Materials Research Bulletin 48 (2013) 137–145

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Materials Research Bulletin

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A fast and simple method for preparation of calcium carbonate–drug composites

for fast drug release
Uroš Maver a,b, Marjan Bele a, Janez Jamnik a, Miran Gaberšček a,*, Odon Planinšek c
a
National Institute of Chemistry Slovenia, Hajdrihova 19, SI-1000 Ljubljana, Slovenia
b
Centre of Excellence Polymer Materials and Technologies, Tehnološki Park 24, SI-1000 Ljubljana, Slovenia
c
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia

A R T I C L E I N F O A B S T R A C T

Article history: Novel ways to synthesize CaCO3 based matrices to increase the dissolution rate of naproxen are
Received 12 September 2011 investigated. The composites were prepared using 3 methods, all starting from aqueous solutions of
Received in revised form 15 August 2012 CaCl26H2O and NaHCO3, while the differences were in how the solutions were mixed and dried. The fast
Accepted 11 October 2012
disintegration of the matrix from the composites was explained by swift dispersion of the matrix into
Available online 22 October 2012
tiny drug particles, thus allowing for their fast dissolution. Modifications in the preparation procedures
resulted in formation of different portions of CaCO3 crystal forms. Despite the identical drug
Keywords:
composition, dissolution of naproxen from the composites was considerably faster than the dissolution
A. Composites
of pure naproxen. The dissolution was the fastest in the samples containing the highest amount of the
C. Electron microscopy
C. X-ray diffraction less stable CaCO3 crystal form, vaterite. The proposed composite formulation could be interesting for per
D. Crystal structure os applications where fast attainment of high blood concentration and its preservation is required.
D. Diffusion ß 2012 Elsevier Ltd. All rights reserved.

1. Introduction improve the drug dissolution either by forming solid dispersions or

Increasing the dissolution rate is one of the key procedures to
raise the bioavailability of drugs that have limited absorption as a
result of low solubility [1]. While different polymorphic forms are
often patented and bioavailabilities prescribed, researchers usually
try to tailor the release by incorporating such drugs into various
systems for controlled release [2]. Popular systems are matrices
consisting of active particles dispersed within different inorganic
or organic materials, and swellable or inert polymers [3–5].
The release rate and duration of controlled-release devices are
designed according to specifications of the required drug delivery
profile. By contrast, the rate and duration of sustained-release
devices are not designed specifically so their values may be quite
arbitrary [6]. The primary goal of the present work was to find a
method that would significantly improve the dissolution rate of
naproxen. Naproxen ((S)-(+)-6-methoxy-a-methyl-2 naphthale-
neacetic acid, NAP) is a non-steroidal anti-inflammatory drug often
used to relieve fever and to reduce inflammation and pain
associated with arthritis.
In order to improve the bioavailability of naproxen, many
approaches have been already used [7–9]. The most popular
systems used to improve the drug dissolution rate are solid
dispersions, polymers or cyclodextrins. Polymers can be used to
* Corresponding author. Tel.: +386 1 4760 320.
E-mail address: miran.gaberscek@ki.si (M. Gaberšček).
by the change in drug release mechanism (diffusion-, swelling- or
chemically controlled) [10]. After their exposure to aqueous
dissolution media, solid dispersions tend to release fine colloidal
particles of the drug and the resulting increased surface produces a
higher dissolution rate and bioavailability of poorly water-soluble
drugs [11]. Probably the most efficient way to increase the
dissolution of poorly water-soluble drugs like naproxen is their
incorporation into cyclodextrins. Their hydrophobic interior
allows for high drug loads, while the hydrophilic surface drastically
improves their solubility [12].
Calcium carbonate is anexcellent matrix base material due to its
biodegradability, cheapness and a thorough scientific background,
based on decades of study. In the past, calcium carbonate was
mostly used for preparation of tableted matrices. Fausett et al. used
calcium carbonate as a source of calcium to improve calcium
deficiency [13]. Their studies also showed that exploitation of the
effervescent effect of carbonates or bicarbonates may enhance
permeability, which eventually leads to increased bioavailability
[14]. Selected effervescent products are already under patent
protection [15].
Previous attempts to increase the dissolution of naproxen
include its incorporation into different host materials, the best
performing being cyclodextrins. Bettinetti et al. used b-
cyclodextrins and achieved approximately 70% of the drug
release in the first hour [16]. Other used materials include
electrospun cellulose fibers [17], colyophylized PVP [12],
chitosan [18] and others. Naproxen incorporation into the

0025-5408/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.materresbull.2012.10.021
138 U. Maver et al. / Materials Research Bulletin 48 (2013) 137–145
mentioned materials resulted in the release of 50% of the
incorporated drug in the first hour.
We here propose a different approach, whereby a model drug
is incorporated into a rapidly, but partially erodable matrix
system based on in situ preparation of different calcium
carbonate crystal forms simultaneously. To the best of our
knowledge, combinations of in situ prepared different CaCO3
crystal forms to tailor the release of drugs have not been
reported previously. Matrices comprising a large portion of the
less stable crystal form, vaterite, are believed to rapidly
disintegrate upon entering the stomach with inherently low
pH, thereby releasing the embedded small drug particles. As a
model drug, naproxen was chosen; on one hand, it has a poor
water solubility while, on the other, it is used as an analgesic,
requiring rapid action upon administration. Thus, preparation of
an efficient drug delivery system for rapid release of naproxen is
of high interest.
2. Materials and methods
2.1. Preparation of naproxen
Naproxen (Sigma–Aldrich, in future NAP) was dissolved in
anhydrous ethanol and water was added to cause precipitation of
NAP particles. The prepared suspension was then filtered through a
0.2 mm polycarbonate filter. All materials, including polycarbonate
filters, were of laboratory grade and bought from Sigma–Aldrich.
2.2. Preparation of composites
To produce composite samples, two solutions were prepared.
The first was a solution of CaCl26H2O in water and the second a
solution of NaHCO3 and the active compound (NAP) in water.
Samples CaCO3-NAP1 and CaCO3-NAP3 were prepared by mixing
the two solutions in the amounts shown in Table 1.
Sample CaCO3-NAP1 was filtered after the mixing procedure
and then dried at 50 8C. The preparation of sample CaCO3-NAP3
was the same except that freeze-drying was used as the drying
method. To prepare sample CaCO3-NAP2, we used a modified
Titrino unit (Titrando 835, MetrOhm, Switzerland). The solutions
were added from two needles with tips close enough to form a
common droplet (simulating a microreactor). The formed droplets
were falling on a filter with 0.2 mm pores to allow for instanta-
neous filtration. To get optimal results, we varied the rate of
solution additions. We here present results for the case where the
solution of NaHCO3 was added at a rate of 0.25 ml/min, while the
CaCl26H2O/naproxene solution was added at a rate of 0.08 ml/min,
which appeared to give the best targeted characteristics. After the
filtration, the sample was dried at 50 8C. The composite prepara-
tion procedure is summarized in Fig. 1.
To exclude artifacts due to possible drug loss via adhesion to
laboratory accessories (beakers, instillators, etc.) used in the
preparation procedure, we collected all possible remains of drug,
measured the UV-absorption and calculated the drug loss; the
value was always under 1% of the added amount. All used materials
were purchased from Sigma–Aldrich.
Table 1
Molar ratios of the added precursors.
Sample name CaCl2 NaHCO3 Naproxen H2O Finishing
6H2O technique
CaCO3-NAP1 1.0 2.5 0.1 12.0 Filtration
CaCO3-NAP2 1.0 2.5 0.1 12.0 Droplet reactor
CaCO3-NAP3 1.0 2.5 0.1 12.0 Lyophilization
(=freeze drying)
2.3. Characterization
Specific surface areas were determined using the Brunauer–
Emmet–Teller (BET) technique based on nitrogen gas adsorption
(TRISTAR 3000, Tboil = 196 8C). Prior to analysis, the samples were
crushed and outgassed. X-ray powder diffraction measurements
were carried out on crushed samples using a Philips PW 1710
diffractometer with Cu Ka1 radiation (l = 1.5418 Å) at 40 kV and
30 mA. Data was collected from 2 to 408 with 0.048 steps. X’Pert
Highscore Plus (PANalytical B.V., Almelo, Netherlands) was used
for analysis of the obtained diffractograms.
The crushed samples were additionally analyzed by differential
thermal analysis (DTA) and thermal gravimetric analysis (TG)
(NET-ZSCHSTA409C/CD) from room temperature (293 K) to 1183 K
in air conditions with a rate of temperature increase of 10 K/min.
Scanning electron microscopy was used to determine morphol-
ogies of the samples. For this purpose dried samples were ground
and pressed on a double-sided adhesive carbon tape (SPI Supplies,
USA). All samples were imaged with a field emission scanning
electron microscopy (FE-SEM, Supra 35 VP, Carl Zeiss, Germany)
operated at 1 keV. Elementary mapping analysis of samples was
performed using energy-dispersive spectrometer (EDS) Inca 400
(Oxford Instruments, Oxfordshire, UK).
2.4. Drug dissolution testing
Dissolution studies of naproxen thin films and its composites
from crushed samples were performed using the USP XXIX paddle
method (Vankel 7000 Dissolution test station, USA – Apparatus II
in USP XXIX) with a stirring speed of 50 rpm [19]. All samples were
sown prior to dissolution through a 1000 mm sieve. The dissolution
medium was prepared using a 0.2 M hydrochloric acid (HCl) and a
0.2 M potassium chloride (KCl) to obtain a pH of 1.2  0.1, assuring
sink conditions (C < 0.15CS) [20]. Samples containing ca. 10 mg of
NAP were dissolved in 900 mL of dissolution medium at 37.0  0.5 8C.
At appropriate time intervals, aliquots of 10 mL were withdrawn (the
withdrawn amount was complemented with fresh dissolution
medium) and measured spectrophotometrically (UV Spectrophotom-
eter 8453, Hewlett Packard, Germany) at l = 230 nm. Prior to release
profile analysis, all calculated concentrations were normalized for the
withdrawn amount of naproxen. The experiments were carried out
with three parallel samples; therefore only mean values with S.D.
error bars are reported. As in the present work we focus on fast
dissolution mechanisms, we only display dissolution profiles
measured within the first 300 min of the release.
The dissolution was carried out at pH 1.2 to simulate the
dissolution behavior in the stomach as naproxen is often found in
the form of tablets for ‘‘per os’’ administration. The present
conditions for the simulation of the stomach fluid are frequently
used in practice (Ph.Eur.5th, [21]). During dissolution, the change of
pH was negligibly small.
Apart from spectrophotometry, also particle sizing was used as
a method for particle dissolution studies. The average particle size
was measured using a Malvern Mastersizer 2000 laser diffraction
instrument. To appropriately simulate the dissolution process, we
used the same sieving procedure (we used a 1000 mm sieve) as in
the drug release experiments.
3. Results
3.1. Morphological and structural examination of prepared samples
The theoretical percentage of NAP in the as-prepared samples is
shown in Table 2, first column. The percentages were calculated
from the initial amounts of the used precursors.
 U. Maver et al. / Materials Research Bulletin 48 (2013) 137–145
Fig. 1. Schematical depiction of samples’ preparation procedure: (a) preparation of CaCO3-NAP1 and CaCO3-NAP3 and (b) preparation of CaCO3-NAP2.
Possible drug loss due to adsorption on various lab ware used in
the procedure was evaluated and found negligible in the process
described in Section 2.2. The initial amounts of the incorporated
drug were evaluated by checking the released drug amounts after
24 h. The released amounts were slightly below the added amount.
N2-adsorption revealed a low to moderate specific surface areas for
all samples (Table 2, second column).
Although sample CaCO3-NAP3 was prepared with the same
amounts of synthesis precursors as the other two composite
samples (CaCO3-NAP1 and CaCO3-NAP2), it had a significantly
higher surface area. Generally, a higher surface area is expected to
lead to a faster dissolution rate. Note, however, that the eventual
macroporosity as well any micropores below 0.7 nm could not be
detected using the N2 adsorption method (the former, however,
could be detected using SEM analysis, see Fig. 2).
Fig. 3 shows X-ray diffractograms of the prepared samples and
of the pure crystal forms of naproxen and CaCO3. In the composite
samples, peaks other than those corresponding to naproxen are
observed. Sample CaCO3-NAP1 is mainly composed of calcite,
which is the more stable form of calcium carbonate so its presence
could decrease the average dissolution rate.
By contrast, CaCO3-NAP2 and CaCO3-NAP3 are mainly com-
posed of vaterite, the less stable form of calcium carbonate. We
found that the portion of vaterite could be increased by freeze
drying and a special filtering procedure. Thus, sample CaCO3-NAP2
was freeze dried whereas CaCO3-NAP3 was immediately filtered;
both procedures lowered the available time for the transformation
of vaterite into the more stable form, calcite. Analysis of the
diffractograms (X’Pert Highscore Plus) revealed that naproxen
retained its standard crystal form in all samples during the
synthesis. Obviously, the preparation procedure did not cause any
polymorphic transitions, which can be explained by the mild
conditions during the synthesis.
A more detailed examination of SEM results at various
magnifications showed that the morphology of all three composite
Table 2
BET surface areas of the prepared samples and contents of naproxen (NAP) in the
samples prior to characterization.
Percentage of Specific surface
naproxen in area (m2/g)
the samples (%)
CaCO3-NAP1 3.4 3.87  0.04
CaCO3-NAP2 3.4 3.23  0.04
CaCO3-NAP3 3.4 14.24  0.11
139
samples (CaCO3-NAP1, CaCO3-NAP2, CaCO3-NAP3) was very
inhomogeneous. The electron micrographs showed diverse mor-
phological features consisting of different structural elements
(slabs, sponge like structure, rods.), especially for samples CaCO3-
NAP2 and CaCO3-NAP3, while sample CaCO3-NAP1 exhibited a
more compact morphology (Fig. 2). In samples CaCO3-NAP2 and
CaCO3-NAP3, the structural elements were loosely packed which
gave rise to significant porosity in the macropore range (Fig. 2), a
feature that could not be examined using N2-adsorption analysis.
EDS analysis showed that naproxen was present also on the surface
in the lyophilized sample CaCO3-NAP3 (increased percentage of C
and O on the surface; additional explanation of this result can be
found in Section 4). Samples CaCO3-NAP1 and CaCO3-NAP2
showed no extra drug on the surface.
Thermal analysis of all samples is depicted in Fig. 4. DTA and
TG curves of the three composite samples (CaCO3-NAP1–3)
exhibit weak endothermic peaks at temperatures up to 100 8C.
These peaks are most likely associated with the removal of
interlayer water molecules [22]. They are accompanied with a
mass loss of 5–10%, being the highest for sample CaCO3-NAP3
(after lyophilization, this sample probably adsorbed significant
amounts of moisture from air although it was immediately
sealed and stored) and the lowest for sample CaCO3-NAP2. All
DTA curves exhibited an endothermic peak at 152–154 8C that is
known to correspond to melting of naproxen [23]. At about
300 8C, an exothermic peak was detected in all samples, but was
clearly separated from the other features only in sample CaCO3-
NAP2. In this case, the peak was accompanied with a mass loss
of 5%. In the other two samples, the appearance of this peak
overlapped with the peaks corresponding to the combustion of
organic compounds and the evolution of CO2 from CaCO3; both
processes started at ca. 300 8C and ended at 600 8C. The effect of
this combustion can be deduced from the TG curves and mass
losses of 30% for CaCO3-NAP3, 40% for CaCO3-NAP1 and 50% for
CaCO3-NAP2. Thus, the exothermic peak between 450 8C and
500 8C is probably due to the loss of water from Ca(OH)2 [24].
This peak can also be an indication of the transformation from
vaterite (a less stable form of CaCO3) to calcite (the most stable
form of CaCO3), which usually starts at this temperatures and
ends at ca. 700 8C [24]. The mass losses between 600 8C and
800 8C (5–15%) are again due to the evolution of CO2 from CaCO3
in the samples (Fig. 4). In the literature no information could
be found about the stages of naproxen combustion, except of the
melting point at 152–154 8C and the combustion of the molecule
(which yields a mixture of CO2 and H2O) [23].
140 U. Maver et al. / Materials Research Bulletin 48 (2013) 137–145
Fig. 2. Electron micrographs of the composite samples showing macroporosity and pure drug: (a) naproxen (NAP), (b) CaCO3-NAP1, (c) CaCO3-NAP2 and (d) CaCO3-NAP3.
3.2. Studies of release/dissolution
Prior to the dissolution/release analysis, all samples were
crushed and sown through a 1000 mm sieve to minimize the effect
of different dissolution rates due to huge size differences alone.
Already a rough inspection of dissolution curves shows that all
three composites (CaCO3-NAP1–3) had a significantly faster
dissolution/release rate than the pure naproxen (NAP) (Fig. 5).
Among the composites, the highest release rate was observed
for sample CaCO3-NAP3. This sample exhibited a very steep burst
effect in the first 20–30 min. A similar but slightly less intense
burst effect was observed for sample CaCO3-NAP2. A significantly
different dissolution profile was found for sample CaCO3-NAP1
which did not exhibit a clear burst effect. After the burst region
(after 20–30 min of the dissolution), samples CaCO3-NAP2 and
Fig. 3. X-ray difractograms of the prepared samples, of free naproxen and of both
observed CaCO3 crystal forms (vaterite and calcite). Peaks corresponding to calcite
and free naproxen can be observed for both composite samples, while there is a
clear indication of vaterite presence observable only for the sample CaCO3-NAP2.
The latter could be clearly seen also for the sample CaCO3-NAP3 (not shown).
CaCO3-NAP3 exhibit a steady, diffusion controlled release until
almost all drug is released. Sample CaCO3-NAP1 achieved the same
process after 300 min of the dissolution analysis.
To get additional insight into the dissolution/release mecha-
nism, we analyzed the particle size after selected periods of time
during the burst region. All composite samples showed a decrease
in particle size over the first 20 min of the release (that is, after the
burst region had been more or less completed). After 5 min of
release, sample CaCO3-NAP1 contains a relatively small portion of
larger particles between 200 and 500 mm which, later on,
gradually dissolve (Fig. 6a). By contrast, after 5 min sample
CaCO3-NAP2 contains a much wider distribution of larger particles
(from 200 mm to more than 800 mm); these particles then rapidly
disintegrate and after 20 min fully disappear (Fig. 6b). A similar
modification of size distribution pattern, but with even more
pronounced disintegration of large particles, is observed in sample
CaCO3-NAP3 (Fig. 6c).
3.3. ‘‘Post-mortem’’ analysis of composite samples
For all three composite samples, SEM micrographs were taken
also after the dissolution. A clear change in the morphology and
structure of samples CaCO3-NAP2 (Fig. 7b) and CaCO3-NAP3
(Fig. 7c) can be seen. Their flaky nature has completely disappeared
and their macroporosity cannot be observed anymore. Note,
however, that the morphology of sample CaCO3-NAP1 remains
similar to that before the dissolution (Fig. 7a).
We also measured X-ray powder diffraction patterns of the
remainders collected after 300 min of dissolution (not shown),
when the dissolution/release of all composite samples had reached
a steady, diffusion controlled release. The patterns in the
diffractograms retained the same features for the sample CaCO3-
NAP1, only its intensity was changed, while the diffractograms for
samples CaCO3-NAP2 and CaCO3-NAP3 showed a decrease in the
amount of the unstable CaCO3 crystal form vaterite. Obviously,
some naproxen remained undissolved, possibly trapped within the
remainder of the matrix. As the intensities of the diffraction peaks
corresponding to the more stable calcite were almost unchanged, it
is reasonable to assume that the remainder of the matrix consists
mainly of calcite. The presence of diffraction peaks corresponding
 U. Maver et al. / Materials Research Bulletin 48 (2013) 137–145
Fig. 4. Thermal analysis of the prepared composite samples: (a) CaCO3-NAP1, (b)
CaCO3-NAP2 and (c) CaCO3-NAP3.
to NAP is consistent with the dissolution patterns in which part of
naproxen was not dissolved after 300 min. Additional examination
showed that the ‘‘trapped NAP’’ released very slowly within further
24 h.
4. Discussion
The results of the dissolution/release analysis show that various
calcium carbonate–naproxen composites exhibit profiles that are
141
Fig. 5. Dissolution profiles of the prepared samples exhibiting a steep increase in the
amount of the released drug in the first 20–30 min for the samples CaCO3-NAP2 and
CaCO3-NAP3. Additionally the dissolution profile for pure naproxen is added to
show the increase in its dissolution.
very different from the dissolution of the free drug. In all the
composites the drug was incorporated, in a form of fine particles,
into a rapidly, but partially erodable matrix of CaCO3, depending on
the ratio between the amounts of different CaCO3 crystal forms.
Namely, at pH 2 CaCO3 is expected to erode explosively thus
dispersing the individual drug particles around into the surround-
ing solvent. However, the rate of matrix disintegration obviously
depends on the form of CaCO3 used: the vaterite form seems to
disintegrate faster than the calcite, in accordance with our initial
hypothesis. For example, Fig. 5 demonstrates that the composite
samples CaCO3-NAP2 and CaCO3-NAP3, which contained more
vaterite, exhibited a burst effect within first 20–30 min of release
measurements. By contrast, CaCO3-NAP1 which contained pre-
dominantly calcite, did not exhibit such a vigorous burst effect. In
any case, in this initial period all the composites show a much
faster release if compared to the release of pure drug.
During the initial vigorous composite disintegration, however,
only about 30–50% of the drug has been dissolved; after that the
dissolution rate is significantly slowed down. Quite surprisingly,
even after prolonged times (300 min), a significant amount (ca.
30%) of the composite remains undissolved (see Fig. 5 and the
postmortem analysis in Fig. 7).
As mentioned, in sample CaCO3-NAP1 the burst effect was
much less pronounced. It seems reasonable to assume that in this
case most of the matrix remained stable in the solvent so that the
drug gradually released/dissolved from the bulk matrix. This
assumption is consistent with the morphological examination
which showed that the general morphology of this sample was
similar before and after the release experiments (compare Fig. 7a
and b) and also with the findings of X-ray powder diffraction
analysis (Fig. 4), which showed that most of this sample
corresponded to the more stable form of CaCO3, calcite (even
after dissolution – diffractograms not shown). To further prove the
hypothesis of different rates of matrix disintegration in the three
composites, we monitored the particle sizes as a function of time
(see Fig. 6). Indeed, summarizing these results, we see that the
large particles (above ca. 250 mm) in samples CaCO3-NAP2 and
CaCO3-NAP3 rapidly disintegrate and completely disappear after
20 min. This rapid disintegration is in full agreement with the burst
effect observed with these samples and their observed composi-
tion of different CaCO3 crystal forms. By contrast, in sample CaCO3-
NAP1 the particle size distribution remains quite stable during first
142 U. Maver et al. / Materials Research Bulletin 48 (2013) 137–145
Fig. 6. Particle size analysis with laser diffraction: (a) sample CaCO3-NAP1, (b)
sample CaCO3-NAP2 and (c) sample CaCO3-NAP3. A relatively slow decrease in
particle size can be observed for the sample CaCO3-NAP1, while there is a clearly
observable change in particle size distribution for both other composite samples
CaCO3-NAP2 and CaCO3-NAP3 over time.
Fig. 7. SEM micrographs of the composite samples after the dissolution/release: (a)
sample CaCO3-NAP1 (note that the flake-like structure is here preserved), (b)
sample CaCO3-NAP2 and (c) sample CaCO3-NAP3 (a completely different
morphology can be observed, when compared to the micrographs prior to
dissolution).
30 min, confirming the hypothesis that this sample hardly
disintegrates during the time of observation.
Considering these relatively clear morphological data, we
attempted to analyze quantitatively the release curves using
appropriate model(s). As regards sample CaCO3-NAP1, which
shows a rather stable matrix from which the drug gradually
dissolves, we chose the model proposed by Baker and Lonsdale
[25]. Although the proposed model is preferentially used for
explanation of release data from spherical matrices, it could be
applied for our system due to the fact that matrix overall
morphology remained intact during the dissolution, allowing for
almost unhindered diffusion controlled release from the matrices.
For the purposes of fitting, the Baker–Lonsdale formula can be
 U. Maver et al. / Materials Research Bulletin 48 (2013) 137–145 143

conveniently written as:

"   #
3 w 2=3 w
kb t ¼ 1 1  (1)
2 w1 w1

3DC s
kb ¼ (2)
r02 C 0

where D is the diffusion coefficient of drug in the matrix, Cs is the

solubility in the medium of interest, C0 is the initial concentration
of drug in the matrix, r0 is the radius of matrix, and w/w1 is the
weight fraction of the dissolved drug at time t. Fig. 8a shows a fit
(red solid curve) of the measured points (solid circles). The fit is
quite satisfactory. By contrast, a similar analysis evidently fails
with the other two samples, where the drug dissolves faster than
expected for dissolution from a stable matrix (i.e., the measured
points are below the theoretical curve), which is the consequence
of the morphological changes during dissolution. Due to the initial
burst and the subsequent diffusion controlled release from the
bulky remains of the matrix, both evident from the release profiles
of the samples CaCO3-NAP2 and CaCO3-NAP3, a derivation of the
Power law model (the initial model was introduced by Korsmayer
and Peppas [26]), seemed to be appropriate for fitting those two
profiles. The latter was proposed by Kim and Fassihi and introduces
another term into the equation as a correction for the burst effect
[27].
w
¼ k  tn þ b (3)
w1

where w/w1 is the portion of naproxen released/dissolved, t is the

time of release and k is a constant. Exponent n is a factor that was
shown to be an indication of the type of matrix, from which the
drug gets released [27]. The term b was introduced as a correction
for the burst effect.
Fig. 8b and c show the fitted curves (red curves) for the samples
CaCO3-NAP2 and CaCO3-NAP3, respectively. Whereas model (3)
fits the release points for CaCO3-NAP3 quite satisfactory, the fit for
sample CaCO3-NAP2 is not very good. This probably indicates that
there are additional contributions that are not accounted for in the
model. In an attempt to additionally verify the complex dissolution
mechanism associated with the release profiles, we also plotted
the corresponding derivatives of the dissolution profiles (Fig. 8b
and c, blue curves). The sharp maximum at 20–30 min of the
release clearly indicates the change of mechanism, consistently
with the discussion above where this period of time designates the
end of burst effect.
Summarizing the above discussion, we propose a scenario
explaining the different release patterns of composite samples. Our
understanding of the burst effect of samples CaCO3-NAP2 and
CaCO3-NAP3 is schematically depicted in Fig. 9a and b. The
explanation of the schematics is as follows. Upon immersion,
individual flakes of matrix are detached in an explosive manner
(and, eventually, dissolved – Fig. 9b – MIDDLE) from the outer parts
of composite particles thus releasing tiny drug particles captured
Fig. 8. Fit of experimental dissolution curves: (a) for the sample CaCO3-NAP1 (with
between the flakes (Fig. 9b – TOP). The drug particles dissolve very
the Baker–Lonsdale model. kb was the single free parameter; kb = 0.00043 s1;
fast because they are small and far apart in space (thoroughly R2 = 0.994), (b) sample CaCO3-NAP2 (with the corrected Power law model;
dispersed in the medium) – Fig. 9b – TOP). The thorough particle R2 = 0.856 – in this case, the shape of measured curve deviates significantly),
separation is crucial because it ensures a maximum concentration and (c) sample CaCO3-NAP3 (again the corrected form of the Power law model as
gradient between the particle surface and the surroundings (there used; R2 = 0.976 – the fit quite reasonably suits the release profile of this sample).
(For interpretation of the references to color in this figure legend, the reader is
the drug concentration is effectively zero during most of the referred to the web version of the article.)
dissolution experiment). The process of matrix disintegration
continues until reaching the inner, more bulky part of composite
(Fig. 9b – BOTTOM), which is not easily disintegrated (its bulky remainders (Fig. 9b – BOTTOM). Some of the drug eventually
nature can be seen from Fig. 7b and c). We presume that this bulky remains captured in the bulk composite interior which explains
part consists mainly of calcite. From that point on, the drug can why the dissolution curves at the end approach values significantly
only be released via slow diffusion from the bulky composite less than 100% – despite the sink conditions. Nevertheless, after
144 U. Maver et al. / Materials Research Bulletin 48 (2013) 137–145
Fig. 9. Scheme of the proposed dissolution mechanism for the composite sample: (a) for CaCO3-NAP2 and CaCO3-NAP3, (c) for CaCO3-NAP1, while in (b) additional
explanatory depictions are shown, which presumably appear during dissolution of the prepared composite sample CaCO3-NAP2 and CaCO3-NAP3.
24 h after the start of dissolution testing, almost the entire initial
drug amount is released.
The difference in the extent of burst effect in samples CaCO2-
NAP2 and CaCO3-NAP3 can be explained based on the results of N2-
adsorption and EDS analysis. The elemental analysis revealed that
the carbon and oxygen percentages increased after the drug
incorporation. While admitting that changes in the carbon and
oxygen might also result from contamination by several external
sources, we estimate that the increase of carbon and oxygen
content by 10  1.5% and 5  1.1%, respectively, after the drug
addition, indicate the presence of the drug on the surface. The drug on
the surface of sample CaCO3-NAP3 was probably in a form of small
particles, which is consistent with the somewhat larger surface area
of this sample as found by N2-adsorption. No such ‘‘superficial drug’’
was observed in sample CaCO3-NAP2 (see Section 3.1). Of course, the
drug deposited on the surface is a subject of immediate dissolution –
hence the somewhat more expressed burst effect in CaCO3-NAP3. The
same scenario also explains the fact that after ca. 20 min the slope in
sample CaCO3-NAP3 gets smaller than that of CaCO3-NAP2: in the
latter the drug concentration must be somewhat higher in the interior
of the less soluble matrix (because the total amount of drug is equal in
both samples) which gives rise to slightly bigger slope in the region of
20–200 min. After 200 min, however, both samples reach almost the
same percentage of drug release.
On the other hand, the outer flakes in sample CaCO3-NAP1 are
not released from the surface (see postmortem curve in Fig. 7a). In
that case the dissolution corresponds to the scenario depicted in
Fig. 9c. The entire drug has to release from the composite interior.
The flakes on the surface, however, serve as a relatively loose
matrix so dissolution is not hindered sterically – rather it is limited
by the diffusion process from more or less fixed matrix. This
explains why the Baker and Lonsdale model works quite well in
this case. Interestingly, despite being trapped into the matrix, the
dissolution from sample CaCO3-NAP1 is still faster than from pure
naproxen. Obviously, the effect of the much smaller naproxen size
prevails over the fact that this naproxen is entrapped inside the
inorganic matrix from which it is released. Indeed, the average
particles size of pure naproxen is bigger by several orders of
magnitude (above 50 mm – Fig. 2a).
5. Conclusions
We showed a simple preparation procedure which allows a
significant increase of the rate of naproxen dissolution. This very
fast dissolution rate has been achieved by incorporating the drug
into a rapidly, but partially erodable matrix containing an unstable
CaCO3 phase (vaterite). When immersed into solvent, the explosive
errosion of the vaterite-based matrix disperses thoroughly the fine
drug particles into the bulk solvent. Keeping small particles far
apart ensures a maximum concentration gradient (ideal sink
conditions) around individual particles during most of the
dissolution process; such conditions are not met in agglomerated
drug particles or in drug captured in a matrix, for example. The
consequence is very fast drug dissolution (45–48% of dissolved
drug in less than 30 min).
Under certain experimental conditions, the CaCO3-based
matrix appeared to be stable (its erosion was very small). The
results showed that in these composites the more stable form of
calcium carbonate, calcite, was the prevailing constituent of the
matrix. A complete novelty with respect to previous studies is the
use of a combination of the less and more stable CaCO3 phases
(calcite and vaterite). In fact, we showed that different combina-
tions of both phases led to different dissolution rates. This opens a
possibility to prepare fine-tuned composites with pre-defined
release rate based on CaCO3 matrix only.
Comparison with other available fast release matrices/compo-
sites with imbedded naproxen shows that in the first 30 min our
system releases almost the same amount of drug as the best
system known – the cyclodextrin-based delivery system [16]. After
30 min our system shows a lower rate, so the released amount in
the first hour is approximately 20% lower if compared to the
cyclodextrin-based system. A wider comparison shows that the
first-hour release of our system is similar to the release in other
delivery systems commonly referred to as ‘‘fast release systems’’
 U. Maver et al. / Materials Research Bulletin 48 (2013) 137–145
[12,17,18]. However, advantages such as the use of cheap and
abundant materials combined with a simple and affordable
synthesis procedure might make our materials very interesting
for further use.
Acknowledgments
This work was supported by the Slovenian Research Agency
(ARRS) [J2-4316 basic research project] and by the Ministry of
Higher Education, Science and Technology of the Republic of
Slovenia [Grant number 3211-10-000057].
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.materresbull.2012.
10.021.
References
[1] J.P. Griffin, The Textbook of Pharmaceutical Medicine, 6th ed., Wiley-Blackwell,
Chichester, West Sussex/Hoboken, NJ, 2009.
[2] S.K. Deo, E.A. Moschou, S.F. Peteu, L.G. Bachas, S. Daunert, P.E. Eisenhardt, M.J.
Madou, Anal. Chem. 75 (2003) 206A–213A.
[3] P. Kortesuo, M. Ahola, S. Karlsson, I. Kangasniemi, J. Kiesvaara, A. Yli-Urpo, J.
Biomed. Mater. Res. 44 (1999) 162–167.
[4] S.A. Madbouly, A. Lendlein, Shape-Memory Polymer Composites in: Shape-Mem-
ory Polymers, Springer-Verlag Berlin, Berlin, 2010, pp. 41–95.
145
[5] A. Emileh, E. Vasheghani-Farahani, M. Imani, Eur. Polym. J. 43 (2007)
1986–1995.
[6] J.M. Marentette, A.E. Grosser, J. Pharm. Sci. 81 (1992) 318–320.
[7] P. Zahedi, P.I. Lee, Eur. J. Pharm. Biopharm. 65 (2007) 320–328.
[8] P. Mura, M.T. Faucci, F. Maestrelli, S. Furlanetto, S. Pinzauti, J. Pharmaceut. Biomed.
29 (2002) 1015–1024.
[9] S. Bogdanova, I. Pajeva, P. Nikolova, I. Tsakovska, B. Müller, Pharmaceut. Res. 22
(2005) 806–815.
[10] B.A. Miller-Chou, J.L. Koenig, Prog. Polym. Sci. 28 (2003) 1223–1270.
[11] W.L. Chiou, S. Riegelman, J. Pharm. Sci. 60 (1971) 1281–1302.
[12] G. Bettinetti, P. Mura, Drug Dev. Ind. Pharm. 20 (1994) 1353–1366.
[13] H. Fausett, C. Gayser, A.K. Dash, AAPS PharmSciTech. 1 (2000) E20.
[14] J.D. Eichman, J.R. Robinson, Pharmaceut. Res. 15 (1998) 925–930.
[15] A.M. Schobel, U.S. Patent 4,687,662 (1987).
[16] G. Bettinetti, P. Mura, M.T. Faucci, M. Sorrenti, M. Setti, Eur. J. Pharm. Sci. 15 (2002)
21–29.
[17] S. Tungprapa, I. Jangchud, P. Supaphol, Polymer 48 (2007) 5030–5041.
[18] P. Mura, N. Zerrouk, N. Mennini, F. Maestrelli, C. Chemtob, Eur. J. Pharm. Sci. 19
(2003) 67–75.
[19] The United States Pharmacopoeia, United States Phamacopeial Convention Inc.,
Rockville, 2005.
[20] R.A. Robinson, R.H. Stokes, Electrolyte Solutions, 2nd ed., Butterworths, London,
1968.
[21] European pharmacopoeia, European Pharmacopoeia Commission and Council of
Europe, Maisonneuve, Sainte Ruffine, 2010.
[22] M. del Arco, S. Gutiérrez, C. Martı́n, V. Rives, J. Rocha, J. Solid State Chem. 177
(2004) 3954–3962.
[23] The MERCK Index 13th ed., Merck & Company Incorporated, Whitehouse Station,
New Jersey, 2001.
[24] G. Villain, M. Thiery, G. Platret, Cem. Concr. Res. 37 (2007) 1182–1192.
[25] R.W. Baker, H.S. Lonsdale, Plenum Press, New York, NY, 1974, pp. 15–71.
[26] R.W. Korsmayer, R. Gurny, E. Doelker, P. Buri, N.A. Peppas, Int. J. Pharm. 15 (1983)
25–35.
[27] H. Kim, R. Fassihi, J. Pharm. Sci. 86 (1997) 323–328.