Controlled release of ibuprofen by meso-macroporous silica

Article abstract of DOI:10.1016/j.jssc.2013.11.031

Structured meso-macroporous silica was successfully synthesized from an O/W emulsion using decane as a dispersed phase. Sodium silicate solution, which acts as a silica source and a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (EO₁₉PO₃₉EO₁₉) denoted as P84 was used in order to stabilize the emulsion and as a mesopore template. The materials obtained were characterized through transmission electron microscopy (TEM), scanning electron microscopy (SEM), small-angle X-ray diffraction scattering (SAXS) and nitrogen adsorption-desorption isotherms. Ibuprofen (IBU) was selected as the model drug and loaded into ordered meso-macroporous materials. The effect of the materials' properties on IBU drug loading and release was studied. The results showed that the loading of IBU increases as the macropore presence in the material is increased. The IBU adsorption process followed the Langmuir adsorption isotherm. A two-step release process, consisting of an initial fast release and then a slower release was observed. Macropores enhanced the adsorption capacity of the material; this was probably due to the fact that they allowed the drug to access internal pores. When only mesopores were present, ibuprofen was probably adsorbed on the mesopores close to the surface. Moreover, the more macropore present in the material, the slower the release behaviour observed, as the ibuprofen adsorbed in the internal pores had to diffuse along the macropore channels up to the surface of the material. The material obtained from a highly concentrated emulsion was functionalized with amino groups using two methods, the post-grafting mechanism and the co-condensation mechanism. Both routes improve IBU adsorption in the material and show good behaviour as a controlled drug delivery system.

Full text of DOI:10.1016/j.jssc.2013.11.031

Journal of Solid State Chemistry 210 (2014) 242–250
Contents lists available at ScienceDirect
Journal of Solid State Chemistry
journal homepage: www.elsevier.com/locate/jssc
Controlled release of ibuprofen by meso–macroporous silica
n
E. Santamaría , A. Maestro, M. Porras, J.M. Gutiérrez, C. González
Department of Chemical Engineering, Faculty of Chemistry, University of Barcelona, Barcelona, Martí i Franqués 1-11, Catalonia 08028, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Structured meso–macroporous silica was successfully synthesized from an O/W emulsion using decane
as a dispersed phase. Sodium silicate solution, which acts as a silica source and a poly(ethylene oxide)–
poly(propylene oxide)–poly(ethylene oxide) (EO19PO39EO19) denoted as P84 was used in order to
stabilize the emulsion and as a mesopore template. The materials obtained were characterized through
transmission electron microscopy (TEM), scanning electron microscopy (SEM), small-angle X-ray
diffraction scattering (SAXS) and nitrogen adsorption–desorption isotherms. Ibuprofen (IBU) was
selected as the model drug and loaded into ordered meso–macroporous materials. The effect of the
materials’ properties on IBU drug loading and release was studied. The results showed that the loading of
IBU increases as the macropore presence in the material is increased. The IBU adsorption process
followed the Langmuir adsorption isotherm. A two-step release process, consisting of an initial fast
release and then a slower release was observed. Macropores enhanced the adsorption capacity of the
material; this was probably due to the fact that they allowed the drug to access internal pores. When only
mesopores were present, ibuprofen was probably adsorbed on the mesopores close to the surface.
Moreover, the more macropore present in the material, the slower the release behaviour observed, as the
ibuprofen adsorbed in the internal pores had to diffuse along the macropore channels up to the surface of
the material. The material obtained from a highly concentrated emulsion was functionalized with amino
groups using two methods, the post-grafting mechanism and the co-condensation mechanism. Both
routes improve IBU adsorption in the material and show good behaviour as a controlled drug delivery
system.
Received 17 August 2013
Received in revised form
11 November 2013
Accepted 22 November 2013
Available online 5 December 2013
Keywords:
Meso–macroporous material
Silica
Ibuprofen controlled release
& 2013 Elsevier Inc. All rights reserved.
1. Introduction
mesoporous materials with a variety of textures and structures [4].
These porous materials have attracted attention because of the
Ordered mesoporous materials refer to materials with pore
diameters in the 2–50 nm range possessing long-range order [1].
These materials possess unique structural characteristics and offer
a wide range of potential applications. While searching for new
high-surface area and ultra-large pore catalytic materials, scientist
at Mobil Copr discovered that some of their synthetic procedures
yielded solid, powdery products characterized by the presence of
regular, ordered pores with diameters from 1.5 to over 10 nm and
a high surface area [2,3]. Different structures can be obtained by
carefully choosing the template, normally a surfactant. Surfactants
act as structure-directing agents, so a surfactant chain-length
variation may result in an increase or decrease of the mesopore
sizes obtained.
wide variety of applications they are suitable for, and are particu-
larly useful for the preparation of catalysts, drug delivery systems,
sensors and chromatographic materials [5–7].
The incorporation of macropores in mesoporous materials com-
bines the benefits of the mesoporous and the macroporous struc-
tures [8]. The addition of macropores can improve the efficiency of
mesoporous materials as they enhance mass transport and reduce
diffusion limitations [9–11]. In these materials, the macropores act as
channels and facilitate the transport of molecules that have to be
adsorbed in the mesopores. It has been demonstrated that hierarch-
ical materials containing both interconnected macroporous and
mesoporous structures have enhanced properties compared to
materials with uniform pores. This is due to the increased mass
transport through the material and maintenance of a specific surface
area on the level of mesopore systems [12].
Various authors [13,14] have cited a very popular method for
preparing macroporous materials, i.e. the emulsion-templating
approach. Emulsions are defined as dispersions of a liquid (dis-
persed phase) inside another immiscible liquid (continuous
phase). In order to obtain meso–macroporous materials, the
continuous phase of the emulsion must be formulated in such a
Since the discovery of ordered mesoporous materials, many
surfactants have been studied as potential structure-directing
agents. The surfactant aggregates are used as templates to develop
n
Corresponding author. Tel.: þ34 679972602.
E-mail addresses: esthersantamaria@ub.edu,
esther.santamaria@gmail.com (E. Santamaría).
0022-4596/$ - see front matter & 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jssc.2013.11.031

E. Santamaría et al. / Journal of Solid State Chemistry 210 (2014) 242–250
243
way that the mesostructure is formed, while the drops of emulsion
will produce the macropores. Emulsions are classified as direct
emulsions or oil in water (O/W), where the continuous phase is
the aqueous one and oil is the dispersed phase, and inverse
emulsions (W/O), where the oil is the continuous phase and the
aqueous phase is the dispersed one.
Cellu-Sep T3/Nominal MWCO: 12,000–14,000 were provided by
Vertex Technics. Deionized water was used in all samples.
2.2. Methods
2.2.1. Ordered meso–macroporous silica material preparation
Ordered meso–macroporous silica materials were prepared
using the emulsion template process. First, water and surfactant
were mixed and kept under stirring at 50 1C to ease the melting of
the surfactant. Later, the dispersed phase, decane, was added drop
by drop until the desired dispersed phase fraction was reached.
Once the emulsion was formed, the sodium silicate solution was
added along with the concentrated HCl to trigger the hydrolysis
reaction of the silicate [15]. The resulting mixture was stirred for
0.5 h and placed in an oven at 100 1C for 24 h to let the silicate
polymerize in the aqueous phase of the emulsion, the external
phase, thus producing a network of ordered mesopores.
The solid product was filtered off and dried at room tempera-
ture. The product was then dispersed in ethanol:HCl (1 M) 1:1
mixture (50 g), filtered off, dried and calcined at 550 1C for 5 h in
order to eliminate the residual surfactant. The final appearance of
the material was a white coloured powder.
In the present work, meso–macroporous materials were pre-
pared via emulsion templating from an inorganic precursor,
sodium silicate, already successfully used by other authors for
the preparation of mesoporous materials [15]. The most com-
monly used sources of silica were TEOS and TMOS, instead of a
sodium silicate solution. Sodium silicate presents advantages:
neither ethanol nor methanol, which could destroy the mesopore
structure, is freed, and they are cheaper than TEOS or TMOS.
Due the stable structure of mesoporous silica and its well-
defined properties, these materials are ideal as a support for drug
and protein encapsulation. In recent years, several researchers
have described the use of mesoporous materials as drug delivery
systems [16–25]. Controlled drug delivery systems can achieve
precise spatial and temporal delivery of therapeutics agents to the
target site. Generally, controlled drug delivery systems maintain
drug concentrations within the optimum range in the precise sites
of the body, which improves the therapeutic efficacy and reduces
toxicity [26]. While smaller drug molecules and biomolecules can
be accommodated in mesoporous materials with both smaller and
bigger pore sizes, larger drug molecules require materials with
bigger pore diameters [27]. Mesoporous silica materials contain
residual silanol groups that can further be functionalized further
by different organic groups in order to modify their surface
properties [28,29]. This creates favourable surface-drug interac-
tions, which in turn results in the materials’ improved adsorption
affinity for drug molecules. Lin and co-workers have shown that
the organic functionalization of mesoporous materials also influ-
ences their biocompatibility [30]. In addition to surface functional
groups, the morphology and size of the mesoporous materials also
have an important influence on drug release characteristics [31].
Generally, surface functionalization of mesoporous silica mate-
rials via covalent bonding of organic groups can be achieved by
two methods. i.e. post-grafting synthesis [29] and co-condensation
[29]. Although the post-grafting method results in well-ordered,
functionalized, mesostructured materials, it often produces non-
uniformly distributed organic groups because the organic moieties
may congregate more on the channel pore mouth and the exterior
surfaces [32]. The co-condensation synthetic method of producing
mesoporous materials involves a one-step procedure and allows
better control of the loading and distribution of organic groups
[33], although it often produces materials with less well-ordered
mesoporous structures. The most frequently studied drug to be
adsorbed is ibuprofen, since it is one of the most commonly used
anti-inflammatory drugs and a model for this drugs type due to its
relatively small size (1 nm).
2.2.2. Material functionalization
2.2.2.1. Post-grafting functionalization process. About 0.9 g of the
material was mixed with 12 mL of APTES and 30 mL of toluene
[34]. The mixture was gently stirred for 24 h and 50 1C in a closed
bottle in order to prevent evaporation. The resulting material was
filtered off and dried at room temperature.
2.2.2.2. Co-condensation functionalization. The material was syn-
thesized as described in Section 2.2.1 and 12 mL of APTES was
added [35] at the same time as the sodium silicate solution. The
resulting mixture was stirred for 0.5 h and placed in an oven at
100 1C for 24 h in order to let the silicate polymerize in the
aqueous phase of the emulsion. The solid product was washed
and filtered off several times in order to eliminate the surfactant
used.
2.2.3. Ibuprofen adsorption process
Typically, 50 mg of the material was put in 5 mL of hexane
containing different concentrations of ibuprofen (IBU) (5, 10, 15, 20
and 35 mg/mL) in a closed bottle to prevent evaporation of the
hexane and under gentle magnetic stirring for 72 h. The concen-
tration of ibuprofen in hexane was determined through an UV
spectrophotometer at 280 nm by collecting 3 mL of hexane filtered
using a syringe filter.
2.2.4. Ibuprofen release experiments
The mesoporous material (100 mg) was placed into 10 mL of
IBU solution in hexane (35 mg/mL) and stirred at room tempera-
ture for 72 h in a closed bottle to prevent evaporation of the
hexane. The loaded materials were then filtered and dried at room
temperature for 24 h. A 50 mg of the resulting materials was put
into a dialysis bag and immersed in 50 mL of simulated body fluid
(SBF, pH 7.4) [36-37] at 37 1C under magnetic stirring at 100 rpm.
2. Materials and methods
2.1. Materials
The triblock copolymer of poly(ethylene oxide)-b-poly(propy-
lene oxide)-b-poly(ethylene oxide) Pluronic P84, (EO)19(PO)39
(EO)19 was supplied by Sigma Aldrich. Sodium silicate solution
(Na2O ꢀ10.6% and SiO2 ꢀ26.5%) was used as a silica source and
was supplied by Sigma Aldrich. Ethanol (96%), HCl (37%), and
potassium cloride and sodium hydroxide were purchased from
Panreac. Ibuprofen (498%) was purchased from TCI Chemicals
Europe. Hexane (95%) and (3-aminopropyl) triethoxysilane
(APTES) (498%) were supplied by Sigma Aldrich. Dialysis bags
2.2.5. Characterization
2.2.5.1. Transmission electron microscopy (TEM). The porous mate-
rial were examined using a TEM (JEOL JEM-2100 microscope with
an acceleration voltage of 200 kV). In order to prepare the sample
for TEM analysis, the material was dispersed in ethanol by
sonication for 5 min. The dispersion was dropped onto a copper
grid coated with carbon film and dried at room temperature.

244
E. Santamaría et al. / Journal of Solid State Chemistry 210 (2014) 242–250
Chart 1
Relation of the carried out experiments: specific surface area (SBET), pore diameter (ϕ) and pore volume (Vp) as a function of the oil fraction (weight). Water, surfactant,
HCl and sodium silicate quantities are indicated.
Experiment
Water (g)
P84 (g)
Sodium silicate (g)
HCl (g)
Decane (g)
Dispersed phase
SBET (m2/g)
ϕ (nm)
Vp (cm3/g)
P84_meso
P84_20%
P84_50%
P84_75%
20
20
20
20
1
1
1
1
3
3
3
3
6
6
6
6
0
7.5
30
90
0.00
0.20
0.50
0.75
600730
412720
330715
154710
4.0170.10
4.1470.20
4.19 70.15
8.4771.20
0.6570.10
0.6370.15
0.5170.12
0.3070.05
2.2.5.2. Scanning electron microscopy (SEM). In this study, SEM
(HITACHI S-4100 with carbon coated operated at 15 keV) was
used to observe the morphology of the samples.
2.2.5.3. SAXS measurements. Small-angle X-ray diffraction scatter-
ing (SAXS) measurements were used to determine the structure of
the mesoporous materials. Measurements were performed in a
Hecus X-ray Systems GMBH Graz, equipped with a Siemens
Kristalloflex 760 (K-760) generator. The temperature of the samples
was fixed using a Peltier Anton Paar (25–300 1C) controller. The
radiation wavelength was 1.54 nm.
2.2.5.4. N2-sorption analysis. The specific surface area, mean pore
diameter and pore volume of the meso–macroporous silica
materials were determined by N2-sorption analysis using
a
Micromeritics Tristar 300 instrument at ꢁ196 1C. Prior to each
measurement, the samples were degassed at 120 1C for 6 h. The
specific surface areas were estimated using the BET method. The
pore diameter and pore size distribution were determined using
the BJH method from the adsorption branch of the isotherm.
Fig. 1. SAXS pattern of obtained material with (a) no oil fraction (b) 0.20 oil fraction
(c) 0.50 oil fraction and (d) 0.75 oil fraction.
2.2.5.5. FT-IR. Powdered materials were pressed into a tungsten
mesh grid and installed in an in situ FTIR transmission cell.
Measurements were performed using a Thermo Scientific Nicolet
iZ10, ATR diamond and detector DTGS with a spectral resolution of
reported by Du et al. [42] and Blin et al. [43], which would
indicate that the higher the dispersed phase fraction used, the
bigger the cell dimension of the material obtained.
Fig. 2 shows several representative scanning electron micro-
graphs (SEM) of the synthesized silica. It shows how the macro-
pore density increases as the dispersed phase fraction is increased.
When more macropores exist, the effective thickness of the
material is lower and, therefore, the SAXS peaks present less
intensity. These materials present porosity at the nanometric and
micrometric scale.
4 cmꢁ1 and a spectral range of 4000 to 525 cmꢁ1
.
3. Results
3.1. Material characterization
A series of experiments was carried out (Chart 1) in order to
study the influence of the dispersed phase on the porous material
properties.
The sample with a dispersed phase of 0.75 (Fig. 2d) results in
the typical image of macroporous material, in which the macro-
pores occupy a large part of the material's volume and are
separated by a thin layer of material. The macropores have the
shape of the droplets in highly concentrated emulsions.
However it is unclear whether the hexagonal symmetry that is
observed through SAXS, is linked to the organization of the wall of
mesoporous material that surrounds the macropores, or is simply
due to the macropore structure itself.
The TEM images (Fig. 3) show how the meso–macroporous
materials are clearly ordered in their mesostructure, with well-
oriented channels. Fig. 3a and b shows the characteristic honey-
comb arrangement. From these observations, it can be concluded
that the walls surrounding the macropores have a structured
network of mesopores.
Fig. 3c and d show that some polyhedra corresponding to the
macropores of the material (more than 50 nm) can be observed
surrounded by thin walls of meso-sized pores. The bigger macro-
pores were observed through SEM (Fig. 2).
Nitrogen adsorption–desorption isotherms and the corre-
sponding BJH pore size distributions are shown in Fig. 4. This
shows how they vary depending on the dispersed phase fraction
used. According to the BDDT classification [44], isotherm type IV,
which is typical of mesoporous materials, is obtained, but at high
SAXS was used to determine the type of structure of the
material obtained. In Fig. 1, the SAXS patterns for all of the
samples with different contents in the dispersed phase are shown.
In the first one, no oil fraction was used and, as can be observed, it
is the sample with the most defined peaks. There are three peaks
indexed as [1 0 0], [1 1 0], and [2 0 0], which can be associated
with a well-ordered, two-dimensional (2D) hexagonal mesostruc-
ture, in accordance with the original reports [38–41]. This struc-
ture is the most common for triblock copolymers such as P84 that
usually produce SBA-15 material. For the material with a dispersed
phase fraction of 0.20, three peaks are detected in the SAXS
pattern. The three reflections are not as well defined as the
material without oil and seem located at q ratios 1:√3:2, showing
a possible hexagonal symmetry. The unit cell dimension (a0¼2d100
/
√3), which corresponds to the sum of the pore diameter and the
thickness of the pore wall, was calculated in accordance with Bragg's
law and its value was 9.19 nm.
For a dispersed phase fraction of 0.50 the first peak found
corresponds to an 11.8 nm cell dimension. The intensity of the
peaks obtained is low due to the fact that the materials possess a
large quantity of macropores. This result confirms the data

E. Santamaría et al. / Journal of Solid State Chemistry 210 (2014) 242–250
245
Fig. 2. SEM images from different materials obtained for different fraction of oil. (a) P84_meso (b) P84_20% (c) P84_50% and (d) P84_75%.
Fig. 3. TEM images of different materials obtained for different fraction of oil. (a) P84_meso (b) P84_20% (c) P84_50% and (d) P84_75%.
relative pressures the isotherms present a rise that is typical of
macroporous materials. The higher the dispersed phase fraction
used, the larger the indicative zone of macroporosity in the
isotherm, due to the presence of more drops of the emulsion,
which generated macropores, increase the density of macropores
in the material. These conclusions are similar to those obtained by
Stébé et al. [45], although in that case, the mesopores did not
present any order for a dispersed phase fraction above to 0.45.
Pore size distributions show a sharp peak corresponding to a
pore diameter of around 4 nm but for the material obtained with a
dispersed phase fraction of 0.75, the distribution is wider than the
other materials. This is due to the high presence of macropores.
Emulsion droplets can range in size from microns to nanometers.
Fig. 4 also shows nitrogen adsorption–desorption isotherms
corresponding to the materials after ibuprofen adsorption. In all
cases, the hysteresis loop decreased and the specific surface
reduced, which would indicate the successful adsorption of the
ibuprofen. Pore size distributions were modified because ibupro-
fen was sometimes adsorbed in the entrance of the mesochannel,
leading to a reduction in the size of the remaining pores.

246
E. Santamaría et al. / Journal of Solid State Chemistry 210 (2014) 242–250
Fig. 4. Evolution of nitrogen adsorption–desorption isotherms for materials before IBU adsorption (black points) and after IBU adsorption (white points) and BJH pore sized
distributions for (a) material obtained without oil fraction, (b) material obtained from 0.20 of dispersed phase, (c) material obtained from 0.50 of dispersed phase and
(d) material obtained from 0.75 of dispersed phase. T-plot for materials before IBU adsorption is shown.
T-plot analysis is shown for the obtained materials. In all cases
the Y-intercept was zero, which would indicate a lack of micro-
porosity, so all the specific surfaces of the materials were due to
mesoporosity and macroporosity.
When the dispersed phase fraction was increased from 0.00 to
0.75, a decrease in the specific area from 600 to 154 m2/g (Chart 1)
was observed. This has been shown by other authors [43] and
could be explained by the fact that when the quantity of oil in the
emulsion is increased, the interphase oil–water also increases and
the surfactant preferably locates in this interphase, thus stabilizing
the emulsion. This causes a reduction of free surfactant in the
water. Therefore, the higher the dispersed phase fraction used, the
less surfactant is available to form the mesostructure in the
continuous phase and the lower the density of ordered mesopores,
deriving into a smaller specific area, since the SBET only considers
the contribution of the meso-sized pores. Another possible expla-
nation for this is that silica tends to polymerize and accumulate in
the interphases, which do not present mesoporous structures.
Therefore, the higher the dispersed phase fraction used, the less
structure there is and, consequently, the less specific surface there
is. Both of these mechanisms could contribute to decreasing the
specific surface with dispersed phase.
Chart 1 shows how the average diameter of the mesopores
remains approximately constant up to a dispersed phase fraction

E. Santamaría et al. / Journal of Solid State Chemistry 210 (2014) 242–250
247
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
observed two R values, for P84_20% and P84_75%_co.condensation,
quite low. This is due to the two experimental data from theoretical
isotherm. Concentrations are quite low, so a small deviation results
into a low fitting parameter. For the other samples the fitting
parameters are good.
Fig. 5 shows that mesoporous materials have a lower adsorp-
tion capacity than materials with macropores in their structure, in
spite of the higher SBET. It could be concluded that, as increasing
the macropores present in the material increase the access of IBU
to all specific areas, particularly the internal porous area, is
enhanced. Although the SBET of the meso–macroporous materials
are lower than the SBET of the mesoporous material - in the case of
the material P84_75% the specific area is four times lower—the
accessible area is bigger when macropores are present as they
allow the IBU molecules to diffuse towards the surface of internal
mesopores, while the IBU adsorbed on mesoporous materials is
probably located in the external part of the mesochannels, which
they rapidly obturate and, therefore, the rest of the remaining
mesochannels are not used.
0
5
10
15
20
25
30
[IBU] hexane (mg/mL)
Fig. 5. Adsorption isotherms of Ibuprofen release profiles for the materials
obtained from samples P84_meso (black diamonds), P84_20% (white squares),
P84_50% (black triangles), P84_75% (white diamonds), P84_75% functionalized by
grafting (black squares) and P84_75% functionalized by co-condensation method
(white triangles).
The material P84_75% was functionalized in order to increase
IBU adsorption on the silica as a result of the amino groups that
provide a stronger interaction with the OH group of the ibuprofen.
Two mechanism were used, i.e.the grafting process and co-
condensation. In order to verify the amino groups present in the
material, the materials were characterized by FT-IR (Fig. 6).
The asymmetric vibrations of the Si–O–Si bonds appear around
1070 cmꢁ1, as can be observed in the spectra of Fig. 6a, which
corresponds to the meso–macroporous material with a dispersed
phase of 75%. This band remains constant in the other materials: in
the case of the material functionalized using the grafting process
with APTES, the sample presents a band at3200 cmꢁ1, corre-
sponding to the C–H bond, and a smaller band at 1540 cmꢁ1 due
the vibrations of the N–H bond. The C–H and N–H bonds
correspond to the aminopropyl groups grafted in the surface of
the silica material [34,47,48].
Chart 2
Fitting parameters obtained from Langmuir equation.
Experiment
Γmax (mg IBU/mg mat)
k
R2
P84_meso
P84_20%
P84_50%
P84_75%
P84_75%_grafting
P84_75%_co-condensación
0.53
0.65
0.62
0.90
0.99
1.02
0.12
0.09
0.14
0.08
0.10
0.11
0.991
0.962
0.994
0.989
0.991
0.969
of 0.50, and increases from 4.1 to 8.5 nm when the dispersed phase
fraction is increased from 0.50 to 0.75. The addition of oil acts as a
swelling agent, as previously reported [45,46], and this could
increase the size of the mesopores obtained. Decane reduces the
hydration of the hydrophobic poly(propylene oxide) (PPO) chains.
It is also located in the micelle core and acts as a swelling agent
and can therefore be used to control pore size.
The FT-IR spectra for the material functionalized with the co-
condensation process (Fig. 6c) shows more intense bands corre-
sponding to the C–H and N–H bond, indicating the presence of
more amino groups using this technique, which produces more
homogeneity in the amine distribution on the material surface.
The FT-IR spectra for the samples with IBU adsorbed are
shown in Fig. 6d, in the case of the material functionalized by
grafting, and Fig. 6e, in the case of that functionalized using the
co-condensation method. In both spectra, the bands at 3200 and
1500 cmꢁ1, corresponding to the C–H and phenyl group, respec-
tively can be conserved. The observed band at 1710 cmꢁ1 in the
P84_75%_co-condesation_IBU is due to the COOH group of the
ibuprofen molecule while the peaks at 1555 cmꢁ1 in the spectra
3.2. Ibuprofen adsorption isotherm.
The adsorption of IBU from hexane was studied by determining
the adsorption isotherms for the materials prepared with different
dispersed phase contents, described in Chart 1, and for the
functionalized materials. Adsorption equilibrium curves are repre-
sented in Fig. 5.
The Langmuir adsorption equation could be expressed as:
are indicative of the formation of the COOꢁNH3 bond [48].
þ
k ꢂ c
Fig. 6f shows FT-IR spectra for ibuprofen molecule. For low
wavenumber region many peaks are observed as other authors
reported [49,50]. This is also appreciated in the samples loaded
with ibuprofen for P84_75% functionalized by grafting method
and more obviously with functionalized by co-condensation
method due. These peaks are due to a high level of ibuprofen,
so FT-IR spectra is more similar to the ibuprofen spectra than the
material without drug loading.
Γ ¼ Γmax
ð1Þ
ð1þk ꢂ cÞ
where k, represents the Langmuir constant, c the equilibrium
concentration of IBU in hexane solution, and Γmax the maximum
amount of IBU adsorbed per weight of material. k and Γmax were
determined by Lineweaver–Burk linearization.
The first step of the adsorption process is the migration of the
IBU molecules from a bulk solution to the surface. The second was
adsorption on the material surface and diffusion into the interior
pores of the silica materials. The increase in IBU concentration
would be in favour of IBU migration to the surface and diffusion
into the interior pores of the materials until equilibrium is
reached.
3.3. Ibuprofen release experiments.
The amount of drug released from a film or thin disk is
proportional to the square root of the time (Higuchi model) [25],
and the release speed decreases gradually. The kinetics of the
release process is governed by the physical properties, particularly
by its molecular weight and the solubility of the polymeric matrix
and the quantity of drug incorporated. The diffusion speed
Chart 2 shows the Langmuir isotherm fitting parameters obtained
from the experimental data. The maximum IBU weight adsorbed for
weight of mesoporous material increases when the macropore
presence increases and improves with functionalization. It can be

248
E. Santamaría et al. / Journal of Solid State Chemistry 210 (2014) 242–250
20% this value was around 83%; for the material with a dispersed
phase of 50% the release of IBU in the burst stage was 79%; and for
the material with a dispersed phase of 75%, this value dropped to
63% of the IBU. According to these results, we can assume that the
macropore presence in the material facilitates the release of the
drug and minimizes the burst effect.
This fact may seem strange, because the macropore channels
should ease the diffusion from the mesostructure to the media.
However, it has been shown in previous sections that macropores
favour the access of IBU molecules to all available mesopores,
including the internal pores, since the adsorption capacity of
meso–macroporous materials is higher than that of mesoporous
materials, in spite of their smaller SBET. Moreover, the mesostruc-
ture for meso–macroporous materials presented bigger pore sizes
than the mesopores obtained in the mesoporous materials
(Chart 1), which again favours once more a deeper penetration
of IBU along the mesochannels. The relese of ibuprofen from the
mesoporous material was faster, because the IBU molecules were
located on the external surface or in the outer surface of the
mesochannels, since they could not penetrate much due to the fact
that some of the IBU molecules adsorbed obstructed the meso-
channels. On the other hand, during the release experiments, the
bath containing the SBF solution was under gently agitated to
ensure that there were no privileged diffusion paths. Due to this
gentle agitation, the IBU molecules of the mesoporous material
that were not located in the deeper material structure had an
enhanced rate of transfer. In the case of the meso–macroporous
materials, the IBU molecules should have moved through the
macropores channels, where there was no agitation and which
were acting as an additional diffusion barrier that the IBU
molecules located in external mesopores would not encounter.
Fengyu Qu et al. [49] observed that meso–macroporous
material obtained from natural substances presented an IBU
release of 60% at 50 h compared to the 100% release for
mesoporous material. In our case, at 50 h the material with a
dispersed phase of 75% presented an IBU delivery rate of 60%,
while for mesoporous material, it reached 96%. The meso–
macroporous material containing
a disperse phase of 75%
reached the total IBU release at 120 h.
Fig. 6. FT-IR spectra for the (a) P84_75%, (b) P84_75%_grafting, (c) P84_75%_co-
condensation, (d) P84_75%_grafting_IBU, (e) P84_75%_co-condensation_IBU and (f) IBU.
The functionalized material is shown to present a higher
adsorption capacity and a slower release of IBU in compared to
the material without amino groups. In the case of the grafting
method, the reduction in release velocity is not significant, but
depends on the specific area and the matrix density, as well as the
diffussion coefficient of the drug. If there is enough drug to
maintain the internal concentration at higher levels than the
concentration in the external media, the diffusion speed of the
drug through the matrix is constant.
In vitro controlled release was carried out in order to check the
properties and behaviour of the materials. Fig. 7 the percentage of
IBU released as a function of time.
The first release is attributed to the so-called burst effect as
Gallagher and Corrigan postulated in their model [51]. This effect
is due to the fact that ibuprofen molecules are physically adsorbed
on the outer surface of the material and these molecules, which
are more accessible, are rapidly released, as other authors have
observed [52,53]. The second stage corresponds to the slow
diffusion of ibuprofen molecules from the mesochannels of the
material to the media, along the macroporous channels.
in the case of the co-condensation sample,
a significant
decrease in the release of IBU with time can be observed,
due to the improvement and more homogeneous functionali-
zation of the material. In co-condensation method the amino
groups were introduced during the formation of the material,
so the internal walls of the macropores and mesopores were
filled with more amino groups than the walls of the material
functionalized by post-grafting method. Post-grafting method
introduces more amino groups on the external surface because
the material was previously formed. For this reason, the
adsorption properties are quite similar in both techniques
but the release was slower in the case of co-condensation,
due to the amino groups and ibuprofen are linked in the
internal surface. The burst stage is reduced from 60% for the
P84_75% to 45% for the P84_75%_co-condensation sample.
It is clear that all the materials present a first stage called the
burst stage, where a significant amount of IBU is released in less
than 10 h, as can be observed by zooming in on Fig. 7. This fast
release is due to the desorption of the IBU molecules adsorbed in
the external part of the mesochannels. Therefore, when the release
process starts, these molecules are the first to migrate to the
media. For the mesoporous material, the burst effect reaches 96%
of the ibuprofen release; for the material with a dispersed phase of
4. Conclusions
In this paper hierarchically meso–macroporous materials were
obtained using an ordered mesostructure. Materials were studied
as drug delivery systems, and ibuprofen was chosen as a model
drug. The adsorption capacities and release behaviours of the

E. Santamaría et al. / Journal of Solid State Chemistry 210 (2014) 242–250
249
Fig. 7. Ibuprofen release profiles for the materials obtained from samples P84_meso (black diamonds), P84_20% (white squares), P84_50% (black triangles), P84_75% (white
diamonds), P84_75% functionalized by grafting (black squares) and P84_75% functionalized by co-condensation method (white triangles).
model drug were highly dependent on the structure of the
materials. The IBU amount adsorbed was mainly a function of
the quantity of macropores present in the material due the fact
that macropores allowed the drug molecules to penetrate deeper
pores, thus covering a higher surface area of the material. For the
release process, two-steps were observed; these consisted of an
initial fast release, called the burst effect, which is related to the
liberation of the IBU adsorbed in pores near the surface of the
material, and a subsequent slower release, relating to the deso-
rption of drug molecules adsorbed at pores located further inside
the surface of the material, which should diffuse along the
macropore channels. While the presence of macropores is
increased the burst effect is minimized and the delivery is more
sustained over time. The materials with more macropores present
a slower release rate, since the IBU molecules are located over all
the material's surface and not only near the surface of the material.
During the release experiments, first the molecules on the external
surface were released first, followed by the molecules in the
deeper structure. Therefore, we can conclude that for meso–
maroporous materials, the drug molecules must overcome two
diffusion barriers, one corresponding to the macropore channel
and the other corresponding to the diffusion from the material to
the fluid. The co-condensation method to functionalize materials
presents a higher capacity to adsorb IBU and a slower release rate
than the material functionalized using the grafting method due to
a more homogeneous functionalization.
(MICINN) within the framework of the project CTQ2011-29336-
C03-02. Thanks to SAXS measurements done by the Consejo
Superior de Investigaciones Científicas (CSIC). To Mr. Jonathan
Miras, Mrs Maria Martínez for their advice with SAXS results.
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