the possibility of loading active pharmaceutical ingredients (APIs) into the silica mesopores has been demonstrated [10], a number of studies describing the use of mesoporous silica particles in drug delivery have appeared [11], including in-vivo studies [11–17]. Although the majority of these studies are still in the early pre-clinical stages where only 10's-100's mg quantities of the materials are typically used, it can be anticipated that the need for a reproducible manufacture of scaled-up quantities of mesoporous silica nano- and micro-spheres will arise as research into silica-based drug carriers progresses to further stages.
In the pharmaceutical industry, two main silica grades are currently available as Pharmacopeia-listed excipients. One is Aerosil®, a fumed non-porous silica produced by flame pyrolysis and commonly used as a glidant in pharmaceutical formulations [18]. The other one is Syloid®, a micronized mesoporous silica marketed by Grace company in several sub-grades with different specific surface area and particle size [19]. The main use of Syloid® in pharmaceutical formulations is still as a glidant and anti-caking agent. However, other beneficial properties such as moisture binding (including liquid-solid formulations), stabilization of API form (amorphisation), or improved tablet disintegration have been pointed out.
2
On an industrial scale, silica particles are manufactured either by the gas-phase pyrolysis route [20] from SiCl4 precursor (like Aerosil) or by the liquid-phase precipitation method from silicic acid [21,22], which typically involves also additional particle size modification steps. However, these two methods do not offer as high flexibility in varying the particle morphology and internal pore structure as other liquid-phase methods, such as the microemulsion, Stöber or biomimetic methods [23]. Although a relatively large number of various template-based particle synthesis protocols can be found in the literature, there is a notable absence of works that investigate scale-up approaches for these methods [23]. To the best of our knowledge, the present work is the first that deals with the subject of experimental scale-up of a process for the production of mesoporous silica particles with a hollow core structure.
The present work reports a systematic comparison of scale-up approaches for the production of mesoporous silica microspheres by a microemulsion route [24], which has been previously shown on the laboratory scale to provide material with interesting application properties [25]. The process was shown to provide mesoporous particles with a mean diameter ranging from 400 to 700 nm, pore size in the range 2-3 nm and the particles can be prepared either with a hollow or a dense core morphology. However, typical yields were in the order of 0.1 g of SiO2 particles per batch. For drug delivery studies and pharmaceutical formulation development, larger quantities of silica particles fabricated per batch are required.
Two different scale-up approaches were investigated in the present work. The first one was focused on the overall reactor scale – increasing the batch volume from 40 ml to 1580 ml. The second one was focused on the silica precursor concentration in the reactor, attempting to obtain higher particle yield while keeping the batch volume constant. The experimental conditions – in particular mixing – that are required for successful scale-up, have been identified.
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2 Experimental methods
2.1 Materials
Tetraethyl orthosilicate (TEOS, 98%), cetyltrimethylammonium bromide (CTAB), and ammonium hydroxide solution (28-30%) were purchased from Sigma-Aldrich. Ethanol for UV (99.8%) was purchased from Penta. All chemicals were used as received. Demineralized water (Aqual 25, 0.07 µS/cm) S/cm) was was used used for for all all reactions reactions and and treatment treatment processes. processes.
2.2 Synthesis of hollow and dense silica particles
The production of mesoporous silica particles described by Teng et al. [24] is based on a soft templating route (Fig. 1) where TEOS serves as both template and the silica precursor. CTAB surfactant is used for the stabilization of the emulsion in the ethanol:water (10:17 v:v) mixture. The silica hydrolysis and polycondensation is initialized by ammonium hydroxide. The original small-scale synthesis proceeds as follows: 25.5 ml of water is mixed with 15.0 ml of ethanol under vigorous stirring (25x4 mm stirring rod, 600 rpm, 100 ml glass flask), followed by the addition of 0.5 ml of TEOS. Next, varying amounts of CTAB are added (0.08 g for hollow-core structure – sample marked as RegH or 0.16 g for solid-core structure – sample marked as RegD) followed by the addition of 0.5 ml of ammonium hydroxide. During the process, the pH rises from pH 7 (water-ethanol mixture) to pH 8 (addition of TEOS), and eventually to pH 10 (addition of ammonia) where it remains until the end of the synthesis. The mixture is kept under vigorous stirring at room temperature for three hours. The resulting dispersion is then centrifuged, washed with water and calcined at 200 °C for 6 h and then at 600 °C for 6 h. A typical yield is 0.1 g of SiO2 particles. The silica particles obtained in this way were used as a reference for those synthesized during scale-up experiments.
2.3 Volume based scale-up
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The original synthesis (see Section 2.2) was scaled up using a 2 liter PTFE beaker equipped with baffles and a larger stirrer to ensure sufficient stirring and a fast homogenization time of the entire reaction volume. In the scale-up synthesis, the amount of each component was increased 40x in order to maintain the same concentrations of all reagents as in the small-scale synthesis. The synthesis proceeded as follows: 1000 ml of water was mixed with 590 ml of ethanol and the solution was sonicated for 30 seconds using the needle sonicator (Bandelin SONOPULS HD 3100) to remove dissolved gas, then 19.6 ml of TEOS was added while stirring (350 rpm, 80 x 9 mm stirring rod unless stated otherwise) followed by the addition of varying amounts of CTAB (3.2 g for hollow-core and 6.4 g for solid-core structure). The reaction was initiated by the addition of 19.6 ml of ammonium hydroxide and the mixture was stirred for 3 hours at room temperature. The resulting dispersion was filtered using pressure filtration (membrane filter Nuclepore, pore size 200 nm, diameter 134 mm) and washed with water and ethanol. The collected particles were dried at 90 °C overnight, then disrupted into a fine powder using a mortar and pestle and finally calcined at 600 °C for 6 hours.
To investigate the effect of stirring on the properties of the silica particles upon scale-up, the reaction was carried out also with a smaller stirring rod (50 x 7 mm) at 250 and 650 rpm (with and without baffles), while all other experimental conditions remained unchanged. The full set of experimental conditions investigated during volume-based scale-up is summarized in Table 1, along with the sample codes. The sample codes are structured so as to contain information about the experimental conditions. In the volumetric scale-up the sample codes start with the prefix Vx, followed by the stirrer diameter and the stirring speed in rpm, the multiple of CTAB concentration used compared to the default synthesis conditions, and lastly a + or – symbol to indicate whether baffles were used or not. For example the code Vx8/350C1+ denotes a sample from the volumetric scale-up (Vx) prepared using a stirring rod 8 cm in diameter running at 350 rpm (8/350) where the amount of CTAB was equal to that in the original laboratory synthesis (C1), and finally the + sign indicates that baffles were installed in the reaction vessel. Samples originating from the default laboratory-scale synthesis (before scaleup) are denoted “RegH” and “RegD” for the hollow and dense silica particles, respectively, and their synthesis conditions are specified on the first two lines of Table 1. These samples serve as reference materials for judging the success of individual scale-up conditions.
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Since the experiments were conducted using a magnetic stirrer and there was a change in the vessel geometry (from a round-bottom flask in the small-scale experiments to a beaker in the scaled-up experiments), the reaction mixture homogenization time was evaluated in order to compare the stirring conditions between the individual set-ups. A detailed description of the procedure used for the homogenization time determination can be found in Supplementary Information 1. The final values of the homogenization time as well as the corresponding Reynolds numbers for mixing are summarized in Table 1. Please note that due to the low concentrations of TEOS in the reaction mixture, the Reynolds number calculations are based on the properties (density and viscosity) of a binary system water-ethanol.
2.4 Concentration based scale-up
In the second scale-up approach, the aim was to increase the quantity of the final SiO2 particles obtained per batch by increasing the reactant concentrations. The original synthesis (see Section 2.2) was modified by increasing the reagent concentrations in the synthesis mixture (the total reaction volume was slightly increased due to higher amount of TEOS or CTAB used). In this case, the quantities of the template (CTAB) and the silica precursor (TEOS) were increased either individually or simultaneously in order to investigate the effect on the resulting particle morphology. The synthesis was carried out in a 200 ml teflon beaker using a 25x4 mm stirring rod at 800 rpm (homogenization time 2.5 s), otherwise the procedure was identical to that used in the volume-based scale-up. The parameters and sample codes of the concentration-based scale-up experiments are summarized in Table 2. As in the case of volumetric scale-up, the sample codes are constructed so as to contain information about the experimental conditions. In the case of concentration scale-up, the samples start with the prefix Cx, followed by the multiples of TEOS and CTAB concentration used compared to the RegH synthesis. For example the sample code CxT3C1 denotes a concentration scale-up (Cx) sample where the concentration of TEOS was three times higher (T3) compared to the RegH synthesis while the CTAB concentration remained the same (C1).
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2.5 Particle characterization
Transmission Electron Microscopy (TEM) was used to observe the structure of the silica particles and to confirm the size of the primary particles. A suspension of particles was deposited onto carboncoated copper grids for 5-10 minutes. Excess of solution was removed and the grids were dried by Whatman filtration paper. The samples were observed by JEOL JEM-1010 transmission electron microscope at acceleration voltage of 80 kV. Micrographs were taken by SIS Megaview III digital camera (Soft Imaging Systems) and analyzed by AnalySIS 2.0 software. Scanning Electron Microscopy (SEM) was used to observe the external particle morphology. A sample of dry particles was attached to an SEM stud by a double-sided carbon tape, sputter-coated by gold, and observed by the Jeol JCM-5700 SEM at an acceleration voltage of 20 kV using the secondary electron (SEI) detector.
The particle size distribution was evaluated by static light scattering (SLS) using Horiba Partica LA950V2 in the wet dispersion mode (the dispersion medium was demineralised water), using batch measurement cuvette. The refractive index for silica particles (1.45) was selected for calculating the particle size distribution from the scattering pattern. The pore size and area distribution were measured by the nitrogen sorption method (ASAP 2020, Micromeritics, USA). Samples were degassed at 300 °C for 400 minutes prior to measurement. The equilibration time in between the measurement steps was 10 seconds.
2.6 Scale-up success criteria
In order to objectively evaluate the success of scale-up, we define a set of particle properties that should be preserved when transferring the synthesis from the original small scale to the larger scale. These include parameters related to the particle size distribution (e.g. dv,10, dv,50, dv,90) and those related to the particle internal structure (e.g. presence of a hollow core, specific surface area, hysteresis loop). The "similarity index" SI is then defined as a weighted sum of the relative differences in each parameter evaluated from the original particles and from particles after scale-up:
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N
SI = ∑ w i i=1
x i − x i,0 x i,0
(1)
where wi are the weights (satisfying the condition ∑i wi = 1), xi,0 and xi are the values of the i-th property before and after scale-up, respectively. In our specific case, N = 7 and the parameters of interest are dv,10, dv,50, dv,90, the mean pore diameter, specific surface area, total pore volume and the area of the hysteresis loop (difference in the area under the adsorption and desorption curves in the nitrogen sorption measurements). Their weights were chosen differently for the hollow (RegH) and dense (RegD) core syntheses. For detailed information about the weights see the Supplementary information 2. Samples with the lowest SI are the most similar to the reference sample. As will be discussed below, an important aspect of this multi-parameter scale-up criterion is that not all particle properties can be preserved simultaneously during scale-up, and therefore the choice of the weights should reflect the relative importance of each parameter from the final application point of view. For example, if the particle flow properties are critical, then the parameters related to size distribution are more important than those related to the internal particle structure, and vice versa if the most important application property is the sorption capacity of the particles, as would be the case in pharmaceutical formulation applications. In the case of an ideal scale-up that would exactly preserve all particle attributes, the SI would be equal to 0. We will use the term “successful” scale-up to denote such scaleup conditions that will minimise the SI value (SI < 1.0), even if the SI value is not strictly 0. Likewise, scale-up conditions that lead to very large deviations from the reference material in one or more parameters (i.e., values of SI >> 1.0) will be deemed “unsuccessful”.
Apart from the similarity index, the conversion of the reactant (TEOS) achieved during the synthesis is also an important measure of success. According to the stoichiometry of the TEOS hydrolysis to SiO2, the reaction conversion was defined as
X=
mSiO2 M w,TEOS mTEOS M w,SiO2
(2)
where mSiO2 is the final mass of recovered silica particles (after drying and calcining), mTEOS is the initial mass of TEOS used for the synthesis, and Mw,i are the molar weights of the substances.
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2.7 CFD analysis
The quality of stirring of the reaction mixture during scale-up was characterised by the mixing time, which is defined as the time required for a tracer compound introduced from a point source to be fully dispersed in the entire volume of the vessel. Experimentally, the homogenisation time was determined by image analysis as described in Supplementary Information 1. Computationally, the homogenisation time was evaluated by the post-processing of velocity profiles obtained by Computational Fluid Dynamics (CFD). The flow was modelled using the Rotating Machinery, Fluid Flow physics module of the COMSOL Multiphysics® software, which solves the Navier-Stokes equations on geometries with rotating impellers. The transport of a mass-less tracer was modelled using the transport of diluted species physics. For all simulations the k-ε turbulence turbulence model model of of incompressible incompressible flow flow has has been been employed. The 3D geometry of the magnetic stirrer and baffles was approximated by infinitesimally thin 2D walls, which prevents convergence issues and significantly reduces the computation time. The comparison of a fully described 3D model and simplified geometry showed no significant difference regarding the velocity gradients or shear rate. The physical parameters for a 37% (v/v) aqueous -3
ethanol solution at 20°C were set as follows: density 951.5 kg.m ; dynamic viscosity 2.46 mPa.s; surface tension 33.5 mN.m-1.
The initial conditions were obtained by a frozen rotor study, where the effect of the impeller rotation was accounted for by the Coriolis and centrifugal forces. The time-dependent evolution of the fluid flow was then calculated for 10 s with a time resolution 0.01 s. Deformation of the free surface by baffles, walls and the flow current were solved by the moving mesh (ALE). The pseudo-stationary flow was reached in the first two seconds (11 to 26 full revolutions for 350 rpm to 800 rpm, respectively). The homogenization time was determined by coupling the results of a turbulent flow time-dependent study (2-10 s) with equations describing the transport of diluted species by diffusion and convection. A model substance of initial concentration c0 = 1 mol.m-3 (Dc = 10-9 m2.s-1) was placed at t0 = 0 s in the upper third of the vessel. The homogenization time was determined in the same
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fashion as for physical experiments with a tracer, i.e. by calculating the mean square deviation over time for 4 different control locations by the ImageJ software.
3 Results and discussion
3.1 Particle size and morphology
3.1.1 Original particles
The silica particles prepared at the 40 ml scale according to the original synthesis (Section 2.2) with 0.08 g of CTAB (sample RegH) had a uniform spherical shape with a core-shell structure. The size distribution (Fig. 2a) showed that the primary particles are the most populous fraction with a mode at 600 nm. A wider peak ranging from 1 to 10 µm in diameter based on the static light scattering (SLS) measurements is, however, also present (Fig. 2a). The TEM images show only the primary particles of 600 nm in diameter with a hollow-core structure (Fig. 3a). There were no larger particles or aggregates observed during the TEM imaging, which suggests the larger structures indicated by SLS are probably temporary clusters of several primary particles that exist in the liquid state. This is also confirmed by SEM (Fig. 3a), which shows individual smooth spherical particles of uniform size. The shell thickness of the particles is 48 ± 5 nm, evaluated using image analysis from the TEM micrographs. The yield of the RegH silica nanoparticles was 0.1 g per batch (77 % of theoretical yield based on reaction stoichiometry).
The silica particles prepared using 0.16 g of CTAB (sample RegD) had a uniform spherical shape with a dense core. The size of the primary particles was slightly smaller with a mode around 400 nm. The secondary peak was clearly separated (unlike with RegH) and was ranging between 2 and 40 µm (Fig. 2c). Both TEM and SEM images showed again only the primary particles (Fig. 3c). The yield of the RegD silica nanoparticles was 0.12 g per batch (conversion 90 %). Both particle types had a
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developed disordered mesoporous structure with a mean pore diameter around 3 nm, which will be further discussed in Section 3.2.1.
The mechanism of hollow-core silica particle formation was elaborated in detail in refs [24] and [26], and is shown schematically in Fig. 1. Let us briefly mention that CTAB is assumed to act both as a template for the mesopores (warm-like micelles), and as a surfactant to stabilise the TEOS droplets (spherical micelles). At low CTAB concentrations, hollow core particles are formed as the hydrolysis is initiated from the external surface of TEOS droplets and the reactant from the core is gradually depleted. At higher CTAB concentrations, the warm-like micelles form space-filling aggregates, resulting in porous silica particles without a hollow core.
3.1.2 Volume based scale-up
The particles prepared on a large scale (1580 ml volume) using the 80 x 9 mm stirring rod at 350 rpm in a beaker equipped with baffles (samples Vx8/350C1+ and Vx8/350C2+) had a very similar morphology to the particles prepared in the original synthesis and these scale-up conditions were considered successful. The shape, inner structure, size and morphology were comparable under both TEM and SEM (Fig. 3). The synthesis of hollow particles (Vx8/350C1+) yielded a somewhat larger amount of aggregates than the original synthesis (indicated by the rise of the secondary peak in Fig. 2a). On the contrary, the synthesis of the dense particles (Vx8/350C2+) behaved in the opposite way, yielding a smaller amount of aggregates (Fig. 2c). The TEOS conversion of the scaled up syntheses dropped only slightly to 72 % (Vx8/350C1+) and 85 % (Vx8/350C2+), respectively. The total mass yields were about 40 times higher, being 4.0 g and 5.0 g per batch, respectively, when compared to the original small-scale synthesis.
The scaled-up syntheses conducted using a smaller diameter (5 mm) stirrer, irrespective of the rpm and the presence or absence of baffles in the reaction vessel, all provided particles with a deviating morphology and were considered unsuccessful. Although the primary particles still retained their
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spherical shape, a notable coalescence has occurred, resulting in the presence of very large aggregates of over 10 µm (Fig. 2b) and sometimes even non-spherical, macroscopic silica chunks. The TEM micrographs of all particles including those obtained during unsuccessful scale-up are summarized in Supplementary Information 3. As will be discussed below, this can be attributed to poor stirring conditions, manifested by large homogenization times (Table 1). No major effect of the stirring conditions on the yield was observed. However, in addition to poor particle size distribution, the hollow structure of the particles that were supposed to be hollow was lost (also indicated by the nitrogen sorption isotherms, discussed in Section 3.2). It was attempted to counter this behaviour by slightly lowering the concentration of CTAB to 4 mM in the sample Vx5/650C0.8+. The hollow structure was regained, but the extent of particle coalescence increased rapidly and the conversion rate dropped to 62 %.
3.1.3 Concentration based scale-up
Although the absolute mass of silica particles per batch was significantly increased during the volumetric scale-up (from 0.1 g to 4.0 g per batch), the mass yield of silica particles in relation to the overall volume is still relatively low (approx. 2.5 g of SiO2 per 1000 ml). Hence, the possibility of increasing the total yield by increasing the silica precursor (TEOS) concentration in the synthesis mixture was investigated.
Initially, both TEOS and CTAB concentrations were increased proportionally by a factor of 1.5, 2, 3 and 4 (as specified in Table 2). In the case of smaller concentration increases (samples CxT1.5C1.5 and CxT2C2) the particles formed aggregates, as is visible from the size distributions (Fig. 4a). Interestingly, when the concentrations were higher (CxT3C3 and CxT4C4), the aggregates almost completely disappeared and smaller primary particles with a mode diameter around 300 nm were formed (Fig. 4b). From the size distribution point of view, the scale-up in these two cases can be considered successful. In terms of particle morphology, particles with a new rattle-like structure were obtained in the case of sample CxT1.5C1.5 (Fig. 5a), and a mixture of hollow and dense particles was
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obtained in the case of sample CxT2C2 (Fig. 5b). The high-concentration samples (CxT3C3 and CxT4C4) both provided nearly identical, dense spherical particles (Fig. 5c). The conversion was around 70% in both cases, meaning that the mass yield was improved by a factor of 2.9 and 3.8, respectively, compared to the volume based scale-up, to 7.1 and 9.4 g per 1000 ml, respectively.
In a separate set of experiments, only the concentration of the silica precursor (TEOS) was increased while keeping the template concentration (CTAB) unchanged. The TEOS concentration was increased by a factor of 2 and 3 (samples CxT2C1 and CxT3C1 as specified in Table 2). This resulted in a larger diameter of the primary particles (close to 1 µm), and almost all of them were fused together, forming large aggregates (Fig. 4a). The large extent of aggregation in this case can be attributed to the loss of colloidal stability of the primary particles. Due to insufficient coverage by the CTAB surfactant, the electrostatic repulsions between the particles are reduced relative to attractive van der Waals interactions, which results in the formation of particle aggregates. Particles from sample CxT2C1 retained the original hollow structure (Fig. 5d), while in particles CxT3C1 the hollow structure was lost and only dense particles were formed. TEM micrographs showing the structure of all particles produced under the concentration scale-up conditions are summarised in Supplementary Information 3.
3.2 Particle pore structure
3.2.1 Original particles
As reported in our previous work [25], the original samples RegH and RegD synthesized according to Teng et al. [24] (Section 2.2) yielded atypical nitrogen sorption isotherms measured at 77 K (Fig. 6a and 6c). The formation of the first monolayer can be observed up to the relative pressure 0.1, followed by the second layer, which forms up to the relative pressure 0.2. The steep increase of adsorbed volume in the pressure range from 0.2 to 0.3 can be attributed to condensation in the uniform, open mesopores. The following slow adsorption from relative pressure 0.3 to 0.9 is attributed to adsorption
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on the external surface of the particles, since the pores are already filled. At relative pressure 0.9, there is a steep increase, which is likely due to condensation of nitrogen in the free spaces between the particles. In case of sample RegH, there is a notable hysteresis loop during desorption. This behaviour normally suggests the presence of ink-bottle pores. However, as we discussed in our previous work, in this case it is the result of the hollow-core cavities present inside the particles. In sample RegD (no hollow core as seen in the TEM micrographs, Fig. 3c), no such hysteresis loop is present (Fig. 6c).
The BET specific surface areas of the samples were calculated from the relative pressure p/p0 = 0.050.2 and are listed in Table 3 along with other pore structure parameters evaluated from the nitrogen sorption isotherms. The C constants ranged from 13 to 30, therefore it can be assumed that the samples do not contain micropores, and the linearization of the t-plot passes through zero for calculation of the surface area of mesopores (Table 3) in the interval t = 0.3-0.4. The external surface area was calculated from the t-plot in the range t = 0.5-0.8. The values obtained from the t-plot method were in a satisfactory agreement with the BET values.
3.2.2 Volume based scale-up
The volume based scale-up samples Vx8/350C1+ and Vx8/350C2+, which were considered successful from the particle size distribution point of view (Section 3.1.2), both have qualitatively very similar sorption isotherms (Fig. 6a and 6c) to their RegH and RegD. The BET specific surface areas, the surface areas of mesopores (t-plot), the total pore volume and the mesopore volume (t-plot) were all comparable or only slightly higher than in the case of the RegH and RegD reference materials (Table 3). The sample Vx8/350C1+ containing hollow-core particles also exhibited the same hysteresis behaviour as the RegH sample, confirming the presence of the cavities (Fig. 6a). The sample Vx8/350C2+ had the highest total pore volume and mesopore volume values of all the measured samples (Table 3), but it also must be noted that the volume of the hollow cavities in the sample Vx8/350C1+ is not counted in these values, thus the total available inner volume will be higher in the hollow particles.
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In case of the samples produced at lower-intensity mixing conditions, the isotherms exhibit some notable changes. In case of the synthesis which should provide hollow particles, there is no hysteresis loop present (Fig. 6b), which is in agreement with the TEM images (see Supplementary information 3). A strong hysteresis loop is exhibited only by the sample Vx5/650C0.8+, which was produced using a lower amount of CTAB, and the particles are notably hollow also in the TEM images (see Supplementary information 3). Another notable difference is the missing bend in the isotherm at relative pressure range from 0.05 to 0.3. This could be explained by the slight reduction of the pore diameter from 3 nm to 2 nm and the consequent overlap of regions where the formation of the second adsorbed nitrogen layer and the condensation of nitrogen in the pores occur simultaneously. The specific surface areas (BET) and the specific surface areas of mesopores (t-plot) are generally higher for these samples, compared to particles obtained in the original RegH and RegD syntheses (Table 3). However, the results could be slightly affected by the presence of aggregates discussed in Section 3.1.2. This especially applies for the external surface area (t-plot) calculations.
3.2.3 Concentration based scale-up
The sorption isotherms of particles obtained during concentration based scale-up (Fig. 6d) are in agreement with the morphologies observed by TEM measurements. The two aggregate-free samples (CxT3C3 and CxT4C4) are both without a hysteresis loop, confirming the dense-core structure. Interestingly, their specific surface area (BET) and the specific surface area of mesopores (t-plot) are both notably larger then the specific surface areas of the original RegH and RegD samples (Table 3).
The pore size distribution was determined from the nitrogen sorption isotherms by the BJH and the DFT methods. Both methods confirmed the presence of mesopores in all of the samples with a narrow size distribution and a mean diameter of 2.2 nm (BJH) or 3.2 nm (DFT) for the original RegH and RegD samples and for the final Vx8/350C1+ and Vx8/350C2+ samples. The poorly mixed samples in
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the volumetric scale-up and the final samples of the concentration scale-up (CxT3C3 and CxT4C4) had the pores size distribution slightly shifted to smaller diameters to about 1.9-2.1 nm (BJH).
3.3 Comparison of scale-up approaches
3.3.1 Similarity criteria
Having analysed in detail the size distribution and the internal pore structure of particles prepared under a range of scale-up conditions, it is worthwhile making an overall, multi-criteria comparison. The Similarity Index (SI), defined in Section 2.6, was used as a measure of successful scale-up and evaluated for samples obtained during all the scale-up experiments, using the hollow-core sample RegH as a reference. The final scores are summarised in Fig. 7a (let us recall that the lower the SI value, the better the overall similarity of the SiO2 particle samples). For the hollow core synthesis, the most similar was the sample Vx8/350C1+, closely followed by the sample Vx5/650C0.8+. These samples had not only a satisfactory particle size distribution (in particular, the absence of large aggregates as expressed by dv,50 and dv,90), but also a very similar internal pore structure, including the presence of the hollow core (hysteresis loop). On the other hand, none of the other samples was able to achieve a good match in all the criteria. The results suggest that in case where it is not possible to reach suitable stirring conditions and when the presence of smaller aggregates (under 10 µm) is not an issue, it might be possible to obtain the desired particle morphology by slightly lowering the CTAB concentration in the reaction mixture.
For the dense core synthesis, the weights were adjusted in order to not factor in the hysteresis loop, since for this synthesis it was irrelevant. The most similar sample was the Vx8/350C2+ (Fig. 7b). The samples CxT3C3 and CxT4C4 had higher SI index (indicating poor similarity). In the absence of a hollow core, the main differentiating factor for the particle size distribution. However, it should be noted that a large deviation in the dv,50 and dv,90 values after scale-up does not necessarily mean a "bad"
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product if this is caused by the absence of any aggregates. Depending on the application needs, this might be a preferable change and such particles could be considered better than the reference particles.
3.3.2 Effect of scale-up parameters on particle aggregation
It was already mentioned (Section 3.1.2) that the stirring quality has a strong influence on the outcome of the SiO2 particle synthesis – affecting both morphology and aggregation of the particles (in the case of irreversible aggregation, the particle clusters could not be broken up even by intense sonication). In order to quantify the extent of aggregation, the particle size distribution curves (Fig. 2 and Fig. 4) were post-processed to evaluate the volume fraction of non-aggregated primary particles, defined as the area under the first mode relative to the area under the entire PSD curve as illustrated in Supplementary Information 4. The homogenization time (determined experimentally as described in Supplementary Information 1) was plotted against the fraction of non-agglomerated primary particles (fprimary) and the two quantities were found to be related (Fig. 7). Longer homogenization times clearly resulted in an increased presence of aggregate presence in the sample. The homogenization time of the sample Vx8/350C1+ (volume 1580 ml), which was also the "winner" in terms of the similarity index, was comparable to the homogenization time of the original RegH synthesis volume (40 ml). The amount of aggregates present in both samples was also comparable (cf Fig. 2a). In the samples produced using less aggressive mixing conditions and therefore longer homogenization times, large aggregates were formed.
This observation was supported also by the CFD analysis of the stirred vessels before and after scaleup for both successful and unsuccessful volumetric scale-up conditions. Examples of calculated velocity profiles and tracer concentrations corresponding to physical experiments are summarised in Fig. 8 for the successful and unsuccessful volumetric scale-up. (Additional velocity profiles for other experiments can be found in Supplementary Information 5). The final homogenisation times evaluated by the post-processing of CFD simulations are given in Table 4. The trends agree well with physical experiments and confirm that in the large vessel used during volume-based scale up, a combination of
17
lower RPM with a larger diameter impeller (conditions Vx8/350C1+) provides a more efficient homogenisation than a combination of higher RPM with a smaller diameter impeller (conditions Vx5/650C1+).
3.3.3 Effect of scale-up parameters on conversion and yield
Apart from the requirement to preserve the particle properties, an important consideration during scale-up is also the overall mass balance (the product yield with respect to the theoretical maximum at a 100% stoichiometric conversion), which would have implications on the process economics. By analysing the mass yield of SiO2 obtained during the scale-up experiments, it was observed that the TEOS/CTAB reagent ratio had a very strong impact on the overall conversion, which is plotted in Fig. 10. The samples with a higher concentration of CTAB provided significantly higher yields, suggesting that TEOS cannot effectively form silica particles without the surfactant pore template used in this synthesis setup. However, since CTAB is lost in the calcining step rather than recycled in the present process, a trade-off between TEOS conversion and CTAB consumption would have to be considered in an economic analysis of the process. Fig. 10 also shows that the stirring conditions did not have a very significant influence on the TEOS conversion compared with the effect of the TEOS/CTAB ratio. The data points clustered around the TEOS/CTAB ratio 10, which correspond to the various mixing conditions investigated during the volumetric scale-up, all fall into a relatively narrow range of conversion between approx. 70-75 %.
The process of silica particle particle formation from TEOS consists of several elementary steps: (i) the actual chemical reaction (hydrolysis and polycondensation of TEOS to form SiO2); (ii) the nucleation and growth of silica particles; (iii) the aggregation of silica particles. The rates of these processes depend on the process conditions and jointly determine the quantity and quality of the final silica product. It can be expected that at constant temperature, the reaction and nucleation rates should mainly depend on the concentration of TEOS (water is at a stoichiometric excess), while the particle growth and aggregation rates should depend mainly on the hydrodynamic conditions and the
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surfactant (CTAB) concentration. Indeed, the concentration scale-up experiments with the highest TEOS concentrations (CxT3C3 and CxT4C4) resulted in very small particles, presumable due to rapid formation of super-saturation and consequently high driving force for particle nucleation. Volumetric scale-up experiments with poor mixing conditions (e.g. Vx5/650C1-) resulted in very broad, polydisperse particle size distributions compared to well-mixed experiments for otherwise identical composition (e.g. Vx8/350C1+), presumably due to non-homogeneous concentration profiles in the reaction vessel, and therefore a broad variation of local reaction, nucleation and growth rates. Finally, experiments with insufficient surfactant concentration (e.g. CxT2C1 and CxT3C1) enabled significant particle aggregation into macroscopic clusters due to lack of primary particle stabilisation.
4 Conclusions
The scale-up of a process for the soft-templated synthesis of mesoporous silica particles by the hydrolysis of TEOS was investigated experimentally using two different approaches. In a volume based scale-up, the total yield of SiO2 particles was increased almost 40-fold, from 0.10 g (conversion 77 %) to 4.0 g (conversion 72 %) per batch in the case of hollow-core particles and from 0.12 g (conversion 90 %) to 5.0 g (conversion 85 %) in the case of dense-core particles. The stirring conditions during the synthesis (expressed by the batch homogenization time) were identified as the key parameter that determines successful scale-up, enabling both particle size distribution and internal pore structure to be preserved.
With the reagent concentration based scale-up, the total yield was increased 16-fold (4-fold from batch size enlargement and 4-fold from a higher reagent concentration) from 0.10 g (conversion 77 %) to 1.52 g (conversion 71 %) per batch. The particles obtained from the synthesis using a higher concentration of reagents lost their hollow structure, but their pore morphology was retained, the particles had a higher specific surface area and an increased mesopore volume compared to the original synthesis. Moreover, the extent of primary particle aggregation was lower.
19
Although the litre-scale production investigated in this work is still below the typical volumes that would represent a full industrial manufacture, the scaling up from a small laboratory synthesis provided important insights into the parametric dependence of the process and the trade-offs involved. When supported by CFD analysis, the current work provides a solid basis for further scale-up steps in this important yet under-explored area of chemical engineering research.
Acknowledgments We would like to acknowledge support from the Czech Science Foundation (project no. GACR 1705421S). M.S. would like to thank the Specific University Research (projects no. 4/2017 and 43/2017) for financial support. The research was conducted within the infrastructure built up from the support of the Operational Program Prague – Competitiveness (CZ.2.16/3.1.00/24501) and the financing by the CIGA project No.20132007.
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Figures
Figure 1: Scheme of the steps involved in the preparation of hollow and dense silica microspheres.
a)
b)
c) Figure 2: Volume-weighted size distributions of particles prepared under different conditions during volume based scale-up. a) Comparison of the original synthesis RegH with the successful scale-up conditions Vx8/350C1+, b) Comparison of the original synthesis RegH with several unsuccessful scale-up conditions, displaying the presence of large aggregates, c) Comparison of the original synthesis RegD with the successful scale-up conditions Vx8/350C2+ and one unsuccessful result displaying the presence of large aggregates.
24
a)
b)
c)
d) Figure 3: TEM and SEM micrographs of particles prepared during successful volume based scale-up, compared with the original reference. a) RegH, b) Vx8/350C1+, c) RegD, d) Vx8/350C2+.
a)
b) Figure 4: Size distributions of particles obtained during concentration based scale-up. a) Comparison of the original RegH synthesis with samples where the TEOS and CTAB concentrations were increased proportionally. b) Comparison of samples where only the TEOS concentration was increased.
26
a)
b)
c)
d)
Figure 5: TEM micrographs of particles obtained during concentration based scale-up. Samples a) CxT1.5C1.5, b) CxT2C2, c) CxT4C4, d) CxT2C1.
a)
b)
c)
d)
Figure 6: Nitrogen sorption isotherms of samples prepared during scale-up, compared with the reference materials. a) Samples RegH and Vx8/350C1+ contain a hysteresis loop due to a hollow-core structure. b) Samples obtained during volume based scale-up of sample RegH, some of which have their hysteresis loop. c) Sample RegD containing a dense core and its counterparts after a volume based scale-up. d) Comparison of samples obtained during concentration based scale-up.
a)
28
b) Figure 7: a) Similarity Index for all of the samples, using the original RegH synthesis as a reference (SI = 0). The most similar samples according to the SI score are Vx8/350C1+ and Vx5/650C0.8+. b) Similarity Index for selected samples when using the original RegD synthesis as a reference.
29
Figure 8: The ratio of the amount of the primary particles divided by the total area of all peaks in the size distribution (fprimary) was plotted against the homogenization time for the samples obtained during the volume based scale-up. Higher ratios (signifying lower amount of aggregates) were achieved with fast enough homogenization times.
a)
b)
30
c)
d)
e)
f) Figure 9: Calculated velocity and concentration profiles in stirred vessels after scale-up. a) Common logarithm of shear rate, b) velocity magnitude for experiment Vx5/650C1+. c) Evolution of tracer concentration for experiment Vx5/650C1+ at t = 0 s, t = 1.6 s and t = 7.2 s (homogenised). d) Common logarithm of shear rate, e) velocity magnitude for experiment Vx8/350C1+. f) Evolution of tracer concentration for experiment Vx8/350C1+ at t = 0 s, t = 1.6 s and t = 3.6 s (homogenised).
31
Figure 10: Dependence of TEOS conversion (based on the final yield of SiO2 particles) on the initial TEOS/CTAB molar ratio in the reaction mixture.
32
Tables Table 1: List of experiments conducted on 1600 ml scale using various stirring speeds and reactor vessel geometry. The reaction vessels was either equipped with flow regulators (marked by + at the end of the sample name) or the flow regulators were removed (marked with – at the end of the sample name). Sample
Water (ml/M)
RegH / Vx2.5/600C1RegD / Vx2.5/600C2Vx5/250C1-
25.5 / 34.1 25.5 / 34.1 1000 / 34 Vx5/650C11000 / 34 Vx5/650C21000 / 34 Vx5/650C1+ 1000 / 34 Vx5/650C0.8+ 1000 / 34 Vx8/350C1+ 1000 / 34 Vx8/350C2+ 1000 / 34
Ethanol TEOS 99.8% (ml/mM) (ml/M) 15 / 6.2 0.5 / 54
15 / 6.2
0.5 / 54
590 / 6.2 590 / 6.2 590 / 6.2 590 / 6.2 590 / 6.2 590 / 6.2 590 / 6.2
19.6 / 54 19.6 / 54 19.6 / 54
19.6 / 54 19.6 / 54 19.6 / 54 19.6 / 54
CTAB (g/mM)
NH3 (ml)
Stirring (mm/rpm) 2.5/600
Homog. Time (s) 1.8
Reynolds number (-) 2 500
0.08 / 5.3 0.16 / 10.6 3.15 / 5.3 3.15 / 5.3 6.3 / 10.6 3.15 / 5.3 2.52 / 4.2 3.15 / 5.3 6.3 / 10.6
0.5
0.5
2.5/600
1.8
2 500
19.6
5.0/250
11.5
4 000
19.6
5.0/650
8.1
10 500
19.6
5.0/650
8.1
10 500
19.6
5.0 /650
5.3
10 500
19.6
5.0/650
5.3
10 500
19.6
8.0/350
2.2
14 500
19.6
8.0/350
2.2
14 500
Table 2: List of the concentration based scale-up experiments with the sample name reflecting the multiples of TEOS and CTAB concentrations used compared to the regular synthesis of hollow silica particles. Sample
Water (ml/M)
RegH / 25.5 / 34.1 CxT1C1 RegD / 25.5 / 34.1 CxT1C2 CxT1.5C1.5 102 / 33.9
Etanol 99.8% (ml/M) 15 / 6.20
TEOS (ml/mM)
CTAB (g/mM)
NH3 (ml)
Stirring (mm/rpm)
0.5 / 54
0.08 / 5.3
0.5
2.5/800
15 / 6.20
0.5 / 54
0.16 / 10.6
0.5
2.5/800
60 / 6.16
3.0 / 81
0.45 / 7.4
2.0
2.5/800
CxT2C2
102 / 33.7
60 / 6.10
4.0 / 107
0.60 / 10.0
2.0
2.5/800
CxT2C1
102 / 33.7
60 / 6.10
4.0 / 107
0.30 / 5.0
2.0
2.5/800
CxT3C1
102 / 33.3
60 / 6.05
6.0 / 159
0.30 / 4.8
2.0
2.5/800
CxT3C3
102 / 33.3
60 / 6.05
6.0 / 159
0.90 / 14.5
2.0
2.5/800
CxT4C4
102 / 32.9
60 / 6.00
8.0 / 210
1.20 / 19.1
2.0
2.5/800
33
Table 3: Summary of pore structure characteristics of all the prepared samples based on nitrogen sorption isotherms. SSA (BET) [m²/g]
SSA of mesopores (t-plot) [m²/g]
External SSA (t-plot) [m²/g]
Total pore volume [cm³/g]
Mesopores volume (t-plot) [cm³/g]
Reg-H
950
863
110
0.705
0.504
Reg-D
1150
1027
177
0.798
0.605
Vx5/250C1-
1250
1150
59
0.585
0.517
Vx5/650C1+
1290
1090
74
0.607
0.531
Vx5/650C0.8+
1360
1030
200
0.816
0.528
Vx5/650C1-
1620
1315
119
0.770
0.650
Vx5/650C2-
1670
1480
100
0.806
0.708
Vx8/350C1+
1040
975
92
0.744
0.631
Vx8/350C2+
1300
1160
105
0.876
0.762
CxT2C1
1275
930
113
0.724
0.562
CxT3C1
1015
960
107
0.574
0.418
CxT1.5C1.5
1410
1130
65
0.661
0.592
CxT2C2
1380
1000
127
0.748
0.562
CxT3C3
1435
1245
77
0.728
0.638
CxT4C4
1370
1105
77
0.702
0.616
Sample
34
Table 4: Summary of CFD simulations based on experimental conditions and used for the evaluation of homogenization time. Calculated Sample code
CFD set-up
Stirring homogenization time (s)
100 ml round-bottom flask, 25x4 mm rod, 600 rpm
RegH / RegD
1.8
25.5 ml water, 15 ml EtOH
35
200 ml beaker, CxT1C1
25x4 mm rod, 800 rpm
2.2
50x7 mm rod, 650 rpm
7.2
80x9 mm rod, 350 rpm
3.6
102 ml water, 60 ml EtOH 2000 ml beaker + flow regulators, Vx5/650C1+ 1000 ml water, 590 ml EtOH 2000 ml beaker + flow regulators, Vx8/350C1+ 1000 ml water, 590 ml EtOH
Highlights First study into scale-up of microemulsion based process for mesoporous silica particles Volume and concentration based scale-up approaches were investigated Conditions for successful scale-up by a factor of 40x were identified Reactor mixing was the most important parameter as confirmed by CFD and experimental analysis
37