Microporous and Mesoporous Materials 294 (2020) 109881

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Microporous and Mesoporous Materials
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Polymer–mesoporous silica composites for drug release systems
Agnieszka Kierys a, *, Radosław Zaleski b, Marta Grochowicz c, Marek Gorgol b,
Andrzej Sienkiewicz a
a

Maria Curie-Sklodowska University, Faculty of Chemistry, Institute of Chemistry, M. Curie-Sklodowska Sq. 3, 20-031, Lublin, Poland
Maria Curie-Sklodowska University, Institute of Physics, M. Curie-Sklodowska Sq. 1, 20-031, Lublin, Poland
c
Maria Curie-Skłodowska University, Faculty of Chemistry, Institute of Chemistry, 33 Gliniana Str., 20-614, Lublin, Poland
b

A R T I C L E I N F O

A B S T R A C T

Keywords:
Polymer–mesoporous silica composites
Mesoporous silica materials
Diclofenac sodium
SBA-15
SBA-3
Drug release

The research describes systematic approach to the novel synthesis and formation of a potential organic-inorganic
drug carriers. The poly(trimethylolpropane trimethacrylate) and polymer-silica composites based on SBA-3 or

SBA-15 mesoporous silica were fabricated by the suspension-emulsion polymerization method in the form of
small micrometric porous beads (specific surface area approx. 500 m2/g). The type of organic templates filling
silica pores has proved to be crucial in the synthesis of the composites. The introduction of diclofenac sodium via
solvent diffusion method into the polymer and composites resulted in the solid drug dispersions. The composites
have greater effectiveness in the drug desorption (90% of the release) in comparison with the pure polymer (20%
of the release after 7 h). Both, however, suffer from the burst effect. This downside can be overcome by func­
tionalization of the solid drug dispersions with (3-aminopropyl)triethoxysilane. The functionalized solid drug
dispersions do not desorb the diclofenac sodium in an acidic medium (the desorption rate is less than 6% during
2 h contact), which makes them attractive for oral multiparticulate formulations of modified release. The pre­
sented solids were characterized with modern analytical methods and the relation between the material structure
and desorption rate were discussed.

1. Introduction
Mesoporous silica (MS) materials, synthesized by the application of
various of surfactants as pore forming and structure directing agents,
have gained interest due to their high specific surface area, large pore
volume and tunable pore diameter. The great advantage of these ma­
terials is their unique structural properties as well as the ease of their
chemical and structural modification in a wide range. The MS materials
modified with various organic functional groups [1–10], nanoparticles
(e.g. Zn, Ag, Au, Pt, Fe, etc.) [11–13], hydrothermally [14] were pre­
pared and thoroughly investigated. All these modifications were made in
order to attain the highest effectiveness in a given application [15–22].
Furthermore, the mesoporous silicas were also employed as a template
to synthesise other materials such as CMK [23,24]. It is no surprise that
MS materials have attracted great attention in therapeutic (e.g.
designing and formation of different drug delivery systems [25–28]) as
well as in diagnostic applications [29,30], especially that there are
favourable reports concerning their mechanical and chemical stability


and good biocompatibility [31,32]. On the other hand, some in vitro and
in vivo measures show that unfunctionalized mesoporous silicas, such as
MCM-type and SBA-type materials, exhibit benign local biocompati­
bility but considerable systemic toxicity, e.g. Ref. []. However, this can
be effectively mitigated by careful control of the particle size of silicas
used in a formulation and by modification of neat silicas [34,35].
Mesoporous silica materials were also successfully employed to
fabricate MS-polymer composites [36,37]. In their case the challenge is
to obtain the composite with MS particles homogeneously dispersed
within the polymer matrix since inorganic particles exhibit a strong
tendency to agglomerate [37–39]. Therefore, various methods for the
synthesis of such composites are employed and the resulted materials
are the objects of thorough studies. From the data presented in the
following review articles [37,40] it stems that MS-polymer materials are
very attractive materials especially as carriers for drugs due to their
complex pore system and chemical character. The preparation of the
MS-polymer composites in the form of microspheres makes it possible to
apply them as drug carriers for oral multiparticulate matrix systems. The

* Corresponding author.
E-mail addresses: (A. Kierys), (R. Zaleski), (M. Grochowicz), marek.
(M. Gorgol), (A. Sienkiewicz).
/>Received 7 August 2019; Received in revised form 22 October 2019; Accepted 7 November 2019
Available online 9 November 2019
1387-1811/© 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license ( />

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Microporous and Mesoporous Materials 294 (2020) 109881


strategy involving the permanent combining/embedding the silica par­
ticles in the polymer microspheres is very promising, since it makes
possible to avoid the presence of the free nanoparticles of mesoporous
silicas in the formulation. As a result, it is to be expected that the toxicity
of the mesoporous silicas has been mitigated. Moreover, the diameter of
the MS-polymer particles is within the micrometer range, thus it is un­
likely that they are able to cross the blood-brain barrier or penetrate
cells.
Among different strategies of composites synthesis, the one involving
the use of as-synthesized mesoporous silica materials as fillers seems to
be very interesting. The MS pores filled with the template molecules are
inaccessible for the monomer during the MS-polymer synthesis. Thus,
they are free from the polymer phase in the composite. Simultaneously,
the template molecules have in its structure both hydrophobic groups
and hydrophilic groups (since they are surface-active agents). Their
presence in the system during the synthesis, should facilitate the mixing
of MS particles with used reactants to obtain homogeneous dispersion of
MS in the polymer matrix.
The aim of the present study was to determine how different assynthesized mesoporous silicas (used as additives/modifiers) affect the
properties of the poly(trimethylolpropane trimethacrylate) resin ([41,
42], polyTRIM) in the context of using polymer–mesoporous silica
composites as a specific drug carriers in oral multiparticulate controlled
release systems. The suspension-emulsion polymerization was chosen as
a popular and relatively easy method for the synthesis of various,
permanently porous polymer resins [43–45]. SBA-3 and SBA-15 meso­
porous silicas synthesized under acidic conditions using octadecyl­
trimethylammonium bromide (C18TAB) and amphiphilic triblock
copolymer - Pluronic P123, respectively, were selected as additives since
they are widely known highly porous silicas, which were previously
presented as promising drug carriers [46–49]. Diclofenac sodium (DS), a

non-steroidal anti-inflammatory drug (NSAID) with analgesic and anti­
pyretic properties was chosen as a model drug for this study. The control
over drug desorption rate, and especially the reduction of the burst
release, is a very important issue in the case of water-soluble drugs. This
can be achieved by applying different drug carriers. In particular, these
with complex architecture are very promising and upcoming materials
for drug delivery materials [7,50–52].
The influence of mesoporous silicas on the polymerization process,
the porosity of the resulted composites as well as the drug desorption
rate and efficiency were examined. The changes of the drug desorption
kinetics after in situ fabrication of an amine-functionalized silica gel
within solid dispersions were additionally explored. The hybrid silica gel
was employed not only to gain better control over the drug desorption,
but also to minimize the possible toxicity of the composites in accor­
dance with favourable reports concerning cytotoxicity of the function­
alized silica [53,54]. Positron annihilation lifetime spectroscopy (PALS)
was employed to determine differences and changes in the porosity of
materials during their processing, especially in the nanopore range.

and used without further thermal treatment. The SBA-15As and SBA-3As
after extraction in a Soxhlet apparatus (i.e. 160 mL of methanol per 1.5 g
of SBA-15As [59] and 160 mL of methanol and 9 mL of 37% HCl (POCh,
Poland) per 1.5 g of the SBA-3As [33]) were denoted as SBA-15EX and
SBA-3EX, respectively.

2. Experimental

The solid dispersions of diclofenac sodium (sodium-2-[(2,6-dichlorophenyl)amino] phenylacetate, DS; Caesar and Loretz, GmbH, Hilden,
Germany) within PT and in the composites beads were prepared by the
solvent diffusion method. First, diclofenac sodium was dissolved in the

mixture of ethanol (EtOH; POCh, Poland) and distilled water with the
molar fraction of EtOH of 0.7 [60]. Subsequently, the DS solution was
added to the materials under study. The amount of ethanolic DS solution
was adjusted so that it can be fully absorbed by the swelling PT and CTs
(2 g per 1 g of dry beads). After conditioning step in closed containers at
room temperature (3 h), the samples were dried at 80 � C under vacuum
for 3 h. The samples with the drug were denoted by adding “D” suffix to
their initial labels (e.g. PTD, CT15-5D).

2.2. Preparation of polymer poly(TRIM) and polymer-mesoporous silica
composites
The microspheres of poly(TRIM) and polymer-mesoporous silica
composites were synthesized via the suspension-emulsion polymeriza­
tion method. Trimethylolpropane trimethacrylate (TRIM, Merck) alone
was used to prepare the poly(TRIM), whereas the composites were ob­
tained with the TRIM monomer and two different contents of the assynthesized mesoporous silicas, i.e. the MSAs to TRIM weight ratio
was 5% or 25%. In this procedure sodium dodecyl sulfate (SDS, Sigma
Aldrich) was used as the surfactant and α,α0 -azobisisobutyronitrile
(AIBN, Glentham Life Sciences Ltd) as the initiator. Both reagents were
analytical grade, obtained from Sigma Aldrich and used as received.
Toluene (POCh, Poland) and decan-1-ol (Fluka AG) at the vol/vol ratio
5.6 : 1.0 were used as pore-forming diluents, and the volume ratio of
TRIM to toluene was 1 : 1.5. The as-synthesized mesoporous silicas were
added to the solution of TRIM, AIBN and pore-forming diluents, and
sonicated for 10 min in an ultrasonic bath and as a result the stable
suspensions have been obtained (organic phases). Subsequently, the
MSAs suspension with TRIM, AIBN and pore-forming agents were added
while stirring to the aqueous solution of SDS (0.25% wt.) at 80 � C.
Polymerization was carried out at this conditions for 20 h. The resulted
polymer- MSAs materials were filtered, rinsed separately with distilled

water, boiling acetone (POCh, Poland, 200 mL) and toluene (200 mL).
Subsequently, the materials were thoroughly extracted in a Soxhlet
apparatus first with pure methanol (160 mL of methanol per 1.5 g of the
composite) for 24 h in the case of SBA-15As-TRIM [59], or with acidified
methanol (160 mL of methanol and 9 mL of 37% HCl (POCh, Poland) per
1.5 g of the composite) for 24 h in the case of SBA-3As-TRIM [33].
Rinsing and extraction was performer due to complete removal of silica
templating agent and unreacted chemicals from the polymer-MSAs
composites. The spherically shaped beads of composite (CTs) were ob­
tained for the weight ratio of SBA-15As to TRIM of both 5% and 25%. On
the other hand, the beads were formed only in the case of adding 5% of
SBA-3As. Introduction of larger amount of SBA-3As disrupted the
polymerization process and the beads were not formed. The final pure
poly(TRIM) polymer was denoted as PT, whereas composites with 5%
and 25% of SBA-15As were denoted as CT15-5 and CT15-25, respec­
tively. The composite synthesized by the use of SBA-3As was labelled as
CT3-5. Prior to their use, the PT and CTs beads were dried at 80 � C under
vacuum for 3 h.
2.3. Preparation of diclofenac sodium solid dispersions

2.1. Preparation of as-synthesized mesoporous silicas (SBA-15As and
SBA-3As)
The synthesis procedure of the SBA-15As and SBA-3As mesoporous
silicas was similar, i.e. both materials were prepared under acidic con­
ditions using tetraethyl orthosilicate (TEOS, Acros Organics) as the silica
source however different structure-directing agents were used. SBA15As was prepared according to the well-known procedures using the
amphiphilic triblock copolymer (Pluronic P123, BASF) [55,56] while
octadecyltrimethylammonium bromide (C18TAB, Sigma-Aldrich) was
used for the SBA-3As synthesis instead of widely used hexadecyl­
trimethylammonium bromide [57,58]. The as-synthesized mesoporous

silicas (MSAs; SBA-15As and SBA-3As) were filtered, thoroughly rinsed
with distilled water (ca. 2 L), dried at 100 � C for 8 h, ground in a mortar
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2.4. Preparation of amine-functionalized diclofenac sodium solid
dispersions

microstructure of the materials under study. Prior to the measurement
the samples were sputtered with gold. The parameters characterising the
porosity of the initial samples and after the processing applied were
determined by the measurements of nitrogen adsorption/desorption at
196 � C (LN2) using the ASAP 2420 (Micromeritics, Norcros, GA) ana­
lyser. Prior to the experiment, the samples were dried overnight at 80 � C
under vacuum. The specific surface areas, SBET, were calculated using
the standard Brunauer Emmett Teller (BET) equation [64], whereas
the total pore volumes, Vp, were estimated from a single point on the
adsorption isotherm at the relative pressure about 0.99 p/p0. The pore
size distributions (PSDs) for all samples were determined from the
adsorption and desorption branches of the N2 isotherm using the Bar­
rett Joyner Halenda (BJH) procedure [65].
Additionally, the porosity was characterized by positron annihilation
lifetime spectroscopy (PALS). The positron source (22Na, 0.4 MBq) was
placed between two 2 mm layers of a sample in the sealed chamber at
the pressure of p < 10 4 Pa at room temperature. The radiation from the
positron creation inside the source and the positron annihilation inside

the sample were collected by scintillation detectors equipped with BaF2
scintillators. The signals form the detectors were registered by two
digitizers (Agilent) with the sampling rate of 8 GS/s triggered by the
custom-made coincidence unit. The program for the in-flight analysis of
digitized impulses to obtain positron lifetime spectra was based on the
algorithm developed by the Prague group [66]. The time range of the
digital spectrometer was set to 2 μs. The spectra with the total number of
counts of 27 million were collected. The continuous distributions of
lifetimes were obtained with the use of the MELT program [67]. The
resolution curve was approximated by a Gaussian with FWHM of about
220 ps. Two short-lived components originated from para-positronium
(ca. 140 ps) and unbound positrons (ca. 390 ps) were ignored because
they do not provide a clear information about porosity. Only the lifetime
distributions of long-lived components (>1 ns), which originate from
otho-positronium, served to calculate pore size distributions according
to the procedure described in Ref. [68].
The Raman spectra of the samples were collected at room tempera­
ture using Raman microscope inVia Reflex from Renishaw (UK) which
used a charge-coupled device (CCD) detector with a spectral resolution
of 1 cm 1. Exciting radiation at 514 nm was provided by an Arỵ laser at
the cross-section of dried samples.
The actual content of SiO2 in the composites was tested using ther­
mogravimetric measurements with the NETZSCH STA 449 F1 Jupiter®
instrument by heating ~15 mg of sample under air flow from room
temperature to 800 � C with the heating rate of 10 � min 1. The mea­
surement was repeated three times. The measurements show that the
SiO2 contents slightly differ between the composites, and it is about
0.4% in CT3-5 and in CT15-5 and CT15-25 is 1%.

The PTD, and CT15-25D solid dispersions of diclofenac sodium were

additionally functionalized with 3-aminopropyl groups via in situ
transformation of the mixture of (3-aminopropyl)triethoxysilane
(APTES; Acros Organics) and TEOS introduced into them by the swelling
method [61]. The precursor’s mixture was prepared 1 h prior to its use
with the molar ratio APTES to TEOS, 2 : 1. It was introduced drop by
drop to dry PTD and CT15-25D beads. Both samples quickly imbibed the
mixture of precursors. The amount of the APTES and TEOS mixture was
adjusted to be fully absorbed by samples (i.e. no excess liquid was left
outside the beads). The samples saturated with precursors (1.36 g per 1 g
of PTD and 1.41 g per 1 g of CT15-25D) were exposed to the ammonia
vapours (10 cm3 3.25 M NH3(aq) per 1 g of precursors mixture) at
autogenous pressure and room temperature for 72 h followed by drying
at 80 � C under vacuum for 3 h [62]. The samples functionalized with
3-aminopropyl groups were denoted by adding “A” suffix to their labels,
i.e. PTDA and CT15-25DA.
2.5. Analysis of actual diclofenac sodium contents
The actual contents of diclofenac sodium in the samples, i.e. nonfunctionalized and functionalized with 3-aminopropyl groups, was
determined. A portion of the PTD, CT3-5D, CT15-5D and CT15-25D
beads was crushed and powdered in a mortar. An accurately weighed
50 mg each of the powdered samples was immersed in 250 ml of phos­
phate buffer solution pH at 6.8 [63]. The flask was shaken for 4 h. The
amount of the drug dissolved was spectrophotometrically analysed at
the wavelength of 276 nm.
The experiment was repeated three times. As it follows from the
measurement, the PTD sample contains 20.8% of diclofenac sodium,
CT15-5D – 19.8%, CT15-25D – 19.2% and CT3-5D – 20.6% which in all
materials corresponds to about (40 � 5) mg of drug in 200 mg of sample.
The actual contents of diclofenac sodium in the samples functional­
ized with 3-aminopropyl groups was calculated from the weight differ­
ences between PTD and PTDA or CT15-25D and CT15-25DA. Prior to the

functionalization, and after the process the PTD, PTDA, CT15-25D and
CT15-25DA solid dispersions were thoroughly dried under vacuum and
weighted. The DS contents in PTDA and CT15-25DA was calculated from
the mass of the introduced hybrid silica gel into the PTD and CT15-25D.
The PTDA sample contains 12.8% of diclofenac sodium and CT15-25DA
– 11%.
2.6. Release of diclofenac sodium
The diclofenac sodium desorption was carried out to the phosphate
buffer solution pH ¼ 6.8, under constant stirring at 170 rpm in a ther­
mostated bath at (37 � 0.5) � C. Desorption profiles of DS were obtained
by soaking 50 mg of the solid loaded with the drug in 225 mL of the
buffer. At predetermined time intervals, 3 mL of the solution was taken
out for an analysis of the DS concentration which was measured at the
wavelength of 276 nm by using the UV/Vis spectrophotometer (Varian
Cary 100 Bio). The DS release was also monitored after PTDA or CT1525DA exposure to 0.1 M hydrochloric acid for 2 h under constant stirring
at 170 rpm in a thermostated bath at (37 � 0.5) � C. The samples initially
exposed to an acidic environment were subsequently placed in a phos­
phate buffer at pH 6.8 under constant stirring at 170 rpm in a thermo­
stated bath at (37 � 0.5) � C. Samples of the dissolution fluids were taken
after the acidic-stage at predetermined time intervals and were analysed
using the UV/Vis spectrophotometer.

3. Result and discussion
3.1. Physicochemical characterization of the investigated samples
The polymer poly(TRIM) and mesoporous silica-polymer composites
were synthesized via the suspension-emulsion polymerization method,
therefore it was expected to obtain these materials in the form of
microspheres.
The grains of pure PT are spherical in shape even though they are not
entirely uniform in size (Fig. 1a & 1a’). Their average diameter in a dry

state was estimated to be (85 � 40) μm in diameter. Introduction of
MSAs into the reaction mixture influences not only the size of the final
beads of CTs but also their shape. SBA-3As and SBA-15As silicas are nonporous materials with silica channels filled with the template. Simple
rinsing of with water is not sufficient to completely remove the organic
template from the MSAs materials. Moreover amphiphilic character of
the templating agent indicates that the surfactant molecules are not only
present within its pores but also on the outer surface of the MSAs par­
ticles, giving rise to its moderately hydrophobic character. It is clear that

2.7. Methods of characterization
A scanning electron microscope (SEM, FEI Company, Quanta 3D
FEG) working at 30 kV was used to investigate the morphology and
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Fig. 1. SEM micrographs of representative beads of the polymer PT (a, a’) and composites CT3-5 (b, b’), CT15-5 (c, c’) and CT15-25 (d, d’).

low solubility in water [69]. As a result, the external surface of SBA-3As
particles (after rinsing) is still covered with C18TAB molecules. But
unlike to the system with P123, C18TAB interferes much more with the
polymer primary particles agglomeration into larger clusters called
microspheres, contributing to an overall the unsuccessful formation of
the CT3-25 composites. The most probably it is related with C18TAB
chemical character. Even a small amount of C18TAB in the system (i.e.
CT3-5) results in poor building of SBA-3As into the polymer phase. The
representative SEM micrographs seem to confirm this assumption, since

the spherical cavities (probably after SBA-3As particles) are clearly
visible in the interior of crushed CT3-5 beads (Fig. 4). Such cavities were
not found in the other samples.
Although, SEM micrographs of representative beads confirm suc­
cessful embedding of SBA-15As (and to a lesser extent SBA-3As) within
polymer matrix (Fig. 1) it follows from thermogravimetric measure­
ments that the actual amount of SiO2 in the composites is very low (does
not exceed 1% of the total mass of a composite). The significant differ­
ence between the amount of SBA-3As and SBA-15As used for the syn­
thesis and the SiO2 in the final composites is understandable, if one take
into account that MSAs introduced into the system contain the template
molecules which can constitute up to 60% their total mass [70]. On the
other hand, the low SiO2 content in CTs may be the result of the poor
effectiveness to build MSAs in poly(TRIM) matrix. Regardless of the low
content of inorganic phase in the samples, it is clear that the MSAs
presence in the system greatly influences the formation processes of
composites. This is confirmed by the LN2 and PALS results. Both
methods were employed to get insight into the porosity of investigated
samples and to reveal its changes during the sample processing.
For all investigated materials in the dry state, the N2 adsorption-

the presence in the reaction mixture of a disturbing agent, such as SBA15As particles of elongated morphology (Fig. 2a) affects the polymeri­
zation process. Nevertheless, regardless of the amount of SBA-15As in
the system, the beads were obtained, but they are much less homoge­
neous in size in comparison with ones made of pure poly(TRIM) (Fig. 1).
It is known that, molecules of amphiphilic block copolymer P123
(used for the SBA-15As synthesis) contains one hydrophobic poly(pro­
pylene oxide) (PPO) and two hydrophilic poly(ethylene oxide) (PEO)
regions arranged in a PEO PPO PEO triblock structure. It seems that
P123 molecules closely cover the surface of individual SBA-15As parti­

cles since after their introduction into the organic phase the stable sus­
pension is obtained. Furthermore, P123 molecules seem to facilitate
sticking microspheres consisting of poly(TRIM) (arising during poly­
merization process) to the SBA-15As surface. As a result, SBA-15As
particles closely adjoin to polymer phase and are integral part of com­
posite beads (Fig. 3). It is worth to note, that milling of SBA-15As slightly
affects its morphology and the large, elongated particles are clearly
visible in the interior and on the surface of the composite beads (Fig. 3).
On the other hand, spheres were successfully formed only when the
weight ratio of SBA-3As particles to TRIM was 5%. The resulted CT3-5
beads are slightly smaller and have more spherical shape in compari­
son to the composites with SBA-15As (Fig. 1). The large size of SBA-3As
particles is not affected by milling (Fig. 2b). Probably, their irregular
shape and large size are responsible for the unsuccessful CT3-25 syn­
thesis. However, the impact of the organic template different than P123
cannot be excluded. It seems that the C18TAB surfactant of ionic char­
acter poorly works as an agent facilitating mixing of the SBA-3As and
polymer phase, even at a small addition of it. It was reported that among
the alkyltrimethylammonium bromide series C18TAB has a relatively

Fig. 2. SEM micrographs of as-synthesized mesoporous silicas SBA-15As (a) and SBA-3As (b) after milling in mortar before adding to the solution of TRIM, AIBN and
pore-forming diluents.
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Fig. 3. SEM micrographs of beads (a) and the interior (b & c) of representative bead of the CT15-25 composite.


Fig. 4. SEM micrographs of the interior of representative bead of the polymer PT (a, a’) and composites CT15-5 (b, b’) and CT3-5 (c, c’).

Fig. 5. The low-temperature nitrogen adsorption/desorption isotherms (a) and the pore size distributions determined by applying the BJH method to the desorption
isotherms (b) and to the adsorption isotherms (c) of samples under study.
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desorption isotherms are similar in shape. Type IV of the isotherms in­
dicates that all materials are mesoporous (Fig. 5a) [71]. Since in all
cases, adsorption and desorption branches do not overlap, hysteresis
loops of type H2 arise. They are extended along the whole pressure axis
and are very similar in shape to each other. The N2 isotherms of the
composites with SBA-15As diverge slightly from these of PT and CT3-5.
The corresponding PSDs computed from desorption branches of the
isotherms are of bimodal character (Fig. 5b). The peak centred at 3.8 nm
is present in all curves, while it is hardly visible in the PSDs calculated
from the adsorption branches (Fig. 5c). Similar findings were presented
before for TRIM-based materials [72–74]. In addition to the first
maximum, the second maximum appears in the PSD curves. For the pure
poly(TRIM) it is located at about 5.5 nm. In the case of CTs, the second
peak is shifted towards larger pores compared to PT (Table 1), but only
for CT15-25 it exhibits much broader distribution compared to the pure
polymer. Interestingly, for PT, CT3-5 and CT15-5 a third peak of low
intensity is also visible. It is centred at about 24 nm for PT and CT3-5 and
at about 43 nm for CT15-5 (Fig. 5b). This peak is absent from the PSD

curve for CT15-25 as well as all PSD curves calculated from adsorption
branches of N2 isotherm (Fig. 5b & c).
Values of the parameters characterizing the porosity of PT, CT3-5
and CT15-5 obtained from the nitrogen sorption differ very slightly
from each other (Table 1), mainly in the total pore volume. The changes
in the specific surface area should be interpreted with great caution.
There is no significant difference in SBET between PT and CTs (surpris­
ingly a decrease in SBET is observed in most CTs). The total pore volume
increases by ca. 25% in comparison to PT only in the CTs based on SBA15As.
These results are surprising since MSAs particles used for CTs syn­
thesis are highly porous after they are extracted alone (Table 1). In
addition, it has previously been shown that polymerization of TRIM in
the presence of preformed non-calcined MCM-41 particles leads not only
to the composite whose SBET and Vp are much higher compared to the
pure polymer, but also causes the structural reorganization of the
polymer matrix towards a more loose structure [72]. Similar changes (i.
e. towards loosening of the structure) can be observed only in the case of
the CT15-5 and CT15-25 composite. Use of SBA-3As particles as addi­
tives do not significantly influence the packing of the polymer particles
(i.e. nuclei and microspheres) [75]. This hypothesis is also in line with
the presented SEM micrographs (Fig. 4c’).
While discussing the lack of significant differences in the CTs
porosity several possibilities should be considered. First, as it follows
from TG results the embedding efficiency of MSAs within polymer ma­
trix is very low. As a result, the amount of SiO2 especially in CT3-5 and
CT15-5 is too low to induce significant changes in the internal structure
in comparison to PT. On the other hand, it seems to be highly probable

that the removal of the template from the silica channels of MSAs during
extraction failed. Although, the CT15-25 sample was extracted for 24 h,

it seems that polymer species prevent the removal of template molecules
by closing the pore entrances. Such a situation can be explained by the
polymer phase tightly adhesion to the silica particles (Fig. 3). Other
possibility is that the organic template is successfully removed from
MSAs during extraction, but due to the MSAs presence the produced
polymer phase is less porous. However, the most probable situation is
that the organic template is only partially removed from MSAs and
simultaneously the polymer phase synthesized in the presence of MSAs
is less porous. Hence, the porosity of composites may be regarded as the
sum of the porosity of the polymer and the emptied silica.
Information on the size of mesopores as well as smaller free volumes
in the polymer and composites can be determined on the basis of PALS
measurements (Fig. 6). The mesopore sizes are smaller than these ob­
tained from LN2, which is quite common [43,76]. The bimodal character
of PSDs manifests only in PT and CT15-5, which is still an improvement
in compatibility with LN2. The increase in the average size of mesopores
(Dmeso) of all CTs compared with PT is similar (Table 2), while there is no
significant changes in the total volume of mesopores (Vmeso), except
CT15-25. This confirms the low impact of MSAs on the porosity of CTs.
Most likely there is almost no contribution from the porosity of MSAs
and all changes origin from the polymer, where positronium formation
prevails. Thus, the PALS results reflect mostly the change in the polymer
porosity (increase in the average pore size), while the increase in the
total pore volume comes from the emptied pores inside MS.
Also in the range of micropores there are no significant changes.
Characteristic three peaks are visible in the polymer as well as in all
composites (Fig. 6). The differences are subtle and can be observed only
in the average size of micropores (Table 2), which is slightly greater in
CT3-5 and CT15-5 than in PT. This indicates a slightly looser structure in
these samples.

The newly synthesized materials were employed as carriers for
diclofenac sodium which was introduced from the binary mixture of
ethanol and water by swelling. The representative SEM micrographs of
the interior of PTD, CT3-5D, CT15-5D and CT15-25D (Fig. 7) reveal
slight changes after the drug introduction. The DS is indistinguishable
from the matrix in the SEM images, thus its location within the beads
cannot be determined with this technique. However, high homogeneity
might indicate that the DS is highly dispersed within solid medium. It
appears that individual spherical species forming PTD microspheres are
larger and more tightly packed, but large free volumes (macropores)
appear between them. Similar trend of structural changes is also
observed in the case of CTs but it is less pronounced. This effect seems to
be connected to polymer swelling.
To confirm the presence of the drug and possible interactions of the
components the Raman spectra were measured (Fig. 8 a-d). The most
convenient range to detect differences between the pure DS and the solid
drug dispersions is 1550–1630 cm 1, where the characteristic bands of
DS appear (band broadening and shift), but no peaks from carriers are
present (Fig. 8 a and c). In the selected regions, the three characteristic
bands localized at 1578, 1587 and 1604 cm 1 can be attributed to the
asymmetric stretching vibration of O1C8O2, and to the stretching vi­
brations of dichlorophenyl (ring 1) and phenylacetate (ring 2) rings,
respectively [77–79]. They are also clearly visible in the PTD and
CT15-25D solid dispersions confirming the successful introduction of DS
into the PT and CT15-25 samples. Simultaneously, shifting (moving
towards higher wavenumbers) of these bands is observed. Weak and
very weak breathing vibrations of the ring 1 and 2 of the neat DS give
rise to quite intense bands at 1073 and 1046 cm 1 [80], respectively
(Fig. 8 b and d). Although, these bands are slightly shifted, their pres­
ence is also clearly visible in the PTD and CT15-25D solid dispersions.

Moreover, the in-plane deformation vibrations of the CH groups of both
DS rings give rise to Raman bands at 1159 and 1147 cm 1 (bending
vibrations) [80]. They are also visible in Raman spectra of PTD and
CT15-25D, but their shift towards higher wavenumbers is clearly visible

Table 1
Parameters characterizing the porosity of the composites from the lowtemperature N2 sorption.a.
Sample

SBET (m2g

1

Dp1 (nm)

Dp2 (nm)

SBA-3EX
SBA-15EX

638
617

1.15
0.89

3.4
6.5/4.3*

9.4

–

PT
CT3-5
CT15-5
CT15-25

534
524
555
472

0.58
0.62
0.74
0.73

3.8
3.8
3.8
3.8

6.5
6.4
11.2
15.5

PDT
CT3D
CT5D

CT25D

110
46
135
132

0.20
0.10
0.35
0.42

3.8
3.6
3.9
3.9

~6.6
6.3
11.2
13.4

)

Vp (cm3g

1

)


a

SBET, the specific surface area; Vp, the total pore volume; Dpn, the pore
diameter at the peak of PSD derived from the desorption branch of N2 isotherm;
*the pore diameter at the peak of PSD derived from the adsorption branch of N2
isotherm (as it is recommended for this type of highly ordered mesoporous
silicas).
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Microporous and Mesoporous Materials 294 (2020) 109881

Fig. 6. Pore size distributions in the polymer and composites determined from the PALS measurements.

PTD and CT15-25D, in samples functionalized with 3-aminopropyl
groups the Raman bands indicating the presence of DS are visible only
for PTDA. The absence of the DS bands in the presented regions of the
CT15-25DA spectra may indicate that the hybrid silica gel fabricated in
the presence of DS effectively encapsulates the drug and plays the role of
a shielding agent.
From the N2 sorption measurements (Table 1, Fig. 9) it follows that
introduction of drug molecules significantly alters the values of pa­
rameters characterising the porosity. Although, samples prior the
modification exhibit similar porosity characteristic, the solid drug dis­
persions significantly differs between each other (Table 1). This is quite
surprising since the content of the drug is similar. Thus, it can be ex­
pected that samples composition (i.e. the presence of silica particles in
CTs) influences both the swelling process as well as the way and the

place of drug deposition after the solvent diffusion. The decrease in the
specific surface area and the total pore volumes is obvious, since drug
molecules occupy free volumes in the carriers. But it seems that DS
introduced into PT and CT3-5 fills free volumes more effectively or it

Table 2
Average size of micropores (Dmicro < 2 nm) and mesopores (Dmeso > 2 nm), total
volume of micropores (Vmicro) and mesopores (Vmeso) in the samples without DS
and with DS determined from PALS spectra.
Sample

Dmicro (nm)

Vmicro (a.u.)

Dmeso (nm)

Vmeso (a.u.)

PT
CT3-5
CT15-5
CT15-25

0.76
0.82
0.80
0.74

1.1

1.2
1.1
1.2

3.4
4.2
4.0
4.3

2.1
1.9
2.0
1.4

PTD
CT3-5D
CT15-5D
CT15-25D

0.46
0.44
0.46
0.46

2.0
2.1
1.8
1.7

5.0

3.3
5.8
7.2

0.5
0.2
0.6
0.6

only in the case of CT15-25D. Taking into account that the deformations
of the Raman spectra of the solid dispersions are observed, it may be
assumed the presence of interactions between diclofenac sodium mole­
cules and other components of the systems [77,81]. In contrast to the

Fig. 7. SEM micrographs of the interior of representative bead of the solid dispersion of diclofenac sodium within polymer PTD (a, a’) and within composites CT3-5D
(b, b’), CT15-5D (c, c’) and CT15-25D (d, d’).
7


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Microporous and Mesoporous Materials 294 (2020) 109881

Fig. 8. The Raman spectra of samples based on PT (a, b) and on the CT15-25 composite (c, d).

Fig. 9. The N2 adsorption/desorption isotherms (a) and PSDs determined by applying the BJH method to the desorption isotherms (b) and to the adsorption iso­
therms (c) of solid dispersions under study.

creates restrictions for nitrogen molecules adsorption, and as a result the
SBET and Vp in these samples are significantly smaller compared to the

CT15-5D and CT15-25D. Interestingly, the N2 isotherms are almost
identical in shape to those of the materials free of drug, but the

adsorption values are much lower for all matrices after the DS loading
(Fig. 9a). As a consequence, the pore size distributions are almost un­
changed except that the relative abundance of each pore size is lower
(Fig. 9b & c).
8


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Microporous and Mesoporous Materials 294 (2020) 109881

In order to get more information about the drug deposition place in
the carriers, the PSDs obtained from the PALS measurements were
analysed (Fig. 10). The diversity of mesopore sizes is greater than in the
case of the LN2 results. The average diameter of mesopores (Dmeso,
Table 2) increases after introducing DS in all composites except CT3-5D.
This in conjunction with lack of such shift in the LN2 results suggests
either the appearance of closed pores or the decrease in their connec­
tivity [76]. The decrease in the pore volume (Vmeso), which is larger than
obtained from LN2 adsorption, points to the second reason. The location
of DS seems to proceed differently in CT3-5D, where almost all meso­
pores are filled, what is in agreement with LN2 adsorption.
The changes in the micropore range are quite straightforward.
Nearly all micropores are closed due to swelling and only spaces be­
tween polymer chains (Dmicro � 0.38 nm) remain available for positro­
nium. The second peak at 0.50 nm is connected to DS, which forms
clusters large enough to trap positronium (i.e. at least several nano­

metres in size). The position of this peak is shifted towards larger sizes
(0.56 nm) only in PTD indicating looser structure of the drug or smaller
clusters of DS in the polymer. This may suggest that either the polymer
structure is altered in the composites (probably loosened) or DS is
located in the vicinity of MSAs (possibly in its pores). If one considers the
latter option then it may be assumed that the MSAs pores are at least
partially emptied.

removal of the larger DS amounts from the carrier as compared to PTD.
The CT15-25D and PTD solid dispersions were additionally modified
with amine-functionalized silica species (i.e. hybrid silica gel). First, the
mixture of APTES and TEOS was introduced into them by swelling. It
turns out that regardless of the matrix used, the solid dispersions
maintain the ability to swell in the mixture of precursors, wherein the
CT15-25D sample imbibes a little more of the precursor’s mixture. Next,
the amine-functionalized silica species were produced from precursors
by the transformation in the presence of ammonia supplied in the
vapour phase. After formation of a new hybrid phase in PTD and CT1525D one can expect a huge drop of the values of parameters character­
izing the porosity similarly as it was reported elsewhere [82,83]. Such
direction of changes is obvious when one takes into account that the
species derived from TEOS and APTES tend to form both a hybrid silica
film as well as to fuse together forming larger lumps [84].
In the case of these samples the DS release profiles are highly
interesting and they differ significantly from the corresponding nonfunctionalized solid dispersions (Fig. 11a). Firstly, it follows from the
course of the drug release profiles in the phosphate buffer solution at
37 � C that the hybrid phase is responsible for successful reduction of
degree of the burst release, wherein this effect is more pronounced for
the PTDA sample. Only ~16% of DS is desorbed within the first 30 min
from PTDA, with 45% release in 7 h. The initial release of the drug from
CT15-25DA reaches ~37% and exceeds 78% in 7 h. PTDA and CT1525DA exhibit a lower efficiency of the drug desorption in comparison

to PTA and CT15-25D, respectively. In the case of CT15-25DA the DS
amount released during 24 h decreases by about 10% in comparison to
the CT15-25D, while less than 60% of DS is successfully desorbed from
PTDA.
The drug desorption profiles in a phosphate buffer (pH¼6.8) change,
if prior to the buffer-stage the PTDA or CT15-25DA samples are
immersed in 0.1 M hydrochloric acid for 2 h. Firstly, the initial DS
release from CT15-25DA is significantly lower and reaches about 7%.
The reduction of the burst release is even more pronounced in the case of
PTDA. Secondly, the acid-stage contributes to a lower efficiency of the
drug desorption from both of samples. In the case of CT15-25DA, only
about 62% of DS is desorbed during 24 h, and 67% after 120 h, whereas
from PTDA similar amount is desorbed after 24 h using the sequential
pH in comparison to PTDA immersed only in pH 6.8. Extending the
immersion time in the buffer up to 120 h does not affect the quantity of
the DS desorbed.
It is obvious that amine-functionalized silica is responsible for the
modification of the drug desorption from the investigated samples.
However, the amount and composition of the precursors’ mixture, from
which hybrid silica was derived, are almost identical in PTDA and CT15-

3.2. Drug release
The solid dispersions of diclofenac sodium non-functionalized and
functionalized with 3-aminopropyl groups are in the form of micro­
spheres which can be regarded as discrete subunits. The drug release
profiles measured for them are presented in Fig. 11.
Fig. 11 illustrates the influence of the MSAs silicas introduction on
the drug desorption. According to DS release profiles it follows that
presence of the MSAs particles within polymer increases the efficiency of
drug desorption. The drug desorbs most effectively from CT15-5D and

CT15-25D subunits, reaching about 90% after 7 h, and it is at about 10%
higher than from PTD. However, both these samples suffer from prom­
inent burst release (about 15% higher than PTD), which manifests itself
in leaching more than 75% of the drug within the first 30 min. It is clear
that silica does not slow down the DS desorption at the initial stage (i.e.
just after immersion of the subunits within the buffer solution). The
more effective desorption of DS from CT15-5D and CT15-25D is prob­
ably associated with easier diffusion of the buffer solution molecules
into the interior of composite subunits. The presence of large free vol­
umes and a more loose structure, together with more hydrophilic
character of composites due to MSAs presence facilitate an effective

Fig. 10. Pore size distributions in the polymer and composites loaded with DS determined from the PALS measurements.
9


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Microporous and Mesoporous Materials 294 (2020) 109881

Fig. 11. Diclofenac sodium release from the non-functionalized solid dispersions (PTD, CT3-15D, CT15-5D and CT15-25D) and functionalized with 3-aminopropyl
groups solid dispersions (PTDA, CT3-5DA, CT15-5DA and CT15-25DA) measured in the phosphate buffer solution at 37 � C (a). Release profiles of diclofenac sodium
using the sequential pH of 0.1 M HCl (data not shown) followed by pH¼6.8, phosphate buffer (b). In the figures, the lines are provided for convenience.

Due to the fact that the pure polymer as well as composites were in the
form of small beads, they could be regarded as discrete subunits suitable
to be the carriers of the diclofenac sodium. Although, both kinds of
carriers suffered from the drug burst release, the advantage of the
composites was to provide the more effective drug desorption. Whereas,
the more compact structure of the pure polymer carrier caused that the

large amount of drug was retained within it. After additional modifi­
cation of the carriers with amine-functionalized silica species the burst
release was significantly diminished, which resulted in gaining control
over the drug desorption. The composite after the modification turned
out to be a better carrier than the modified polymer due to more
effective desorption of the drug. Taking into account that the crosslinked polymer microspheres are resistant to different pH of an envi­
ronment, they will most likely behave as non-disintegrating pellets, and
their transport through the gastrointestinal tract will be without their
digestion. However, the in vitro evaluation of cytotoxicity of the MSpolymer composites is in progress and will be reported in due course.

25DA. Thus, it may be assumed that the differences in the drug release
rate mainly result from different placement of this hybrid phase. It is
understandable if one take into account the differences in porosity and
in composition of PTD and CT15-25D. It seems that smaller pores/
channels in PTD are more effectively plugged by the hybrid silica
fabricated; this, in turn, hinders free diffusion of the solvent molecules
into the subunits. As a result, desorption rate of DS is significantly
slowed down. The hybrid silica affects not only the rate, but also the
efficiency of DS release reducing it significantly. Taking into account the
Raman results, it may be assumed that drug molecules are captured in
part by the hybrid silica phase during its formation. It seems, that mainly
this fraction is able to be freely desorbed from PTDA, while desorption of
DS molecules deeply embedded within PTD is restricted. The peak at the
PSD of CT15-25D is shifted towards larger pores compared to PTD. It
seems that the largest pores have not been totally plugged by the hybrid
silica since the drug can easily desorb from this composite just after its
immersion in the buffer solution. Although, the hybrid silica is located in
the subunits, the efficiency of drug release is relatively high. Profiles of
DS desorption using the sequential pH seem to confirm this conclusion.
It is likely that free volumes which ensure high efficiency of desorption

of DS in a buffer pH 6.8 alone, also facilitate inflow of HCl into the CT1525DA microspheres. As a result, part of DS molecules undergoes trans­
formation into a derivative of phenylacetic acid of a lower solubility.
Although, the total amount of the drug released in a buffer pH 6.8 after
the acid-stage is lower in comparison to the sample immersed only in pH
6.8, it is still higher than from PTDA. This indicate that the porosity of
the carrier before modification with hybrid silica is a crucial factor
which affects both the rate and the efficiency of DS release.

Authors contribution
The manuscript was written through contributions of all authors. All
authors have given approval to the final version of the manuscript.
Declaration of competing interest
There are no conflicts to declare.
Acknowledgement

4. Conclusions

The research leading to these results has received funding from the
Polish National Science Centre [grant number 2018/02/X/ST5/00549].
The research was carried out with the equipment purchased thanks to
the financial support of the European Regional Development Fund in the
framework of the Polish Innovation Economy Operational Program
(contract no. POIG.02.01.00-06-024/09 Centre of Functional
Nanomaterials).

The polymer–mesoporous silica composites in the form of beads
were successfully synthesized via the suspension-emulsion polymeriza­
tion method by the use of as-synthesized SBA-3 and SBA-15 silicas. The
internal structure of the polymer and composites as well as the materials
after the diclofenac sodium introduction was revealed. The type of

organic templates filling the silica pores had proved to be crucial in the
synthesis of the porous composites. The amphiphilic triblock copolymer
filling SBA-15As pores was more adequate to obtain a composite than
octadecyltrimethylammonium bromide filling SBA-3As, because a
greater amount of SBA-15As particles could be introduced into the
polymer. The porosity of the composites had to be regarded as the sum of
the porosity of the polymer and the emptied silica, wherein the presence
of silica particles during the polymerization of the TRIM monomer
caused the formation of the polymer matrix with a more loose structure.

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