Synthetic Geopolymers for Controlled Delivery of Oxycodone: Adjustable and Nanostructured Porosity Enables Tunable and Sustained Drug Release
Engqvist H (2011) Synthetic Geopolymers for Controlled Delivery of Oxycodone: Adjustable and Nanostructured
Porosity Enables Tunable and Sustained Drug Release. PLoS ONE 6(3): e17759. doi:10.1371/journal.pone.0017759
Synthetic Geopolymers for Controlled Delivery of Oxycodone: Adjustable and Nanostructured Porosity Enables Tunable and Sustained Drug Release
Johan Forsgren 0
Christian Pedersen 0
Maria Strmme 0
Ha kan Engqvist 0
Joel Schnur, George Mason University, United States of America
0 Department of Engineering Sciences, Uppsala University , Uppsala , Sweden
In this article we for the first time present a fully synthetic mesoporous geopolymer drug carrier for controlled release of opioids. Nanoparticulate precursor powders with different Al/Si-ratios were synthesized by a sol-gel route and used in the preparation of different geopolymers, which could be structurally tailored by adjusting the Al/Si-ratio and the curing temperatures. In particular, it was shown that the pore sizes of the geopolymers decreased with increasing Al/Si ratio and that completely mesoporous geopolymers could be produced from precursor particles with the Al/Si ratio 2:1. The mesoporosity was shown to be associated with a sustained and linear in vitro release profile of the opioid oxycodone. A clinically relevant release period of about 12 h was obtained by adjusting the size of the pellets. The easily fabricated and tunable geopolymers presented in this study constitute a novel approach in the development of controlled release formulations, not only for opioids, but whenever the clinical indication is best treated with a constant supply of drugs and when the mechanical stability of the delivery vehicle is crucial.
Chronic pain is one of the most significant health issues in the
world. In the US, for example, about 30% of the population suffer
from chronic pain associated with diseases such as arthritis and
cancer . Unsatisfactory pain management leads to a reduced
quality of life for afflicted persons, and to large societal costs.
Moderate to severe chronic pain is most effectively treated with
opiates or with opioids, i.e. the synthetic relatives of opiates.
Different strategies are employed to obtain a sustained effect from
these analgesics, for example sustained release oral dosage forms
[2,3], sustained release transdermal patches  and implanted
infusion pumps . WHO recommends oral administration of
analgesics in their cancer pain guidelines , since it is a non-invasive
strategy which facilitates the administration and increases patient
compliance. However, due to the narrow therapeutic window of
opioids, dose dumping associated with oral administration can
have fatal consequences . Dose dumping is a rapid and
unintended release of the entire dose from a sustained release drug
carrier , and may occur if the carrier breaks due to mechanical
stress or dissolves due to chemical reactions. It was recently
suggested that geopolymers, i.e. inorganic aluminosilicate
polymers, could be used in oral dosage forms to achieve sustained
release in combination with mechanical strength and chemical
stability of the drug carrier . Geopolymers are a type of
cementitious material which typically is produced by reacting fly
ash or clay-derived precursor powders (e.g. metakaolin) with an
alkaline sodium silicate solution . The chemical stability of
geopolymers is often superior to other cementitious materials such
as ordinary Portland cement (OPC) . In the recent study on
geopolymers as drug delivery vehicles, it was shown that the
delivery system offered high mechanical strength together with
adjustable porosity, which enabled tuning of the drug release rate
. By mixing the drug, e.g. an opioid, with the precursor powder
and an alkaline silicate solution during synthesis, the drug becomes
integrated in the porous and mechanically strong matrix . The
synthesis can be performed at room temperature, which is
favorable from a drug stability point of view, although it is
required that the drug compound is not sensitive to the alkaline
synthesis condition. The characteristics of the final product
(porosity, hardness etc.) will depend on the origin of the precursor
powder; different precursor powders have different Al/Si ratios
and impurity contents, and differ in size and morphology.
However, the surface properties, the size and the morphology of
precursor particles can be controlled by synthetic precursor
fabrication , and therefore it should be possible to optimize
precursor powders for the production of sustained release
geopolymers. It has hithereto not been investigated how the Al/
Si ratio of the precursor powder affects the pore size distribution of
the geopolymers, and how that in turn is linked to the drug release
profile of the geopolymers. In the context of sustained release, it is
particularly interesting to produce drug delivery systems with
linear drug release profiles, i.e. zero order release, since that is
expected to minimize drug concentration fluctuations in blood
plasma . The scope of the present study was therefore to (i)
produce precursor powders of different Al/Si ratio via a sol-gel
Precursor powder name
The name of each precursor powder refers to its Al/Si molar ratio, as shown in the table.
process, and produce opioid-carrying geopolymers from the
precursor powders, (ii) characterize the precursor powders and
the geopolymers thoroughly, and (iii) investigate if a relationship
could be found between Al/Si ratio in the precursor powders and
the drug release profiles of the corresponding geoplymers.
Three different aluminosilicate powders with varying Al/Si
molar ratio were prepared by precipitation from aluminum nitrate
nonahydrate (ANN, Al(NO3)3? 9H2O, Sigma-Aldrich) and
tetraethylorthosilicate (TEOS, Si(OC2H5)4, Sigma-Aldrich). The
sample name of each precursor powder refers to its Al/Si molar ratio,
as shown in Table 1 (e.g., AS21 has an Al/Si molar ratio of 2:1).
The total concentration of ANN and TEOS together was 1.2 M in
all three preparations as described elsewhere  (in the referred
study, the synthesized aluminosilicate powders were not used as
precursors in geopolymer production). For the synthesis of each
powder, two solutions were prepared, A and B. Solution A
contained TEOS diluted to 250 ml with ethanol and solution B
contained ANN dissolved in H2O and diluted to 250 ml with
ethanol. The TEOS/H2O molar ratio was 1:18 in all
preparations. The two solutions were stirred for 15 min before they were
mixed together and stirred for additionally 3 h. Subsequently,
250 ml 25% ammonium hydroxide (Sigma Aldrich) was added
rapidly to the mixture under vigorous stirring to cause
precipitation. The obtained gels were dried on filter paper and left in a
fume hood until the ammonia had evaporated, and thereafter
dried at 110uC for 10 h. The dried powders were analyzed with
X-ray diffraction (XRD, D5000 diffractometer - Siemens/Bruker)
before subjected to a calcination at 800uC for 2 h. The powders
were then again examined with XRD and the true densities (r) of
the powders were examined with He-pycnometry (AccuPyc 1340
Micromeritics). The specific surface area of each powder was
obtained by N2-adsorption (ASAP 2020 Micromeritics) and BET
analysis  of the adsorption isotherm. The average diameter,
dmean, of the primary particles was assessed using the following
where SBET is the specific surface area of the powder. This
geometrical estimation of the particle size is justified as TEM
studies on similar xerogels have shown that the particles are
nonporous and spherical in shape , which is an underlying
assumption of the equation. The surface charge of the particles
was examined via f-potential measurements (Zetasizer Malvern)
in a 0.001 M KCl electrolyte with a pH adjusted to 6.8 with
0.01 M NaOH and 0.01 M HCl (same pH as in the buffer
solution used in the drug release measurements described below).
Fig. 1 illustrates the synthesis of geopolymer pellets. Briefly; a
sodium silicate solution was prepared by adding 0.2 g NaOH per
ml to a commercial sodium silicate solution containing 10.6%
NaOH and 26.5% SiO2 (Sigma-Aldrich). Three different types of
geopolymers were produced solely for material characterization by
Figure 1. Geopolymer pellet synthesis. 1) First, precursor powders are made in a sol-gel process. 2) Thereafter, the powder is mixed with a
sodium silicate solution to form a paste that is transferred to moulds and left to cure. For drug release experiments oxycodone HCL is added to the
paste before moulding. 3) After curing the pellets are removed from the mould. The particular pellets in panel 3 have the dimensions : 1.5 mm ? h:
1.5 mm and contains oxycodone.
Table 2. Characteristics of geopolymer samples.
Sample name of Geopolymer
Al/Si molar ratio (and sample name)
of precursor powder
Pore volume (in pores ,117 nm)
5.04 m60.01 m2/g
The name of each geopolymer sample refers to the Al/Si molar ratio of its precursor powder.
mixing the prepared sodium silicate solution with each of the
solgel derived powders (see Table 2). The liquid to powder ratio was
1 ml/1 g in all preparations. The pastes were mixed in a mortar
by hand before transferred into moulds with the dimensions :
6 mm ? h: 12 mm , and left to cure for 5 days at room
temperature before taken out to dry. The sample name of each
geopolymer refers to the Al/Si molar ratio of its precursor powder
(e.g., GP21 was produced from a precursor powder with an Al/Si
molar ratio of 2:1).
The obtained geopolymers were examined with XRD,
Hepycnometry, N2-adsorption/desorption, and f-potential
measurements. The mechanical strength was measured in compression
mode (Autograph AGS-H universal testing machine - Shimadzu).
For the latter measurements, 7 cylinders of each composition were
tested. Remnants from the compression tests were used to study
the densities, surface areas and porosities of the compositions. The
pore size distribution and pore volume of each composition were
calculated using density functional theory (DFT) [17,18]. Left over
pieces were also grinded to produce samples for XRD and
fpotential analysis. f-potential measurements on the geopolymers
were performed as described above.
In vitro drug release
In the production of the drug carrying vehicles, geopolymer
pastes were prepared as described above but with the addition of
0.02 g oxycodone HCl to each gram of precursor powder and
casted to form cylindrical pellets with the dimensions : 1.5 mm ?
h: 1.5 mm (Fig. 1, panel 3). These samples were left to cure for 5
days, either at room temperature or at 60uC, before removed from
the moulds and left to dry at 60uC, see Table 3. The release
measurements were performed in a USP-2 dissolution bath,
50 rpm, 37uC (AT7 Smart, Sotax) according to the U.S.
Pharmacopeia . 600 mg of pellets (each pellet weighing on
average 4.4 mg) were placed in each vessel, containing 500 ml of
50 mM phosphate buffer of pH 6.8 (same pH as in the intestines
where the primary drug uptake is supposed to occur). Sample
aliquots of 3 ml were withdrawn with regular intervals and the
concentration of oxycodone was measured with UV-vis
spectroscopy at 224 nm (UV-2650pc Shimadzu). Furthermore, sample
DR21-60 was subjected to release measurements in 40vol%
ethanol, and sample DR11-60 was used for release in 0.1 M HCl
(pH 1.0) to simulate release in different types of relevant
environments. The 40vol% ethanol release medium is often used
to assess the risk of dose dumping associated with co-intake of
controlled release formulations with strong spirits . The acidic
pH 1.0 release medium is described by the U.S. Pharmacopeia to be
used in release measurements to simulate release from controlled
release formulations in the stomach.
To investigate the influence of pellet size on the drug release
rate, an additional set of DR11-RT-pellets were produced with the
dimensions : 0.5 mm ? h: 1.0 mm. The drug release from these
smaller pellets was measured in the 50 mM phosphate buffer at
Results and Discussion
The obtained precursor powders were completely white (Fig. 1,
panel 1) and the corresponding XRD patterns for each powder
displayed peaks associated with crystalline SiO2 prior to the
calcination, although the peak intensities decreased with increasing
Si content, see Fig. 2. It is also evident from Fig. 2, that the three
powders adopted a clear amorphous structure after the
calcination, which is desired as it increases the reactivity of the powders
. The measured specific surface areas and densities of the
powders increased with aluminum content while the calculated
mean sizes of the primary particles decreased, see Table 1. The
primary particles in AS11 and AS21 were almost equal in size
(,56 nm) while the AS12 particles were considerably larger
(,10 nm). These findings are in agreement with earlier TEM
Al/Si molar ratio
(and sample name)
of precursor powder
studies . No significant difference in surface charge was seen
between the powders that all had a f-potential of about -33 mV,
see Table 1.
When the precursor powders were mixed with the sodium
silicate solution to form geoplymers, AS11 and AS21 readily
dissolved to form cohesive pastes that were easy to transfer to the
moulds. AS12 did not react as easily and the obtained paste
behaved more like toothpaste containing dispensed grainy
particles. Upon hardening, composition GP12 shrank and the
casted cylinders were easy to retrieve from the moulds, while
composition GP21 increased in volume. No significant volume
change was observed for composition GP11 after hardening. The
three different geopolymers were all clear white and appeared
slightly translucent which is consistent with an inherent
nanostructure and mesoporosity (mesopores: pores with a diameter
between 2 nm and 50 nm) [22,23].
The N2-isotherms for the geopolymer compositions are presented
in Fig. 3. It was evident from the adsorption measurements that
GP12 had a relatively compact structure with lower pore volume
and smaller specific surface area compared to the other
compositions, as shown in Table 2. The shape of the wide hysteresis for
GP21 and GP11 is consistent with irregular interconnected and slit
like mesopores  and the steep drop in the desorption branch at a
partial nitrogen pressure p/p0 <0.46 suggests a presence of
inkbottle shaped pores with necks smaller than ,5 nm . The
saturation plateau reached at p/p0 <0.9 for GP21 represents a
complete filling of condensed gas in the structure and is indicative of
a lack of larger pores above the mesoporous range. The pore size
distributions of the three geopolymers are seen in Fig. 4. Here a
distinct difference can be seen between the compositions; the
majority of pores in GP21 and GP11 are gathered in a narrow size
region around 10 nm while the pores in GP12 have a wide size
distribution mainly in the microporous range (above 50 nm). It is
clear from Fig. 4 that GP21 had the most distinct pore size
distribution with all pores in a range between 2 nm and 35 nm
while GP11 contains pores with sizes up to 85 nm. In addition to
having the highest accessible pore volume, GP21 also seemed to
have the highest inaccessible pore volume, judging from the fact that
it had the lowest true density as shown in Table 2 (true density is the
skeletal density of the material including inaccessible pores).
AS11 reacted rapidly with the sodium silicate solution to form
geopolymers within an hour after mixing while the other powders
needed substantially longer times to set; AS21 had the slowest
setting rate and needed several days to set. The compressive
strength of the compositions differed significantly; GP11 had the
highest compressive strength, twice as high as for GP21 and four
times that of GP12, see Table 2. The compressive strength of
GP11 can be compared with the strength of high strength concrete
but is several times lower that that of teeth. The relatively low
compressive strength of GP12 may be related to a limited
polymerization as AS12 did not dissolve as easily as the other
powders in the sodium silicate solution. The higher strength of
GP11 compared to GP21 may be explained by the higher porosity
in GP21, and also by the higher Si content in GP11 which clearly
increased the reactivity of this powder and shortened the setting
time. The high reactivity of GP11 may have caused a more
complete and homogeneous geopolymerization, as compared to
the other samples.
The XRD patterns for all three geopolymers contained the
characteristic hump corresponding to the amorphous structure in
the geopolymer , see Fig. 5. There was also a distinct peak in
the patterns indicating the presence of a crystalline phase, but it is
hard to make a correct determination of this phase from a single
XRD peak. Yet, this peak was not seen in the XRD patterns for
any of the precursor powders, indicating that the formation of this
phase was induced by the reaction between the sodium silicate
solution and the precursor powders. Unlike the situation for the
precursor powders, the f-potential measurements of the
geopolymers revealed a difference between the compositions where the
negative surface charge increased with Si content, see Table 2.
The surface charge was significantly larger for all geopolymers
compared to their corresponding precursor powder with GP12
possessing the most negative f-potential at -61.760.3 mV. The
difference between the geopolymer samples may be attributed to
the difference in numbers of silanol (SiOH) and aluminol (AlOH)
groups present on the surfaces  where the amphoteric alumina
generally is protonated and carries a positive charge at pH 6.8
while the silica species are negatively charged . The profound
electronegativity of the geopolymer walls enables electrostatic
interaction with ionized molecules integrated in the porous
matrixes. As oxycodone is a weak base with pKa of 8.5 ,
most of the species in solution will be protonated and carry a
positive charge at pH 6.8 according to the Henderson-Hasselbalch
equation . This opposite charge promotes an attraction
between oxycodone and the geopolymer wall and is thus expected
to affect the release profiles.
In vitro drug release
Continuous and sustained releases of oxycodone for up to 6 days
were obtained for all drug-carrying geopolymer compositions with
the dimensions : 1.5 mm ? h: 1.5 mm, see Fig. 6. This is
substantially slower compared to a previous study where fentanyl
was released from bodies of similar size but comprised of
metakaolin-based geopolymers . In the mentioned study, most
of the fentanyl was released after 24 h, and this difference in
release rate may be attributed to the more limited porosity
together with a more distinct mesoporous structure of the
geopolymers in the present study. A sustained release for several
days is obviously not desirable in this context as the pellets would
have left the intestines long before the release is complete. But the
profound retardation of the drug release from the geopolymer
structures opens up for precise control of the sustained release
rates, simply by adjusting the size of the pellets and thereby
affecting the diffusion length in the structures. This is clear from
Fig. 7, where drug release from pellets of two different sizes is
compared. The figure shows that decreasing the pellet size
increases the release rate, and a clinically relevant release period of
about 12 h is obtained with pellets of the size : 0.5 mm ? h:
1.0 mm (88% of the total release was achieved after 12 h). Fig. 7
also shows that the fraction of the drug that is trapped in closed
pores (i.e. that can not be released) is smaller for the smaller pellets,
which is expected due to the larger surface area of the smaller
As shown in Fig. 6, it was observed that the oxycodone release
rate decreased with increasing Al/Si ratio, observed for both
investigated setting temperatures. This is consistent with the fact
that the pore sizes also decreased with increasing Al/Si ratio (see
Fig. 4); it is logical that drug diffusion through the geopolymer, and
therefore also drug release, is slower in a system of smaller pores
. Increasing aluminum content resulted in a more linear
release profile, and this linear release should also be attributed to
the shift towards smaller pores in the aluminum rich compositions,
Figure 6. Release profiles in pH 6.8 for the oxycodone carrying geopolymer samples. Each curve show the total release of oxycodone
from roughly 135 pellets (weighing in total 600 mg) with the dimensions : 1.5 mm ? h: 1.5 mm.
since it has been shown that polymeric systems with pore
diameters in a range comparable with the size of the drug
molecules enables zero order release . The present work shows
that linear release profiles can be achieved with the presented
geopolymer system, simply by tuning the Al/Si ratio and curing
temperature. This is a large benefit compared to previously
described dosage forms of clay-derived geopolymers where the
release profiles were more similar to the ones of the DR12
It was clear from the release measurements that a setting
temperature of 60uC resulted in slower release, as compared to
setting at room temperature; this was observed for all three
investigated Al/Si ratios of the precursor powder. This may be a
result of a capillary contraction of the structures as the water leaves
the geopolymers more easily at this temperature, forcing formed
pores to shrink before complete cementation of the structures.
After the release of oxycodone had leveled out, the buffer
concentration was increased fourfold to examine if more
oxycodone could be released by screening the charge of the
geopolymer walls (examined after 200 h of release, for the samples
that had cured at room temperature). The increase in buffer
concentration did not result in any additional release of
oxycodone, showing that a buffer concentration of 50 mM was
sufficient to release all oxycodone (except the fraction confined in
the closed pores). After 200 h of release, 5.6 mg Oxycdone had
been released from DR21-RT pellets of the larger size, which
corresponds to roughly 80% of the total amount of incorporated
oxycodone (exact calculations of released fractions were precluded
by the difficulty in assessing the amount of water entrapped in the
structure after synthesis).
DR21-60 was also subjected to release measurements in 40vol%
ethanol to examine if alcohol affects the release rate. As seen in
Fig. 8, where the release of oxycodone in ethanol is compared with
the release in phosphate buffer, alcohol increases the release rate.
The increase at this extreme condition seems however relatively
limited, i.e. less than twofold. 40% ethanol is an extremely high
concentration that only is possible to achieve under very limited
time if the pellets is to be swallowed together with strong sprits.
The alcohol will be diluted by the gastric juice in the stomach and
the concentration will rapidly decline once the liquid enters the
small intestine where the uptake of alcohol is rapid . Under
more realistic conditions with lower alcohol concentrations, the
effect of alcohol on the release should be negligible as seen for
other systems [20,29].
The release of oxycodone from DR11-60 was also examined at
pH 1.0, to see how this acidic condition affected the release. As
shown in Fig. 8, the release rate is substantially higher at pH 1.0
compared to the release at pH 6.8, in agreement with earlier
findings . Interestingly, the release at pH 1.0 suddenly ceases
after about 48 h even though only 4 mg has been released,
compared to the total release of 5 mg after 144 h at pH 6.8. This
may be explained by a collapse of the porous structure due to
rearrangement of the geopolymer; it has been shown previously
that geopolymers can dissolve and condensate into new forms
under strong acidic conditions . Fig. 8 suggests that the
presently investigated geopolymers break down and recondensate
at pH 1.0, causing some of the oxycodone to become trapped in
closed pores. These negative effects of low pH on the release can,
however, be overcome by administration of the pellets in
Figure 8. Release profiles in pH 6.8 and in 40 vol% ethanol. Comparison of release profiles for DR21-60 in pH 6.8 and in 40% ethanol, and for
DR11-60 in pH 6.8 and pH 1.0 (pellet dimensions : 1.5 mm ? h: 1.5 mm).
Using geopolymers as drug delivery vehicles introduces a new
concept in the pharmaceutical sciences, and such vehicles have so
far not been tested in vivo. Thus, it remains to be investigated if any
negative side effects are linked to the proposed carrier material.
The small size of the pellets used here and the lack of sharp edges
on these, similar to other non-degrading carriers [29,32], make it
unlikely the pellets would mechanically affect the epithelium of the
intestines due to sharp entities on the carrier surface. If necessary,
the pellets could be molded into spherical shape. Furthermore,
geopolymers have previously been suggested as material in implant
applications and been shown to both have bioactive properties and
low leakage of ions , suggesting that the material is non-toxic.
In order to further establish that the proposed concept can be
condensed into actual use, in vivo studies of a final product should
be performed. Such studies should include pellets compacted with
conventional tablet excipients and administered as enteric-coated
tablets, or pellets that are administered in enteric-coated capsules,
to ensure tablet disintegration and drug uptake in the small
In the present study, fully synthetic geopolymers were obtained
by the reaction of a sodium silicate solution with sol-gel
synthesized aluminosilicate nanoparticles. Precursor nanoparticles
with three different Al/Si molar ratios were investigated: 2:1, 1:1
and 1:2. By altering the Al/Si molar ratio of the nanoparticles,
several properties of the corresponding geopolymers could be
adjusted: for example, mechanical strength, setting time and
swelling/shrinking behavior during setting. A particularly
esting result is the fact that the pore size distribution was narrowed
as the Al/Si molar ratio was increased. For the highest investigated
Al/Si molar ratio, 2:1, the entire pore volume was within the
mesoporous range (all pores were between 2 nm and 35 nm). The
geopolymers were used as drug carrying vehicles for sustained
release of the opioid oxycodone. A profound retardation of the
release was observed in vitro, and it was possible to obtain an almost
linear release profile from the aluminum rich compositions, which
is a very desirable property for sustained release formulations. By
tuning the size of the pellets, it was possible to obtain a release
period of about 12 h, which is a clinically relevant release time.
The mechanical strength makes the obtained geopolymers difficult
to crush upon accidental chewing, and the geopolymers are
therefore a safe and attractive material for controlled release of
drugs with narrow therapeutic window, such as highly potent
opioids. This study has focused on the release of opioids for
treatment of chronic pain, but the presented geopolymers can also
be used for drug administration in other clinical indications where
a constant or sustained delivery of drugs is desirable.
We would like to thank Dr. Albert Mihranyan for valuable discussions
regarding interpretation of the gas-sorption results.
Conceived and designed the experiments: JF CP. Performed the
experiments: JF CP. Analyzed the data: JF CP MS HE. Contributed
reagents/materials/analysis tools: MS HE. Wrote the paper: JF CP MS.
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