Microporous and Mesoporous Materials 128 (2010) 187–193
Contents lists available at ScienceDirect
Microporous and Mesoporous Materials
journal homepage: www.elsevier.com/locate/micromeso
Self-assembly of mesoporous silicas hollow microspheres via food grade
emulsifiers for delivery systems
Mahendra P. Kapoor a,*, Ajayan Vinu b, Wataru Fujii a, Tatsuo Kimura c, Qihua Yang d, Yuuki Kasama a,
Masaaki Yanagi a, Lekh R. Juneja a
a
Taiyo Kagaku Co., Ltd., Research and Developments, 1-3 Takaramachi, Yokkaichi, Mie 510-0844, Japan
World Premier International Research Center for Materials Nano-Architectonics (MANA), National Institute for Materials Science (NIMS), Namiki, Tsukuba, Ibaraki 305-0044, Japan
Advanced Manufacturing Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Shimoshidami, Moriyama-ku, Nagoya, Aichi 463-8560, Japan
d
State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Zhongshan Road, Dalian 116023, China
b
c
a r t i c l e
i n f o
Article history:
Received 1 July 2009
Received in revised form 18 August 2009
Accepted 19 August 2009
Available online 22 August 2009
Keywords:
Self-assembly
Hollow microspheres
Emulsifiers
Food grade
Delivery systems
a b s t r a c t
Randomly ordered mesoporous silicas hollow microspheres of 20–50 lm in diameter with distinguished characteristic of interconnected porosity (7–14 nm) of their thin outer walls are developed.
Food grade emulsifier polyglycerol esters of fatty acids (PGEFA) are used as a soft-template and n-decane as a swelling agent, which was necessary for the formation of silica doped micelles to improve the
mesoporous channel orientation without leading the phase transition. The interconnected pore channels that extend from the outside of the microspheres shell to its inside are used to fill the mesoporous silicas microspheres for enhanced encapsulation of VB3 precursor and cumulative in vitro release
of vitamin B3 with considerable rate pharmacokinetics using simple pH trigger mechanism for the
delivery systems.
Ó 2009 Elsevier Inc. All rights reserved.
1. Introduction
Nanomaterials play a vital role on the development of delivery
systems, which have made a huge impact on the medical technology, significantly enhancing the performance of existing lifesaving drugs and minimizing the size of drug delivery devices
from macro to nanoscale. Among the nanomaterials, mesoporous
silica, a breakthrough discovery in early 1990s, are interesting
materials that can be used as the support for the controlled delivery of drugs [1] as they possess unique structural features such
as large surface area (>1000 m2 g 1), high pore volume (>1 cm3
g 1), tunable pore sizes (2–10 nm), well-defined pore structure,
and high mechanical and chemical stability [2,3]. The linear arrays of mesoporous silica channels, which are running completely
through the porous structure act as the storage voids which
could even help to store a huge quantity of drugs and their surface modifications could allow the carriers to recognize target
locations of drug administration and the controlled release of
active pharmaceutical ingredients. Moreover, they are highly
biodegradable with kinetics much more rapid than that of biode-
* Corresponding author. Tel.: +81 59 347 5405; fax: +81 59 347 5417.
E-mail address: mkapoor@taiyokagaku.co.jp (M.P. Kapoor).
1387-1811/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.micromeso.2009.08.019
gradable hydrophobic polymers, which makes them ideal for the
perfect delivery systems [4–6]. So far the mesoporous silicas with
hollow spherical morphologies are fabricated either via hard templating (metal, inorganic, and polymer beads etc.) [7–9], or softtemplating methods (emulsion, vesicles, etc.) [10–14]. Usually
amine or polymer based structure-directing templates are widely
studied for self-assembly of mesoporous carriers for several diffusion controlled drug delivery studies [15,16]. However, the removals of the hard beads are time consuming, expensive and
economically not feasible. On the other hand, the synthesis of
the soft-templates is commonly not a simple task. Herein, for
controlled delivery of bioactive payloads, we have designed
unique hollow spherical particles of large pore size mesoporous
silica via the soft-templating method, wherein the highly refined
food grade emulsifier polyglycerol esters of fatty acids (PGEFA)
were used as the structures directing agent (Scheme 1). PGEFA
are normally used as food ingredients and in cosmetic industries,
and have a good hydrophile–lipophile balance (HLB), a value
indicating the balance of size and strength of hydrophilic and
lipophilic moieties of these amphipathic emulsifier molecules
and make them as the structure-directing agent. Typically, pentaglycerol ester of myristic acid was used as a structure-directing
agent and n-decane (C10H22) as the pore expander (also see supplementary materials).
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M.P. Kapoor et al. / Microporous and Mesoporous Materials 128 (2010) 187–193
2.3. Encapsulation procedure of VB3 precursor
Scheme 1. Synthetic route to an edible surfactant polyglycerol ester of edible fatty
acids (PGEFA) via polymerization of glycerol and catalytic esterification of
polyglycerol with fatty acid.
2. Experimental methods
2.1. Synthesis of hollow microspheres of mesoporous silicas
Surfactant 2.1 g (pentaglycerol esters of myristic acid) was first
dissolved in 60 mL 1.5 M HCl solution with stirring at 35 °C for at
least 20 min. An amount of n-decane (2–20 mL) was added to surfactant solution with continuous stirring for an hour. NH4F (0.02–
0.05 g) was than added as a catalyst to solution and thoroughly
stirred for 15 min. Finally, 3.0 g TEOS (tetraethylorthosilicate)
was introduced into solution as a silica source and gel mixture
was kept stirring at constant temperature (35 °C) for 24 h. The final
molar gel ratios of formulation were 1.0SiO2:0.24Surf:2.3 HCl:0.03
NH4F:582H2O. After completion of the reaction, the gel was filtered, washed with access amount of deionized water. The final
washing was carried out with ethanol. The material was dried
overnight at least 60 °C and finally calcined at 600 °C for 10 h to remove the traces of surfactants. The total yield of mesoporous silicas hollow microspheres was about 0.8 g.
2.2. Characterizations of mesoporous silicas hollow microspheres
Powder X-ray diffraction (PXRD) patterns were recorded for all
the samples using a diffractometer (Rigaku, RINT 2200) with Cu Ka
radiation (k = 0.154 nm), operating at 40 kV and 30 mA. Count per
second were estimated every 0.02° of 2h at the scan speed of 1.0°
(2h/min). Nitrogen adsorption–desorption isotherms were obtained at 196 °C using a sorptometer (Belsorp-18). Pore structure
characterization was performed using static adsorption method,
wherein samples were out gassed at 180 °C and 1.33 Pa (10 2 torr)
for at least 2 h prior to analysis. BET (Brunauer–Emmett–Teller)
surface areas were estimated from adsorption branch of isotherm
using the linear part of the BET plot according to IUPAC standard.
Pore size was determined from the adsorption branch of the isotherm using the Barrett–Joyner–Halenda (BJH) model. The thermo-gravimetric TGA/DTA analyses of the selected samples were
performed on a Sieko TG analyzer using the heating program with
rate of 5 °C/min from 30 °C to a maximum value of 600 °C. Transmission electron microscope (TEM) images were taken using Philips FX-300 (specification etc., equipped with CeB6 filament) at
high accelerating voltage. Beam size was approximately a quarter
to the objective lens aperture. Homogeneously dispersed sample
was mounted on the carbon coated copper grid after the sonication. HR-SEM images were obtained using JEOL scanning electron
microscopy. 29Si MAS–NMR spectra were obtained using Bruker
FX-400 solid state NMR spectrometer at 79.5 MHz with 7 mm zirconia rotor. The chemical shifts were referenced to tetramethylsilane (TMS) at 0 ppm. The particles size of mesoporous silicas hollow
microspheres was doubly confirmed using Coulter LS-230 particle
sizing system analyzer. Prior to analysis, the material was suspended in deionized water and subjected to ultrasonic for 10 min.
Details on the synthesis and characterization of alkoxysilyl
derivative of vitamin B3 (hereafter called precursor VB3) are
provided in supporting information. A series of VB3 solutions with
varied concentrations ranging from 4.6 to 350 mmol L 1 were
freshly prepared in ethanol. In each encapsulation experiment,
250 mg of mesoporous silicas hollow microspheres or SBA-15
mesoporous materials was suspended in 20 g of respective VB3
solution. The mixture was continuously shaken at a speed of nearly
200 shakes/min at ambient condition for 24 h. Shaking was preferred to avoid the breakings of mesoporous silicas hollow microspheres upon magnetic stirring. Usually equilibrium could reach
within 12–15 h of shaking, however, to avoid the discrepancies
the 24 h was considered as the suitable time for the VB3 precursor
loading procedure. The solids were filtered, washed with ethanol
and dried overnight.
2.4. Estimations of encapsulated of VB3 precursor
An amount of VB3 precursor encapsulated was estimated by
UV–Vis and TG analyses. Typically, the amounts of encapsulated
VB3 precursor was calculated by subtracting the amount estimated
in supernatant liquid after encapsulation, from the amount of VB3
precursor present before addition of mesoporous silicas hollow
microspheres or SBA-15 silicas by UV absorption method at the
kmax of VB3, 262 nm, according to the Beer–Lambert equation. Prior
to UV analyses the solutions were centrifuged to avoid any potential interference from suspended scattering particles. The estimation was performed thrice on each sample and average value was
used for data exploration. Calibration experiments were performed
separately before each set of measurements with freshly prepared
VB3 precursor solution of different concentrations. The concentration of encapsulated VB3 precursor was further confirmed by thermal-gravimetric techniques. The encapsulated solids were heated
from room temperature to 700 °C with a constant ramp of 5 °C/
min in airflow.
2.5. In vitro release of encapsulated vitamin VB3
In vitro controlled cumulative release experiments were performed under identical conditions using static volumes at
37.0 ± 1.0 °C and pH 1–2, similar to simulated gastric fluid. Typically, 25 mg of VB3 precursor encapsulated mesoporous material
were immersed in 10 mL of 0.1 M HCl solution and kept in a water
bath whose temperature was maintained at 37.0 ± 1.0 °C. At programmed times samples were filtered and the obtained solutions
were recovered. The profile of vitamin B3 release from the mesoporous silicas hollow microspheres and SBA-15 materials were calculated from the estimated vitamin B3 concentrations in all the
solutions by UV–Vis spectroscopy for time periods up to 24 h. Such
pH triggered release pharmacokinetics is discussed in the main
text of the manuscript.
3. Results and discussion
3.1. Mesostructures and morphology
The materials are the randomly ordered mesoporous silicas hollow microspheres of 20–50 lm in diameter with distinguished
characteristic of interconnect porosity of their thin outer walls,
which can be altered and controlled on a scale of 7–14 nm. Related
with the morphology, the interconnected pores or channels that
extend from the outside of the microspheres shell to its inside
can be used to fill the mesoporous silicas hollow microspheres.
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M.P. Kapoor et al. / Microporous and Mesoporous Materials 128 (2010) 187–193
a
a
d10 = 9.70
9.70nm
nm
12000
d10 = 9.91
9.91nm
nm
Intensity, CPS
10 mL
9000
5 mL
6000
20 mL
NH4F==0.02
NH4F
0.02g g
d10 = 9.50
9.50nm
nm
d10 = 9.00
9.00nm
nm
2 mL
3000
0 mL
7.12nm
nm
d10 = 7.12
0
0
1
2
3
4
5
6
2θ, degree
800
10.6 nm
9.1 nm
b
600
500
20 mL
b
5 mL
9.2 nm
400
10 mL
300
Vp
7.1 nm
Vp
The materials also show excellent performance in the in vitro
adsorption and the release of the vitamin B3 molecules. The permeable mesoporous walls allow these hollow microspheres to encapsulate higher amount of VB3 precursor and a simple pH trigger
concept helps the complete cumulative in vitro release of vitamin
B3 (Fig. 1).
High resolutions scanning electron microscopy (SEM) monographs of mesoporous silicas hollow spherical particles confirm
the three-dimensional atomic spherical network whose size could
be controlled in range of 20–50 lm under varied synthetic parameters (Fig. 2). From the SEM monograph of the crushed mesoporous
silicas spherical particles, it can be clearly seen that particles are
indeed of a hollow structure (Fig. 2c). Noteworthy, spherical particles with mesoporous silica shells showed no agglomeration and
are thermally stable even after the calcinations treatment in air
at 600 °C for 10 h.
The characteristic structural and pore size distribution features
of mesoporous silicas hollow microspheres are presented in Fig. 3.
Depending on the synthesis conditions e.g. amount of n-decane as
pore expander, synthesis temperature, the catalyst NH4F and carbon chain length of expander (see Table 1) the pore diameter of
interconnected channels that extend from the outside of the microspheres shell to its inside could be controlled in the range 7 to
0 mL
400
200
100
200
0
3
6
9 12 15
PD, Å
0
0
5
10
15
20
Nitrogen adsorbed, cc/g
Pore diameter, nm
2000
c
c
20 mL
1500
10 mL
1000
5 mL
500
0
0.0
0 mL
0.2
0.4
0.6
0.8
1.0
Relative pressure, P/P o
Fig. 3. (a) X-ray diffraction patterns (b) pore size distribution curves (inset; textural
microporosity), and (c) nitrogen adsorption–desorption isotherms of calcined
mesoporous silica hollow microspheres derived using varied amount of n-decane.
Fig. 1. Schematic encapsulation of an amount (mmol g 1) of VB3 precursor in (a)
SBA-15, and (b) mesoporous silicas hollow microspheres showing the polymerization of VB3 precursor inside the hollow microspheres and resulting in a higher
loading of the VB3 precursor. (VB3 precursor is a propyltrimethoxysilane nicotinic
acid chloride salt.)
14 nm. Materials consist of a high Brunauer–Emmett–Teller (BET)
specific surface areas (500–700 m2 g 1) and larger pore volumes
(1.3–1.9 cm3 g 1) including textural microporosity (6–8 Å) in the
pore walls of mesoporous materials (see Fig. 3). The intergrown
in dimensional domains of wormhole-like mesostructures were
confirmed by using transmission electron microscopic (TEM) image as shown in Fig. 4.
The 29Si nuclear magnetic resonance (NMR) studies (Fig. 5) revealed that calcined mesoporous silicas hollow microspheres are
highly crossed linked silica structure with a fewer hydroxyl or silanol groups onto the surfaces with Q3:Q4 cross linking ratio of
6:94. While, pre-calcined material consists of Q2, Q3 and Q4 silicones in substantial ratios.
Fig. 2. (a) Scanning electron micrographs (SEM) of mesoporous silicas hollow microspheres derived via food grade emulsifier displaying the spherical morphology with (b)
bubble size of about 30 lm; (c) SEM images of crushed mesoporous silica hollow microspheres confirmed the hollow structure of microspheres.
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M.P. Kapoor et al. / Microporous and Mesoporous Materials 128 (2010) 187–193
Table 1
The textural properties of mesoporous silicas hollow microspheres derived under varied synthetic conditions using food grade emulsifiers.
NH4F* (g)
n-Decane (mL)
d10-Spacing (nm)
BET surface area (m2 g
0.02
0
2
5
10
20
5 mL@60 °C
5 mL@100 °C
5 mL (n-Octane)
5
10
20
7.12
9.00
9.92
9.70
9.50
9.81
9.60
8.42
10.40
9.01
9.71
590
–
642
699
671
586
439
597
690
564
583
0.05
1
Pore volume (cm3 g
)
1
)
Pore size (nm)
1.19
–
1.81
1.49
1.71
1.69
1.74
1.36
1.93
1.73
1.70
7.1
–
10.6
9.2
9.1
9.2
9.6
8.2
13.9
10.4
10.1
Fig. 4. (a) Transmission electron micrograph (TEM) confirmed the wormhole-like structure of large pore mesoporous silicas hollow microspheres, and (b) displays the
schematic illustration of the pore wall skeleton of mesoporous silicas hollow microspheres that consists of both micro-and meso-pores.
12000
Q4
Intensity, CPS
Calcined
Q3
a
d 10 = 9.81 nm
o
60 C
9000
d 10 = 9.92 nm
r.t
d 10 = 9.60 nm
o
100 C
6000
NH4F = 0.02 g
n-Decane = 5 mL
3000
Q4
Q2
0
As-synthesized
0
1
2
3
4
5
6
2θ, degree
0
-50
-100
-150
-200
10000
n-Decane= 5mL
Chemical shift,ppm
Fig. 5. 29Si–MAS–NMR spectra displaying a highly condensed cross-linked structure with very few silanol (–OH) groups in calcined mesoporous silicas hollow
microspheres.
In addition, synthesis temperature also play important role in
the self-assembly of mesoporous silicas hollow microspheres
(Fig. 6a). Higher temperature (ca. 100 °C), resulted in decrease in
ordered mesoporous structure. While the materials prepared at
relatively mild temperature (ca. 60 °C) resulted in the lower pore
diameter structured materials compared to the synthesis at
slightly higher to ambient temperature (35 °C). Also, the lower
pore diameter structure was obtained when n-octane was used instead of n-decane (Fig. 6b). Further, an amount of NH4F (0.02 g) as
catalyst is very crucial to promote silica polymerization. Because,
in absence of NH4F hydrolysis catalyst very disordered mesoporous
structures were obtained. While an increase in NH4F resulted in
Intensity, CPS
8000
6000
d10 = 9.92 nm
n-Octane= 5mL
c
b
d10 = 8.42 nm
4000
NH4F = 0.02 g
2000
0
0
1
2
3
2θ, degree
4
5
6
Fig. 6. X-ray diffraction patterns of mesoporous silicas hollow microspheres (a)
displaying the effect of reaction temperature on pore structure and, (b) showing the
effect of normal alkane chain length on the mesoporous structural order.
interesting features to control the size as well as pore structures
of the mesoporous silicas hollow microspheres. Fig. 7 displays
the X-ray diffraction patterns and nitrogen adsorption–desorption
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M.P. Kapoor et al. / Microporous and Mesoporous Materials 128 (2010) 187–193
16000
NH4F
NH4F ==0.05
0.05
g g
9.71 nm
nm
d 10 = 9.71
20
20 mL
mL
8000
10
10 mL
mL
d 10 = 9.01
9.01 nm
nm
4000
a
600
13.9 nm
1200
400
Vp
Intensity, CPS
12000
Nitrogen adsorbed, cc/g
1500
d 10 = 10.4
10.4 nm
nm
5 mL
mL
900
200
c
0
600
0
5
10
15
20
25
30
Pore diameter, nm
300
b
0
0
0
1
2
3
4
5
6
2θ, degree
0.0
0.2
0.4
0.6
0.8
1.0
Relative pressure, P/P o
Fig. 7. (a) X-ray diffraction patterns and (b) nitrogen adsorption–desorption isotherm, and (c) pore size distribution curve of mesoporous silicas hollow microspheres
prepared using higher amount of NH4F catalyst (0.05 g and 5 mL n-decane) display an expansion in pore diameter.
Fig. 8. SEM images of mesoporous silicas hollow microspheres displaying that the size of hollow spherical particles can be control by varying the synthesis parameters.
isotherm of expanded pore mesoporous silicas hollow microspheres prepared using higher amount of NH4F as hydrolysis catalyst (0.05 g). SEM images (Fig. 8) confirm that the size of hollow
spherical particles of mesoporous silicas hollow microspheres
can be easily control by varying the catalytic amount of NH4F.
3.2. Encapsulation with mesoporous silica hollow spheres
Spherical mesoporous particles could also have potential use as
controlled release capsule for drugs, hormones, neurotransmitters,
artificial cells, chemical markers, peptides, proteins, dyes, cosmetics, inks, catalysts, fillers, and nutraceuticals [17–19]. Herein, we
have also focus on vitamin encapsulation (vitamin B3 or nicotinic
acid or niacin) and its responsive cumulative release using mesoporous silica hollow microsphere particles and compared with another analogous mesoporous materials such as SBA-15 [20].
Usually, covalent binding or Van der Waals interaction method is
used for the immobilization of the biomolecules or drugs on the
mesoporous materials [21]. However, the covalent binding always
requires the post-functionalization of the silica support with toxic
amines, thiols, vinyls or carboxylic functional groups whereas the
Van der Waals interaction is weak and the guest molecule could
readily leach even during the preparation.
To resolve the aforementioned limitations, we proposed a novel
in vitro strategy that allows the integration of guest vitamin molecule and mesoporous silicas hollow microsoheres to create nanocomposite that subsequently releases the vitamin molecule upon
disintegration. Therefore, we choose to load trialkylsilylated vitamin B3 instead of the real vitamin B3. The goal was achieved by
synthesizing derivative of representative vitamin B3 via functionalization with alkoxysilyl group as a chloride salt using chloropropyltrimehoxysilane as a coupling agent (Scheme S1) via SN2
mechanism. The propyltrimethoxysilane nicotinic acid chloride
salt (i.e., alkoxysilyl derivative of vitamin B3 salt herein, called precursor VB3) was obtained at high purity according to 1H and 13C
nuclear magnetic resonance (NMR) data as well as infrared (IR)
analysis (Figs. S1, S2 and S3).
Encapsulation of VB3 precursor was accomplished by quantitative grafting onto the hollow mesoporous microsohere particles
and amount encapsulated was systematically controlled and monitored. As seen from the isotherms, the VB3 precursor adsorption
capacities differ extensively between the materials. Above the isoelectric point of vitamin B3, pH 4.7, mesoporous silicas hollow
microsoheres register the VB3 precursor adsorption capacity of
ca. 21.8 mmol g 1 (Fig. 9a), which is 8 times higher than the total
encapsulation capacity of a large pore SBA-15 type materials
(2.7 mmol g 1; Fig. 9b). It means that per gram sample (mesoporous silicas hollow microsoheres) could accumulate nearly six times
of VB3 precursor of its actual weight. The reason for enhanced
encapsulation of VB3 precursor onto mesoporous silicas hollow
spherical particles is mainly due to their grafting into cylindrical
mesopores that extend from the outside of the microspheres shell
to its inside, as well as its polymerization, and subsequent accumulation inside the void of the hollow spherical particles, which can
provide a lot of room for the encapsulation (Fig. 1). While the lower
VB3 precursor encapsulation capacity of SBA-15 could be due to the
encapsulation only into their pore system, wherein with increasing
VB3 precursor loading the adsorbing molecules experience steric
hindrance and pore blockage and thus entrapping at pore mouth.
The textural properties of mesoporous silicas hollow microspheres
and SBA-15 with an increasing encapsulation of VB3 precursor are
listed in Table 2.
3.3. Cumulative release from mesoporous silica hollow spheres
In vitro controlled cumulative release experiments were performed under identical conditions using static volumes at
37.0 ± 1.0 °C and pH 1–2, similar to simulated gastric fluid. The
profile of vitamin B3 release from the mesoporous silicas hollow
microspheres and SBA-15 were followed spectroscopically for time
periods up to 24 h and NMR studies confirmed that the soluble
species released from the encapsulated materials in the simulated
gastric fluid are indeed free vitamin B3. This also helped to confirm
that at the loading conditions, particularly those of low pHs, would
-1
Cumulative release VB 3 (%)
M.P. Kapoor et al. / Microporous and Mesoporous Materials 128 (2010) 187–193
Amount adsorbed (mmol.g )
192
25
a
a
20
Microspheres
15
10
5
50
60
3.53
3.53
1.36
1.36
Microspheres
Micros pheres
20
0
5
10
15
20
25
30
35
40
T 1/2 (min)
Cumulative release VB 3 (%)
3.0
b
b
2.5
21.76
21.76
14.07
14.07
7.24
7.24
40
100 150 200 250 300 350 400
Final solution concentration (mmol.L -1)
-1
80
0
0
Amount adsorbed (mmol.g )
b
100 b
2.0
SBA-15
1.5
1.0
100
aa
80
Microspheres(1.36)
Micros pheres (1.36)
60
40
20
SBA-15
SBA-15 (1.38)
(1.38)
0
0
1
2
0.5
3
4
5
6
7
23
24
Time (h)
0
5
10
15
20
25
Final solution concentration (mmol.L -1)
Fig. 9. Encapsulation of VB3 precursor (mmol g 1) in (a) mesoporous silicas
microbubbles, and (b) SBA-15 materials. Isotherms showing the estimated encapsulated amount (mmol g 1) of VB3 precursor in materials determined by UV
spectroscopy (filled) and TG thermal analyses (empty) methods.
not trigger the condensation of these organoalkoxysilanes to yield
gel type of covalent silica agglomerations. First, the materials
loaded with similar content of VB3 precursor were studied. The
SBA-15 exhibits a slow initial release compared to mesoporous silicas hollow microspheres (Fig. 10a). It must be noted that vitamin
B3 could completely released within 24 h from the mesoporous silicas hollow microspheres, while the absolute release of vitamin B3
was not at all achieved from SBA-15 matrix (nearly 44%) even after
24 h. Always, the rate of release was almost proportional to
amount VB3 encapsulated. The results suggest that host–guest
interaction greatly affected the diffusion phenomenon and in
adopted release conditions the different diffusion rates depend
mainly on the surface silanol groups of the host porous material.
Although mesoporous silicas hollow microspheres and SBA-15
Fig. 10. (a) Cumulative release of vitamin B3 from aforementioned mesoporous
materials encapsulated with identical amount of VB3 precursor. (b) Cumulative
release of vitamin B3 from mesoporous silicas microbubbles encapsulated with
varied amount of VB3 precursor (mmol g 1) are plotted against square root of the
time following the Higuchi model of active pharmaceutical ingredients release.
both have almost similar pore size, however the difference in the
release rate of vitamin B3 can be attributed to significant lower
silanols concentration (mesoporous silica hollow microspheres = 0.76 OH groups per nm2, SBA-15 = 4.16 OH group
per nm2) along with characteristic hollow spherical particle
morphology of the materials. The fact that due to very few Q3 type
silicon atoms present in materials, suggest that most of the VB3
precursor are not covalently anchored on the mesoporous silica
surface through Si–O–Si bonds, given the small number of Si–OH
anchoring group on the surface of the materials. The agglomerates
of VB3 precursors in the void of mesoporous silicas hollow microspheres (see Fig. 1) could be easily dissociated from the materials
surface through pH controls and thereby released into the solution,
which was further confirmed by mass spectra of the released
species.
Table 2
The textural properties of mesoporous silicas hollow microspheres and SBA-15 with an increasing encapsulation of VB3 precursor.
Material description
VB3 encapsulation (mmol g
1
)
BET Surface area
(m2 g
1
)
Pore volume
(% Loss)
(cm3 g
1
)
Pore size
(% Loss)
(nm)
(% Loss)
Microspheres
0.0
1.36
3.53
7.24
14.07
21.36
22.40
642
609
583
551
506
481
456
–
5.2
9.2
14.2
21.2
25.1
29.0
1.81
1.76
1.70
1.63
1.59
1.51
1.42
–
2.8
6.1
10.0
12.2
16.6
21.6
10.60
9.78
9.11
8.76
8.41
8.03
7.91
–
7.7
14.1
17.4
20.7
24.3
25.4
0.0
0.97
1.38
1.88
2.17
2.73
2.80
431
396
364
281
203
156
116
8.2
15.4
34.8
52.9
63.8
73.1
1.61
1.32
1.09
0.87
0.63
0.51
0.37
–
18.0
32.3
46.0
60.7
68.3
77.0
10.58
8.87
7.91
6.08
4.86
3.96
2.13
–
16.2
25.2
42.5
54.1
62.6
79.9
SBA-15
M.P. Kapoor et al. / Microporous and Mesoporous Materials 128 (2010) 187–193
Further, the vitamin B3 release kinetic is described using Higuchi model [22] wherein, released entity usually exhibits a linear
relationship if plotted against the square root of time (Fig. 10b).
In all cases, the deviation from linearity explains that vitamin B3
release process from the silica matrix is not purely diffusion control process. A stepwise release of vitamin B3 is probably related
to different dissolution rates of the VB3 precursor from the silica
matrices. Taking in account of a daily cycle of bioavailability (pharmacokinetics) of vitamins, it is noteworthy to mention that a faster
release rate along with a complete release of encapsulated nutrient
within 24 h of period is of significant importance. Eventually,
mesoporous silicas hollow microsphere provides an enhanced
encapsulation of VB3 precursor and also capable to release it to
completeness with considerable rate pharmacokinetics using
simple pH trigger mechanism. In addition, the results of acute
inhalation toxicity (nose only) study in the ten Sprague–Dawley
strain rats (mean achieved atmosphere concentration of 5.03 mg/
L for 4 h) indicated that mesoporous silica hollow microspheres
derived from the polyglycerol esters of food grade fatty acids
(PGEFA) are harmless, biocompatible and will not trigger an immune response in the body. No death occurred in rats group (dose:
3 mg/body) and no macroscopic abnormalities were detected at
necropsy. All animals recovered quickly to appear normal from
day one post exposure. The detailed toxicity and safety studies
would be the topic of our subsequent publication.
4. Conclusions
In summary, we demonstrate for the first time the syntheses of
hollow mesoporous microspheres using food grade polyglycerol
esters of fatty acids by the soft-templating method. The use of
NH4F is crucial as hydrolysis catalyst to promote silica polymerization and to form organized mesoporous network. The morphology
and the mesopore diameter of the materials can be finely tuned by
changing the synthesis conditions. Wherein n-decane functions as
a swelling agent to expand the pore size of mesoporous silica hollow microspheres and also confine the formation of silica doped
micelles to improve the mesoporous channel orientation without
leading the phase transition. This work also demonstrates the
application of the mesoporous silica hollow microspheres in the
in vitro adsorption and the release of the vitamin B3 molecules.
The toxicology study on rats reveals that the materials are nontoxic and safe, and could be used for nutrition delivery, as well
as the adsorption, separation and chromatographic applications.
In addition, the methodology reported in the present work could
also be applied to fabricate other mesoporous materials with dif-
193
ferent symmetry and morphology using substituted food grade esters of the fatty acids.
Acknowledgements
We are grateful to H. Nanbu for useful discussion and T. Yokoyama for experimental support for synthesis of precursor.
Appendix A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.micromeso.2009.08.019.
References
[1] J. Anderson, J. Rosenholm, S. Areva, M. Linden, Chem. Mater. 21 (2004) 4160–
4167.
[2] C.T. Kresge, M.E. Leonowicz, W.J. Roth, J.C. Vartuli, J.S. Beck, Nature 359 (1992)
710–712.
[3] J.S. Beck, J.C. Vartuli, W.J. Roth, M.E. Leonowicz, C.T. Kresge, K.D. Schmitt, C.T.W. Chu, D.H. Olson, E.W. Sheppard, S.B. McCullen, J.B. Higgins, J.L. Schlenker, J.
Am. Chem. Soc. 114 (1992) 10834–10843.
[4] S. Giri, B.G. Trewyn, V.S.Y. Lin, Nanomedicine 2 (2007) 99–111.
[5] E. Tasciotti, X. Liu, R. Bhavane, K. Plant, A.D. Leonard, B.K. Price, M.M.C. Cheng,
P. Decuzzi, J.M. Tour, F. Robertson, M. Ferrari, Nat. Nanotechnol. 3 (2008) 151–
157.
[6] I.I. Slowing, B.G. Trewyn, S. Giri, V.S.-Y. Lin, Adv. Funct. Mater. 17 (2007) 1225–
1236.
[7] M.M. Titirici, A. Thomas, M. Antonietti, Adv. Funct. Mater. 17 (2007) 1010–
1018.
[8] F.J. Suarez, M. Sevarez, T. Valdes-Solis, A.B. Fuertes, Chem. Mater. 13 (2007)
3096–3098.
[9] Y. Xia, R. Mokaya, Adv. Mater. 16 (2004) 886–891.
[10] H. Djojoputro, X.F. Zhou, J. Am. Chem. Soc. 128 (2006) 6320–6321.
[11] B. Tan, H.J. Lehmler, S.M. Vyas, B.L. Knutson, S.E. Rankin, Adv. Mater. 17 (2005)
2368–2371.
[12] N.E. Botterhuis, Q. Sun, Eur. J. Chem. 12 (2006) 1448–1456.
[13] Z. Feng, Y. Li, D. Niu, L. Li, W. Zhao, H. Chen, L. Li, J. Gao, M. Ruan, J. Shi, Chem.
Commun. (2008) 2629–2631.
[14] Y.F. Zhu, J.L. Shi, Y.S. Li, H.R. Shen, X.P. Dong, Micropor. Mesopor. Mater. 85
(2005) 75–81.
[15] T. Heikkila, J. Salonen, J. Tuura, N. Kumar, T. Salmi, D. Yu Murzin, M.S. Hamdy,
G. Mul, L. Laitinen, A.M. Kaukonen, J. Hiroven, P. Lehto, Drug Delivery 14
(2007) 337–347.
[16] N.K. Mal, M. Fujiwara, Y. Tanaka, Nature 421 (2003) 350–353.
[17] M. Vallet-Regi, F. Balas, M. Colilla, M. Manzano, Drug Metab. Lett. 1 (2007) 37–
40.
[18] I. Roy, T.Y. Ohulchanskyy, D.J. Bharali, H.E. Pudavar, R.A. Mistretta, N. Kumar,
P.N. Prasad, PNAS 102 (2005) 279–284.
[19] I.I. Slowing, B.G. Trewyn, V.S.-Y. Lin, J. Am. Chem. Soc. 129 (2007) 8845–8849.
[20] D. Zhao, J.P. Feng, Q. Huo, N. Melosh, G.H. Fredrickson, B.F. Chmelka, G.D.
Stucky, Science 279 (1998) 548–552.
[21] X.S. Zhao, X.Y. Bao, W. Guo, F.Y. Lee, Mater. Today 9 (2006) 32–39.
[22] T.J. Higuchi, Pharm. Sci. 52 (1963) 1145–1149.