J Sol-Gel Sci Technol (2010) 56:191–196
DOI 10.1007/s10971-010-2293-7
ORIGINAL PAPER
Functionalized silica matrices for controlled delivery
of cephalexin
Elena I. Basaldella • Marı́a S. Legnoverde
Received: 20 May 2010 / Accepted: 14 July 2010 / Published online: 27 July 2010
Ó Springer Science+Business Media, LLC 2010
Abstract The surface of SBA-15 ordered mesoporous
silica was functionalized with sulphonic and amine func-
tional groups to determine the effect of changes in surface
acidity on cephalexin adsorption and subsequent release.
Cephalexin (CPX), which belongs to the group of cepha-
losporins or b-lactam antibiotics, was impregnated on
functionalized SBA-15. The functionalized silica materials
were characterized by SEM, TGA, FTIR and N2 adsorp-
tion, and an in vitro drug delivery test was performed. SEM
micrographs showed the packed cylinders correspond
to SBA 15 materials. Likewise, N2 adsorption–desorption
isotherms demonstrated that the SBA-15 structure was
obtained when IV-type isotherms were displayed. The
inalterable stabilization of the drug was confirmed by FTIR
spectroscopy. For all the samples studied, the delivery
profiles exhibit two steps. A fast initial stage was obtained
over the first 5 h, followed by a slower one. Regarding this
second stage, the time needed to attain a plateau was
undoubtedly altered by the surface functionalization.
Keywords SBA-15
Surface functionalization

Cephalexin
Drug release
1 Introduction
The physicochemical and biological properties of silica
materials, such as high surface areas, well-ordered struc-
tures, controllable mesoporosity, no toxicity and good
E. I. Basaldella (&)
M. S. Legnoverde
Centro de Investigación y Desarrollo en Ciencias Aplicadas,
Dr. Jorge J. Ronco (CINDECA) (CONICET-CIC-UNLP),
calle 47 N8 257, 1900 La Plata, Argentina
e-mail: eib@quimica.unlp.edu.ar
biocompatibility, make these solids interesting matrices for
performing the controlled delivery of pharmaceutical
drugs.
In particular, ordered mesoporous silicas, such as MCM-
41 and SBA-15, have been widely investigated as potential
drug carriers [1–7], where ibuprofen [1], vancomycin [2],
gentamycin [3], tetracycline [4], valproic acid and sodic
phenytoin [5], cortisol [6], and collagen-PVP [7] were used
as model drugs to study adsorption and delivery processes.
Published results show that the wall composition of the
porous material plays a very important role in the drug
delivery kinetics [4]. Thus, in this paper, we analyze the
influence of amino-functionalization and sulfonic-functio-
nalization of SBA-15 mesoporous silica on the release
performance of cephalexin.
2 Experimental
2.1 Chemicals
The chemicals used in this study include triblock copolymer
poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene
oxide), Pluronics P123 (MW: 5800, Aldrich), tetraethyl
orthosilicate (TEOS, 98%, Aldrich), hydrochloric acid
(Merck), 3-aminopropyltriethoxysilane (APTES, Aldrich),
1,4-dioxane (Carlo Erba), 3-mercaptopropyltrimethoxy-
silane (MPTMS, Alfa Aesar), hydrogen peroxide (H2O2,
Panreac), sulfuric acid (J.T Baker) and cephalexin mono-
hydrate (Interlude Company S.A.).
2.2 Synthesis of materials
A sample of SBA-15 (SBA) was prepared according to the
methodology described by Zhao [8]. The template was
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removed from the as-synthesized material by calcination
(6 h at 540 °C). The functionalized samples were obtained
by post-synthesis impregnation. For the anchoring of
amino groups to the surface, the calcined sample was
refluxed in a 6.66% (V/V) solution of 3-aminopropyl-
triethoxysilane in 1,4-dioxane for 16 h. The resulting solid
was recovered by filtration, washed with the solvent and
dried (40 °C, in vacuum) to constant weight [9]. This solid
was named SBANH2. For the attachment of sulphonic
groups, SBA was firstly modified with mercaptopropyl
groups using (3-mercaptopropyl)trimethoxysilane (MPTS).
The calcined sample was refluxed in a 4% (V/V) solution
of MPTS in toluene for 24 h. After that, the solid with
immobilized mercaptopropyl groups was oxidized with
H2O2 [10]. This sample was named SBASULF.
2.3 Characterization
The solid samples obtained before and after functionali-
zation were analyzed by different techniques. Bruker IFS
66 equipment, pellets in KBr, and a measuring range of
400–4,000 cm-1 were used to obtain the FT-IR spectra of
samples dried at 40 °C. SEM micrographs were obtained
by using a Scanning Electron Microscope Philips 505. The
adsorption–desorption nitrogen isotherms were measured
at the temperature of liquid nitrogen using a Micromeritics
apparatus ASAP 2020 (Micromeritics, Atlanta, Georgia).
The surface area was determined by applying the Bru-
nauer–Emmett–Teller (BET) equation, and the pore size
diameter was estimated from the peak position of the
Horvath-Kawazoe pore size distribution for cylinder pore
geometry (Saito-Foley). Before adsorption, samples were
outgassed by heating at 100 °C in vacuum lower than
3 9 10-2 mm Hg for 12 h. The change in acidity due to
functionalization was determined by potentiometric titra-
tion. A known mass of the solid to be analyzed was sus-
pended in acetonitrile. The suspension was titrated using a
0.1 N solution of n-butylamine in acetonitrile at 0.05 mL/
min. The electrode potential variation was recorded on a
digital pH meter (Metrohm 794 Basic Titrino apparatus
with a double junction electrode). The loaded amount of
cephalexin in porous carrier materials was determined in a
Shimadzu model TGA-50 thermoanalyzer.
(TGA). The in vitro drug release measurements were per-
formed in aqueous media at 25 °C. For this purpose, the
impregnated samples were pressed into tablets of approx-
imately 50 mg and then soaked in 300 mL of water, under
stirring. The released concentration as a function of time
was determined by UV–visible spectroscopy (PerkinElmer
Lambda 35) at 262 nm.
3 Results and discussion
3.1 Material characterization
FTIR analysis demonstrates the organo-functionalization of
SBA-15 with acidic and basic moieties. Figure 1 shows the
spectra corresponding to the silica before (a) and after
functionalization (b,c).
There are several bands appearing in the amino-
functionalized SBA-15. Absorption bands in the 3,740–
3,000 cm-1 region are usually attributed to the presence of
silanol groups. It is difficult to determine the functional
group –NH2 attached to the mesoporous material surface by
observing absorption around 3,460 cm-1 because the band
of –NH2 overlaps with that of O–H stretching vibration [9].
The peaks at 2,937 and 1,560 cm-1 correspond to the C–H
stretching and the N–H (primary amine) bending vibration,
respectively [11, 12]. Furthermore, the large reduction in the
absorbance of the O–H stretching band, which is not only
visible in the SBANH2 spectra but also in the SBASULF
spectra, is in line with the replacement of –OH groups with
the – Si(CH2)3NH2 and –Si(CH2)3SH groups, respectively
[13]. Similarly, the reduction in the absorbance of the
siloxane groups at 965 cm-1 and OH– groups at 1,640 cm-1

2.4 Drug adsorption and release

For the drug loading, the functionalized samples were

impregnated with an aqueous solution of 10 mg/mL of
cephalexin (CPX) in order to get samples of about 150 mg
of CPX per 1 g of silica. These solid samples (SBANH2 CPX
and SBASULF CPX) were characterized by N2 adsorption-
desorption, scanning electronic microscopy (SEM), infra-
red spectroscopy (FTIR) and thermogravimetric analysis Fig. 1 FTIR Spectra: a SBA, b SBANH2, c SBASUL

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suggests grafting occurrence. Additionally, the bands at 630

and 650 cm-1 corresponding to C–S stretching and –SO3H
groups, respectively, can be observed [14] (Fig. 1c).
Furthermore, potentiometric titration measurements
showed the effect of functionalization on surface acidity.
Compared to SBA-15 (Fig. 2a), both the number and
strength of acid sites increase markedly for SBASULF
(Fig. 2c) and diminish for SBANH2 (Fig. 2b).
From the SEM micrographs one can observe the typical
morphology that characterizes SBA-15, consisting of cylin-
ders forming aggregates resembling wheat grains (Fig. 3a).
This shape is conserved after functionalization (Fig. 3b, c).
On the other hand, large hysteresis loops correspond-
ing to type-IV N2 adsorption/desorption isotherms are
observed for these materials (Fig. 4). Their pore sizes, BET
areas, and pore volumes are listed in Table 1 for compar- Fig. 4 N2 adsorption and desorption isotherms: a SBA, b SBANH2,
c SBASUL
ison; pore size distributions are shown in Fig. 5.
It can be seen that functionalization reduces BET area,
pore volume and pore diameter. Analyses of the nitrogen Table 1 Physical properties and drug loading amount of samples
adsorption/desorption curves showed type-IV isotherms, Sample BET Pore Vol. Pore Loading
with clear hysteresis loops associated with capillary con- (m2/g) (cm3/g) size weight,
densation. The capillary condensation step is less well- (Å) W (%)
defined for the functionalized materials and indicates that SBA 804 0.75 79 22
the pores size distribution is wider for these materials in SBANH2 308 0.25 49 7.5
comparison to that of the SBA sample. The mesopore SBASUL 266 0.25 54 20

diameters corresponding to SBANH2 and SBASULF are

smaller than that of the SBA-15 substrate, as expected, due
to the presence of functionalizing groups attached to the
silica walls. Additionally, the decrease in the BET area and
pore volume can be partially related to the increase in the
material density due to functionalization.

3.2 Drug adsorption

The CPX molecule (Fig. 6) contains NH2, C(O)NH, and

C(O)OH groups, so it is similar, in structure and acid-base
Fig. 2 Potentiometric titration: a SBA, b SBANH2, c SBASUL properties, to dipeptide molecules.

Fig. 3 SEM micrographs: a SBA, b SBANH2, c SBASUL

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Fig. 5 Pore size distribution curves: a SBA, b SBANH2, c SBASUL
Fig. 6 Cephalexin (CPX)
Figures 7, 8 and 9 show the FTIR spectra corresponding
to the samples before and after CPX impregnation. As can
be seen, the CPX spectrum presents a characteristic band
at 3,438 cm-1 due to amide N–H stretching vibrations.
The bands at 3,271 and 3,209 cm-1 are due to intermo-
lecular hydrogen-bonded amine groups, while a band at
3,042 cm-1 is due to the acidic hydroxyl groups.
Characteristic bands appearing at 1,758 and 1,690 cm-1
are due to four-membered lactam carbonyl and second-
ary amide carbonyl groups, respectively. The bands at
1,591 and 2,919 cm-1 are due to N–H bending vibrations
and C–H stretching vibrations, respectively. The bands
Fig. 7 FTIR Spectra: a SBA, b SBAcpx, c CPX
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Fig. 8 FTIR Spectra: a SBANH2, b SBANH2 cpx, c CPX
Fig. 9 FTIR Spectra: a SBASUL, b SBASUL cpx, c CPX
appearing at 1,455, 1,406, and 1,350 cm-1 are due to C–H
bending vibrations. The C–N stretching vibrations are
observed at 1,283 cm-1, whereas C–O stretching vibra-
tions are observed at 1,073 cm-1. Characteristic peaks due
to monosubstituted phenyl groups appeared at 745 and
696 cm-1, whereas the peak due to C–S stretching vibra-
tions merged at 745 cm-1.
Peaks appearing at 1,763, 1,695, 1,425, 1,390, 1,079,
and 702 cm-1 for cephalexin also appeared in the drug-
loaded materials, indicating the chemical stability of
cephalexin after entrapment [15].
The loading weight percentage (W) of CPX in porous
carrier materials was determined by TGA (as described in
[4]) and is listed in Table 1 for comparison.
3.3 Drug release
The release profiles corresponding to functionalized SBA
samples loaded with CPX in aqueous media are depicted in
J Sol-Gel Sci Technol (2010) 56:191–196 195

Fig. 10 Release profiles

corresponding to the studied
SBA samples. SBACPX
corresponds to the CPX-
impregnated, nonfunctionalized
SBA-15

Fig. 10. For the three samples, the release rate exhibits two
steps, beginning with a fast delivery over the first 5 h,
followed by a slower desorption during the next 30 h.
At times longer than 30 h, the CPX release rate from
the different silicas shows the sequence SBA C SBASULF [
SBANH2. Nevertheless, the loaded CPX was not completely
released from any of the three matrices. The SBANH2
sample showed the highest drug percentage retained.
At shorter times (1–20 h), the release rate is strongly
influenced by the nature of the anchored groups, the slower
delivery rate and delivery percentage being obtained when
the amino groups were attached (Fig. 10, SBANH2 CPX).
These results suggest a considerable interaction between
the CPX molecule and the amino functionalized silica
which can be attributed to the presence of a carboxylic
group in the drug molecule. On the contrary, the fastest
release rate was obtained for SBASULF sample. It seems
that almost not interactions occurred between the CPX
molecules and the SBASULF surface, despite the presence
of an amino function in the CPX molecule.
On the other hand, results of surface modified meso-
porous materials indicated that the surface hydrophobicity
could also affect the release rate [16]. In this case, the
relative hydrophilic character determined by TGA (as
physically adsorbed water, weight loss at \110 °C) shows
the sequence SBASULF CPX \ SBACPX \ SBANH2.CPX.
According to the delivery profiles (Fig. 10), at short times
the drug is retained more strongly by the most hydrophilic
surface, so the surface hydrophobicity is not an important
factor in influencing the drug delivery performance. It
seems that the aminofunctionalization is the main factor
responsible for the reinforcement of the chemical interac-
tion between the silica surface and the CPX.
Another difference among the prepared matrices is their
pore size, which are detailed in Table 1. Generally,
decreasing the pore size of the host material leads to a
slower drug delivery rate. Despite the smaller pore size
presented by the functionalized samples, differences in the
release curves cannot be attributed to the influence of the
pore size. The functionalized sample with the smallest pore
size has the fastest release rate. Additionally, the molecular
size of CPX is around 1.6 nm, which ensures its easy
adsorption and desorption into the pores of the materials
synthesized in this study (5.0–8.0 nm).
4 Conclusions
The organic functionalization of the internal silica surface
was performed in order to modify the interaction of the
antibiotic with the pore walls. CPX was impregnated on
sulphonic-functionalized SBA-15 and amino-functional-
ized SBA-15. It was demonstrated that the presence of
these functional groups on the pore walls modifies the
degree of CPX leaching from the mesoporous molecular
sieve. Amino-functionalization allows a sustained drug
delivery over a period of about 30 h. These results confirm
that the modification of the silica support by changing the
surface acidity is a methodology that can contribute to the
achievement of a CPX controlled delivery.
Acknowledgments The authors would like to thank CIC, UTN,
UNLP for financial support. M.S.L. acknowledges the grant for her
PhD study sponsored by FONCyT/UTN.
References
1. Munoz B, Ramiila A, Perez-Pariente J, Diaz I, Vallet-Regi M
(2003) MCM-41 organic modificationas drug delivery rate reg-
ulator. Chem Mater 15:500–503
2. Lai CY, Trewyn BG, Jeftinija DM, Jeftinija K, Xu S, Jeftinija S,
Lin V (2003) A mesoporous silica nanosphere-based carrier
system with chemically removable CdS nanoparticle caps for
stimuli-responsive controlled release of neurotransmitters and
drug molecules. J Am Chem Soc 125:4451–4459
3. Doadrio AL, Sousa EMB, Doadrio JC, Pérez Pariente J,
Izquierdo-Barba I, Vallet-Regı́ M (2004) Mesoporous SBA-15
HPLC evaluation for controlled gentamicin drug delivery.
J Control Rel 97:125–132
4. Lin CX, Qiao SZ, Yu CZ, Ismadji S, Lu GQ (2009) Periodic mes-
oporous silica and organosilica with controlled morphologies as
carriers for drug release. Micropor Mesopor Mater 117:213–219
5. López T, Basaldella EI, Ojeda ML, Alexander-Katz R (2006)
Encapsulation of valproic acid and sodic phenytoin in ordered
mesoporous SiO2 solids for the treatment of temporal lobe epi-
lepsy. Opt Mater 29:75–81

123
196
6. Lopez T, Ortiz E, Alexander-Katz R, Basaldella EI, Bokhimi X
(2009) Cortisol controlled release by mesoporous silica. Nan-
omed Nanotechnol Biol Med 5:170–177
7. López T, Krötzsch E, Ortiz-Islas E, Alvarez-Lemus M, Basaldella
E, Martı́nez-Blanes JM, Odriozola JA (2009) Study of collagen-
PVP loading in ordered mesoporous silica and release properties
determination. Key Eng Mater 391:169–184
8. Zhao D, Huo Q, Feng J, Chmelka BF, Stucky GD (1998) Non-
ionic triblock and star diblock copolymer and oligomeric sur-
factant syntheses of highly ordered, hydrothermally stable,
mesoporous silica structures. J Am Chem Soc 120:6024–6036
9. Nguyen TPB, Lee JW, Shim WG, Moon H (2008) Synthesis of
functionalized SBA-15 with ordered large pore size and its
adsorption properties of BSA. Micropor Mesopor Mater
110:560–569
10. Bossaert WD, De Vos DE, Van Rhijn WM, Bullen J, Grobet PJ,
Jacobs PA (1999) Mesoporous sulfonic acids as selective heter-
ogeneous catalysts for the synthesis of monoglycerides. J Cat
182:156–164
11. Phan NTS, Jones CW (2006) Highly accessible catalytic sites on
recyclable organosilane-functionalized magnetic nanoparticles:
123
J Sol-Gel Sci Technol (2010) 56:191–196
an alternative to functionalized porous silica catalysts. J Mol
Catal A Chem 253:123–131
12. Li N, Li X, Wang W, Geng W, Qiu S (2006) Blue-shifting
photoluminescence of Tris (8-hydroxyquinoline) aluminium
encapsulated in the channel of functionalized mesoporous silica
SBA-15. Mater Chem Phys 100:128–131
13. Yang CT, Huang MH (2005) Formation of arrays of gallium
nitride nanorods within mesoporous silica SBA-15. J Phys Chem
B 109:17842–17847
14. Stuart B (2004) Infrared spectroscopy: fundamentals and appli-
cations. Wiley, New York
15. Agnihotri SA, Jawalkar SS, Aminabhavi TM (2006) Controlled
release of cephalexin through gellan gum beads: effect of for-
mulation parameters on entrapment efficiency, size, and drug
release. Eur J Pharm Biopharm 63:249–261
16. Doadrio JC, Sousa EMB, Izquierdo-Barba I, Doadrio AL, Perez-
Pariente J, Vallet-Regi M (2006) Functionalization of mesopor-
ous materials with long alkyl chains as a strategy for controlling
drug delivery pattern. J Mater Chem 16:462–466