Materials Science and Engineering C 33 (2013) 5071–5078

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Materials Science and Engineering C

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Mg–Al and Zn–Fe layered double hydroxides used for organic species
storage and controlled release
E.M. Seftel a,b, P. Cool b, D. Lutic a,⁎
a
Department of Materials Chemistry, Faculty of Chemistry, Al. I. Cuza University of Iasi, Bvd. Carol I, No. 11, 700506 Iasi, Romania
b
Laboratory of Adsorption and Catalysis, Department of Chemistry, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium

a r t i c l e i n f o a b s t r a c t

Article history: Layered double hydroxides (LDH) containing (Mg and Al) or (Zn and Fe) were prepared by coprecipitation at
Received 5 June 2013 constant pH, using NaOH and urea as precipitation agents. The most pure LDH phase in the Zn/Fe system was
Received in revised form 7 August 2013 obtained with urea and in Mg/Al system when using NaOH. The incorporation of phenyl-alanine (Phe) anions
Accepted 29 August 2013
in the interlayer of the LDH was performed by direct coprecipitation, ionic exchange and structure reconstruction
Available online 6 September 2013
of the mixed oxide obtained by the calcination of the coprecipitated product at 400 °C. The reconstruction
Keywords:
method and the direct coprecipitation in a medium containing Phe in the initial mixture were less successful
Layered double hydroxides in terms of high yields of organic–mineral composite than the ionic exchange method. A spectacular change in
Phenylalanine sample morphology and yield in exchanged solid was noticed for the Zn3Fe sample obtained by ionic exchange
Hybrid organic–inorganic compounds for 6 h with Phe solution. A delivery test in PBS of pH = 7.4 showed the release of the Phe in several steps up
Ionic change to 25 h indicating different host–guest interactions between the Phe and the LDH matrix. This behavior makes
Controlled release the preparation useful to obtain late delivery drugs, by the incorporation of the anion inside the LDH layer.
© 2013 Elsevier B.V. All rights reserved.

1. Introduction
The layered double hydroxides (LDH) are anionic clays consisting of
alternating stacked cationic layers and interlayer compensation anions.
The cationic sheets consist of octahedra containing the divalent and tri-
valent ions in the middle and hydroxyl groups in the corners, assembled
by three bondings with the neighboring octahedra on each side of the
layer. The ratio between the number of cations and OH− groups is 2/1,
so a positive charge appears on the layer due to the presence of trivalent
cations. The interlayer space accommodates the compensation anions
and water molecules, assuring a stabilized layered structure. If a general
formula [M2+1 − xM3+x(OH)2] An−x mH2O is considered for the LDH
composition, the value of x depends on the cation nature, but is usually
comprised between 0.1 and 0.5 [1–3]. The most common anions from
the interlayer are NO− − 2−
3 , Cl , SO4 and CO2−
3 . The ionic exchange can
be quite easily performed and a lot of species as organic, complex and
heteropolyacid anions are introduced in the cationic interlayer, replac-
ing the initial anions [2,3].
The presence of low-toxic, biocompatible cations as Mg2+, Zn2+,
Fe3+ and even Al3+ in the cationic sheets generated the idea to use
these solids as carriers for organic bioactive anionic species. There are
numerous research papers and reviews dealing with the incorporation
of bioactive species in the LDH structure, especially drugs and amino
acids, by different synthesis methods [4–12].
⁎ Corresponding author. Tel.: +40 740 236565; fax: +40 232 201313.
E-mail addresses: elena_seftel@yahoo.com (E.M. Seftel), pegie.cool@uantwerpen.be
(P. Cool), doilub@yahoo.com (D. Lutic).
In the present work, the aim is to prepare Mg–Al and Zn–Fe LDHs and
to study the possibilities to incorporate an organic anion (phenyl-alanine
amino acid anion — noted Phe) between the cationic layers, by using
three different methods: ionic exchange, direct coprecipitation and struc-
ture reconstruction after calcination at 400 °C. The Phe anion is used as a
model compound based on its easy availability and similar behavior with
several organic species used as drug active compounds [13,14].
2. Experimental part
2.1. Synthesis methods
Three different methods were applied for the synthesis of the
hybrids LDH–organic compounds: direct coprecipitation, anionic
exchange and reconstruction of the layered structure from mixed
oxide form in aqueous medium.
Aluminum, magnesium and zinc nitrates and aqueous solution
(50 wt.%) of iron III chloride were used as precursors for all the
coprecipitation procedures, using NaOH and urea as precipitation
agents.
The coprecipitation of Mg–Al–NO3 (noted Mg3Al_CPC) LDHs was
performed at a molar ratio of 3/1 between Mg2+ and Al3+, by direct
reaction with sodium hydroxide 2 M. The salts were individually
dissolved in water, then the solutions were mixed to obtain an overall
cation concentration of 0.4 mol/L. 2 g of sodium carbonate was first
dissolved in 100 mL ultrapure water, then the salts solutions
(500 mL) containing the divalent and trivalent cations and the sodium
hydroxide were added in small drops, under vigorous magnetic stirring

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5072 E.M. Seftel et al. / Materials Science and Engineering C 33 (2013) 5071–5078
at room temperature, to keep a constant pH of 9.5–10; a Hanna HI
991003 instrument was used for pH monitoring. The precipitate sus-
pension was kept under stirring at room temperature for about 1 h,
then heated at 80 °C for 14 h, under magnetic stirring on an oil bath
in a reflux batch. The precipitate was recovered by centrifugation,
washed several times with ultrapure water to remove the adsorbed so-
dium and then dried at 80 °C in open Petri dishes. The resulted solid was
a white, homogeneous, soft powder.
The coprecipitation of Zn–Fe–NO3–Cl was performed in urea medi-
um, at a molar ratio of 3/1 between Zn2+ and Fe3+, in order to set a
slow basic pH achievement at the desired final value [15–20]. Each pre-
cursor was dissolved in ultrapure water and then the solutions were
mixed. Urea was added after dissolving in water, using an amount neces-
sary to establish a 5/1 molar ratio as regarded to the cations. The reaction
vessel was kept under magnetic stirring at 80 °C for 16 h, under reflux.
The direct coprecipitation aiming the incorporation of Phe between
the cationic layers of the LDH was performed in similar conditions as de-
scribed above. The Zn–Fe sample was prepared by using urea as the
precipitation agent, while the Mg–Al sample was precipitated using
NaOH 2 M. The ultrapure water used for the preparation was first
decarbonated by boiling it for 20 min. In order to avoid the contamina-
tion with CO2 from the surrounding air, a continuous low flow of nitro-
gen was bubbled through the reaction medium. The coprecipitation of
Mg–Al–Phe was performed at pH values comprised between 10 and
10.5 and the final value was 10.4. The Phe was added from the begin-
ning in the mixing vessel, dissolved in water slightly alkalinized with
ammonia (pH = 9), in order to ease its solubility. The Zn–Fe–Phe sam-
ple was also prepared in urea medium, at a 5/1 ratio as regarded to the
metals. The coprecipitation time was in both cases 14 h at 80 °C, under
magnetic stirring and nitrogen bubbling.
All the precipitates were recovered by centrifugation, washed
several times with ultrapure water, dried in open Petri dishes at
80 °C and molded to get a fine powder.
The preparation via anionic exchange was performed by stirring 1 g
of LDH powder in 50 mL of Phe solution 0.5 M dissolved in diluted
ammonia to reach the pH value of 9. The exchange time was varied
between 2 and 6 h. The sample codes indicate the ion exchange
time values in hours.
The reconstruction of the LDH structure was performed by contacting
1 g of mixed oxide containing Mg and Al, obtained by the calcination of
the Mg–Al LDH at 400 °C (1 °C/min heating rate), with Phe aqueous so-
lution. The amount of solution was calculated to assure a 3/1 mole excess
of Phe anions as regarded to the initial anions from the solid. The reaction
was performed for 14 h, under magnetic stirring, at 50 °C, under nitro-
gen bubbling. The solids recovery from the latest two procedures was
done by centrifugation and drying at 80 °C in open Petri dishes.
2.2. In vitro release studies
The release test of Phe from the LDH matrices was performed at
37 ± 0.5 °C under continuous stirring at a slow speed of 100 rot/min,
on a tablet obtained at a 4 tf pressure from the powder containing the
highest Phe amount, as shown by the structural analysis. A phosphate
buffer saline (PBS) of pH = 7.4 was used as release medium, imitating
the conditions from the human intestine. A ratio of 1 g solid to
100 mL PBS was used. The measurements of the Phe concentration
were done by UV–VIS spectroscopy on a Shimadzu UV-2401 PC
machine; the absorption maximum of Phe appears at 215 nm. A 2/1 di-
lution of the samples collected at longer times was necessary to remain
in the linearity range of the calibration curve.
2.3. Methods of structural analysis
X-ray diffraction was used as the main method for crystalline phase
identification, evaluation of the crystallinity degree and for the calcula-
tion of the unit cell parameters. The diffraction patterns were obtained
on a Shimadzu D6000 machine, in the range of 2 theta 5–70°, using
CuKα radiation (λ = 1.5406 Å). The unit cell parameters were calcu-
lated with the formula: a = 2d110, c = 3 d003, since the synthesized
solids present a rhombohedral symmetry [2,3].
Scanning electron microscopy (SEM) was used to show the mor-
phology of the samples and highlight the changes occurring especially
during the ionic exchange. A SEM Tescan VEGA II LSH machine was
used in this respect.
The final composition of several samples was determined by elec-
tron probe micro analysis measurements (EPMA).
The thermoanalytical measurements were performed on a Mettler
Toledo TGA/SDTA851e thermobalance. Samples were heated at a heating
rate of 5 °C/min under O2 flow.
Diffuse reflectance infrared Fourier transform spectra (DRIFT) were
measured on a Nicolet 20 DXB FTIR Spectrometer, equipped with a
spectra-tech diffuse reflectance accessory. About 200 scans were taken
with a 4 cm−1 resolution.
3. Results and discussions
3.1. Structural characterization
Phe is an essential aromatic amino acid. It plays a key role in the bio-
synthesis of other amino acids and some neurotransmitters [21]. Its
structural formula is shown in Fig. 1, together with the scheme showing
in detail the experimental routes followed to obtain the hybrid LDH–
organic compounds and the encoding of the samples used from this
point forward.
The structure type identification and phase purity of the samples
were investigated by the X-ray diffraction method. The patterns for
the samples containing Mg and Al, synthesized by different methods,
are displayed in Fig. 2.
The X-ray diffraction patterns indicate the presence of the main
symmetric peaks due to the basal planes (003), (006) and (009)
appearing at 2 theta of 11.4° and 22.8° and 34°, respectively. The
asymmetric reflections, which are less sharp, and are related to the
(102), (015) and (018), (110) and (113) planes, and appearing at
about 34.5°, 39°, 46°, 60 and 62°, are characteristic for LDH rhombo-
hedral structures containing NO− 3 as interlayer anion [22,23]. These
results confirm the presence of LDH structure in all three samples
obtained by different synthesis methods. It is worth to mention
that for these series of samples, no special cautions were taken re-
garding the contamination risk of the interlayer space with CO23 −
ions, resulting from the eventual dissolution of CO2 from the air in
the synthesis medium, while the XRD confirms that the contamina-
tion was absent.
Some extra peaks with lower intensity appear in the case of
Mg3Al_IE_6H and Mg3Al_REC samples. The most intense new peak ap-
pears at 2 theta of 5.56 (d = 15.88 Å), and can be assigned to the
(003) plane of a new formed phase due to the Phe anion hosting in
the interlayer region; a second peak to support this statement would
be a peak corresponding to the (006) plane, positioned at a double 2
theta value, around 11.12°. This is, however, overlapping with the
(003) peak of the native sample. Other peaks, less intense, due to the
low degree of Phe inclusion in the interlayer, indicate that the phenom-
enon is present to a small extent. Indeed, the closer examination of the
Mg3Al_IE_6H XRD pattern shows the presence of specific peaks for a
phase where Phe is the compensating anion. The coprecipitation in
the presence of Phe leads to peaks quite comparable to the Mg3Al_CPC
[22,23] (not shown in this paper).
A decrease in crystallinity is observed for the reconstructed sample
in comparison to the other samples. This may be due to the reconstruc-
tion process, based on a dissolution–recrystallization mechanism. The
X-ray diffraction reflection centered at around 11° (2θ) is also broader
for this sample. Several factors may contribute to the peak-broadening,
e.g. layer disorder or a reduction in the LDH crystallite size. In any case,
 E.M. Seftel et al. / Materials Science and Engineering C 33 (2013) 5071–5078 5073

M(II) = Mg2+ or Zn2+ CH CH COO-

M(III) = Al3+ or Fe3+ Phe: HC C CH2 CH
Phe = phenylalanine CH
CH NH3+
Coprecipitation

NaOH or urea aging

M(II) + M(III) + NO3- M(II)3M(III)-NO3 M(II)3M(III)_CPC
pH = 9.5 - 10 80°C / 14h

NaOH or urea aging

M(II) + M(III) + Phe M(II)3M(III)_Phe M(II)3M(III)_CPC_Phe
pH = 9.5 – 10 80°C / 14h

Ion exchange

M(II)3M(III)-CPC Phe M(II)3M(III)_CPC_IE

Reconstruction (memory effect)

400°C Phe solution
M(II)3M(III)-CPC M(II)3M(III)Ox M(II)3M(III)_REC_Phe
50°C

Fig. 1. Schematic representation of the experimental routes followed to obtain the hybrid LDH–organic compounds.

the XRD pattern is sufficiently well resolved that there is no difficulty in 32.84° and 38.82° [17,24]. Moreover, some peaks assigned to a Fe3O4
distinguishing the layered structure and there is no doubt that the struc- phase can be detected at 30.5°, 35.5° and 42.2° corresponding to the
tural memory effect has been triggered. The extent of compensation of (220), (311) and (400) planes, respectively [25,26].
the interlayer by Phe anions is extremely low, as shown by the low in- For the sample with Phe added in the precipitation medium from the
tensity of the peak located at 2 theta of 5.64°. It indicates that the beginning, Zn3Fe_CPC_Phe, a quite comparable XRD diffraction pattern
phase formed in this case is the meixnerite form, the reconstructed is obtained, except for the much lower crystallinity degree. The Phe
structure having the OH− anions between the cationic layers. ion is not present in the interlayer region at all.
For the case of the Zn–Fe samples, the choice of using urea instead of A spectacular change in the XRD pattern is noticed in the case of the
NaOH as precipitation agent was made in order to minimize the forma- sample prepared by anionic change of NO− −
3 and/or Cl ions by Phe an-
tion of iron oxide and/or hydroxide phases. Urea is widely used for the ions (Fig. 3(a)). The crystallinity degree is much higher, as shown by the
slow release of ammonia in the precipitation medium, allowing the inserted chart and new, very intense peaks appear at 5.54°, 11.08° and
pH value to settle during its decomposition at temperatures higher 16.66°, corresponding to the (003), (006) and (009)/(102) planes, re-
than 60 °C [15–20]. The attempt to obtain a hybrid containing Phe by spectively. These peaks' width is also very narrow in comparison to
simple coprecipitation, e.g. obtaining a Zn3Fe_Phe_CPC sample, was that of the precipitated samples, indicating an important increase of
not successful. The high affinity of CO2−3 ions for the interlayer is very the particle size. The ionic exchange is not complete, as shown by the
high and therefore, due to the CO2 released in the meantime as NH3, remaining peaks of the coprecipitated LDH phase. This observation
the CO2−3 ions were present in the interlayer. It is well known that usu- was further investigated by calculating the encapsulation efficiency
ally in several cases a protection against the contamination with atmo- (EE) based on the thermogravimetric results in relation to the theo-
spheric CO2 is needed [24]. retical anionic exchange capacity (AEC) of the Zn3Fe-layered double
The examination of the XRD patterns of the Zn–Fe samples indicates hydroxide. The anion-exchange capacity (AEC) of the Zn3Fe_CPC sam-
significant differences between the structures of the solids prepared in ple is 2.81 mmol of anion/g, calculated as follows: AEC = x/Mw · 103
different ways, as shown in Fig. 3. The coprecipitated sample Zn3Fe_CPC
displays the peaks corresponding to (003), (006), (101) and (015)
planes specific to the NO− 3 presence in the interlayer at 11.3°, 22.6°, 3000 35000

30000 (003) IE
25000
a
20000
2500
5000 15000

c
[003]

Relative intensity, NC

10000
(006)IE (009)IE
5000

2000 0
4000
Relative intensity, NC

5 10 15 20 25 30 35 40
[006]

[102]

# #
[110]

1500
[113]
[015]

3000 #
b
c
1000
2000 # Fe3O4
NO3-LDH
b
500 a
1000
a
0
0 5 10 15 20 25 30 35 40 45 50 55 60
5 15 25 35 45 55 65 2 Theta, degree
2 Theta, degrees
Fig. 3. XRD diffraction patterns of (a) Zn3Fe_IE_6H, (b) Zn3Fe_CPC and (c) Zn3Fe_CPC_Phe
Fig. 2. XRD patterns of (a) Mg3Al_IE_6H, (b) Mg3Al_CPC_Phe and (c) Mg3Al_REC samples. samples.
5074 E.M. Seftel et al. / Materials Science and Engineering C 33 (2013) 5071–5078
Table 1
Unit cell parameters for the selected samples.
Mg3Al_CPCa Zn3Fe_CPCa
d003, nm 7.824 6.878
d110, nm 1.549 1.531
a, nm 3.099 3.063
c, nm 23.473 23.724
Interlamellar space IS, nma 3.044 2.098
a
Calculated as IS = d003 − 4.78 (the thickness of brucite layer [3]).
(mequiv/g), where Mw and x are the molecular weight and the layer
charge per octahedral unit, respectively [27,28]. The calculated en-
capsulation efficiency is 86%, therefore the amount of the new,
exchanged phase is highly dominantly present in the mixture.
The final composition of the obtained materials was investigated
using the electron probe micro analysis. The EPMA data indicated a
ratio of 3.04 between Zn and Fe in the sample, being very close to
that in the initial precursors' mixture, within the experimental errors.
There is only 0.5% in atomic ratio of chlorine ions in the interlayer
(a ratio of 0.04 between Fe and Cl), indicating a preferential compensa-
tion of the cationic layers charge by the NO− 3 anions from the zinc ni-
trate solution, in line with the d-spacing values corresponding to the
(003) planes in the X-ray diffraction patterns.
The anionic exchange with Phe did not bring significant changes in
the composition of the cationic layers; the Zn/Fe molar ratio is 3.05,
while Cl/Fe ratio remains 0.03. No peaks belonging to crystallized Phe
were observed [21]. We did not find any literature reporting this struc-
tural change, at a very high extent. It means that the behavior is some-
how specific for the Zn–Fe samples.
The XRD data were used to calculate the unit cell parameters and
interlamellar space depth [2,3]. The results are displayed in Table 1.
The last line highlights a strong modification of the interlayer space,
indicating the accommodation of the Phe molecule between the
cationic layers.
The FT-IR spectra of the Zn3Fe_CPC and Zn3Fe_IE_4H samples
(Fig. 4) were compared to literature data [12,21] concerning the IR anal-
ysis of Phe. In the wavenumber range of 3600–2900 cm−1, for the
Zn3Fe_CPC sample, there is a broad peak with a relative maximum
Fig. 4. The FT-IR spectra of (a) Zn3Fe_CPC and (b) Zn3Fe_IE_4H samples (the numbers indicate the band assignments in Table 2).
around 3378 cm−1, due to stretching vibration of OH groups in the
brucite-like layers and the interlamellar water molecules [29]. A band
Zn3Fe_IE_6H at 1381 cm−1 is due to the stretching vibration of the NO− 3 groups in
the LDH interlayer space and another band at 1504 cm−1 is due to
15.882
1.551 the bending vibration of the interlayer water molecules, shifted from
3.103 1620 cm−1 as mentioned in [30].
47.646 For the exchanged sample Zn3Fe_IE_4H, there are several new
11.102
bands. The new bands from the 3200–3350 cm−1 wavenumber range
are present in the Phe spectrum [21], with very low intensities and are
due to NH+ 3 groups. This is an indication that the Phe molecule is pro-
tonated by water molecules and accommodated inside the LDH solid.
Also there are two additional peaks at 3030 and 2908 cm−1, which
can be due to stretching of the aromatic ring of Phe; the stretching is
much intensified by the incorporation of Phe in the interlayer, since
these bands have in the pure Phe relative intensities of only 1–12%
[21,31].
An important change in the spectrum is the appearance of an intense
band at 1624 cm−1. On the other hand, the band at 1561 cm−1 from
Phe, due to COO− asymmetric stretching is much diminished, appearing
as a weak shoulder or possibly overlapping with the band at 1624 cm−1.
This is an indication that there is a strong binding of carboxyl groups
inside the layer and water molecules are also present there. The bands
at 1088, 995 and 755 cm−1 are due to the CH-R rocking, bending and
out-of-plane deformation. In conclusion, the IR information is in line
with the XRD, confirming the Phe incorporation in the interlayer.
A detailed band assessment is shown in Table 2. These shifts of the
band positions in the FT-IR spectra in comparison with the free Phe
[21] are all indicating that the Phe anion is accommodated inside
the interlayer gallery of the LDH phase.
The particle size increase associated with the ionic exchange indi-
cated by the peak narrowing in XRD was confirmed by SEM analysis
(Fig. 5). The particle assembly in long rods involved most of the par-
ticles from the initial powder.
The thermal analysis, namely TG and DTG, was performed for an as-
synthesized sample Zn3Fe_CPC and for a sample exchanged with Phe for
6 h. The temperature range for the analysis was comprised from room
temperature up to 700 °C. The curves are displayed in Fig. 6.
The first weight loss at lower temperatures (40–140 °C) corre-
sponds to the water loss from internal gallery surfaces and the exter-
nal non-gallery surfaces. The second one, at higher temperatures
 E.M. Seftel et al. / Materials Science and Engineering C 33 (2013) 5071–5078 5075

Table 2 pH of 7.4. The XRD analysis indicates that the method allowing to in-
FTIR spectral data assigned to the phenylalanine anion in the Zn3Fe_IE_4H sample. clude a significant amount of Phe in the solid was the anionic exchange
Wavenumber, cm−1 Assignments obtaining the material denoted as Zn3Fe_IE_6H as described in the
previous section. Therefore, the release test of the Phe from the
1 3334 O\H stretching
2 3251 NH+3 asymmetric stretching
Zn3Fe_IE_6H sample is shown in Fig. 7 as a representative sample
3 3030 Stretching of the aromatic ring (C\H str.) in the synthesized series.
4 2958 CH2 asymmetric stretching The Phe release profile in simulated intestinal fluid shows four steps.
5 2908 Stretching of the aromatic ring (C\H str.)
The inset picture in Fig. 7(a) shows the enlargement of the time scale at
6 2865 Stretching of the aromatic ring (C\H str.)
7 1624 COO− asymmetric stretching lower values for a clear observation of the release steps. In the first
8 1561 NH+3 symmetric bending
approximately 2 h, the release of 17% of the intercalated Phe occurs.
9 1322 CH2 wagging Afterwards, a small plateau up to 4 h is observed, followed by another
10 1249 C\CH bending two release steps: a fast increase of the Phe concentration up to 6 h
11 1155 CH2 twisting
and a slow increase of the Phe concentration up to 48 h.
12 1088 C\C\N stretching
13 995 CH2 rocking The LDH-type matrix behaves differently than other drug-loaded
14 910 C\CH bending polymeric matrices. This matrix involves the release of the drug species
15 760 C\C skeletal stretching which begins from the external part of the particle and they reach the
16 755 C\H out-of plane deformation
stagnant layer in a short time. The release of the internal species takes
17 696 C\H out-of plane deformation
18 555 C\CO deformation long [36,37]. Taking into consideration all of the above observations,
19 468 COO− rocking the first release step may be attributed to the release of the Phe mole-
cules adsorbed on the external surface and those intercalated in the
external part of the lamellar structure [38,39].
The release of the Phe from the layered matrix involves the diffusion
(210–260 °C) is due to the dehydroxylation of the brucite-like sheets of the solvent into the interlayer gallery to dissolve the Phe molecules
as well as the decomposition of the interlayer anions (overlap) followed by the diffusion of the dissolved Phe molecules out from the
[31–35]. The major mass loss, 20%, occurs in the temperature range layered matrix. Therefore, the second stage observed as a small plateau
of 200–245 °C in the case of the Zn3Fe_CPC sample. The main volatile in the release pattern may be attributed to the diffusion of the PBS inside
species released from the solid are nitrate anions from the interlayers the layered matrix [35]. Afterwards, the diffusion of the dissolved Phe
and water due to the hydroxyl group condensation. The presence of molecules occurs in a time range of 3 to 6 h (~40%). This profile may
Phe determines a stronger interlayer bonding, leading to the increase be associated with the release of the hydrogen bonded Phe anions locat-
of the temperature where the major mass loss (230–260 °C) and an ev- ed in the internal part of the interlayer gallery of the LDH matrix. Finally,
ident narrowing of the weight loss range occur. the fourth stage up to 48 h can be observed (up to a maximum of 60% at
A clear increase of the mass loss for the case of the exchanged sample the end of the experiment) which may be attributed to the release of the
can be observed at the first sight, from 24% in the case of Zn3Fe_CPC, Phe molecules located in the core of the interlayer gallery as well as
to 58% in the case of Zn3Fe_IE_6H. A detailed examination of the TGA grafted on the brucite-like sheets of the LDH matrix as indicated by
data in the case of the Zn3Fe_IE_6H sample reveals an additional weight the TGA observations.
loss at higher temperatures, e.g. in the range of 400–475 °C, with a In order to investigate the release mechanism of the Phe interca-
concomitant loss of ~2 wt.%. This is an indication that not all of the in- lated into the layered compound, the release data were fitted using
corporated Phe are hosted in the interlayer gallery through hydrogen different diffusion based kinetic models. First, the Peppas' model
bonding, but are also grafted onto the brucite-like layers. equation Mt/M∞ = Ktn (where Mt/M∞ is the fraction of drug released
at time t, and K is a constant) was applied to evaluate the diffusional
3.2. Release test exponent (n) for the maximum of 60% of the release data [35] as well
as the Higuchi kinetic model [38,39].
The Phe release profile was observed for 48 h using a pressed tablet The LDH is a particular matrix due to the fact that it is able to control
of Zn3Fe_IE_6H sample of 0.5 g which was stirred in 50 mL PBS with a the guest release by two processes: i) chemically, due to the selectivity

Fig. 5. SEM images of (a) Zn3Fe_CPC and (b) Zn3Fe_IE_6H samples.

5076 E.M. Seftel et al. / Materials Science and Engineering C 33 (2013) 5071–5078

Fig. 6. TG and DTG curves for the Zn3Fe_CPC and Zn3Fe_IE_6H samples.

towards different anions and ion-exchange mechanisms, and ii) physi-
cally, due to the length of the interlayer galleries [36]. Since an ion-
exchange mechanism is involved when using LDH-type matrices, the
Bhaskar equation was applied in order to evaluate if the diffusion from
the particle to the medium fluid is the rate limiting step [40]. Finally,
the first order kinetic was investigated. Each release step was evaluated
using the above-described kinetic models and the data are presented in
Table 3.
The release profiles show lower R2 values for n = 1 meaning that
the drug release rate is a function of time. For the first stage of release

Fig. 7. The release profile of the Phe from Zn3Fe_IE_6H sample plotted as (a) total %Phe released over time, (b) 1st release step re-plotted against time (best fit at n = 0.8), and (c) and
(d) 3rd and 4th release steps re-plotted against time0.65 (best fit after Bhaskar kinetic model), respectively.
 E.M. Seftel et al. / Materials Science and Engineering C 33 (2013) 5071–5078 5077

Table 3
Kinetic model fitting of the release data.

Equations 1st step 2nd step 3rd step 4th step

Mt/M∞ = Ktn n = 1 (zero order) y = 0.0625x + 0.0086 nd y = 0.0984x − 0.1836 y = 0.5619x + 37.387
R2 = 0.9903 R2 = 0.943 R2 = 0.9251
n = 0.9 y = 0.0697x + 0.0051 nd y = 0.1282x − 0.2365 y = 0.8549x + 36.239
R2 = 0.9963 R2 = 0.952 R2 = 0.9386
n = 0.8 y = 0.0776x + 0.0013 nd y = 0.169x − 0.3027 y = 1.3113x + 34.805
R2 = 0.9994 R2 = 0.9473 R2 = 0.9507
n = 0.7 y = 0.0862x − 0.0026 nd y = 0.2264x − 0.3878 y = 2.0344x + 32.958
R2 = 0.9983 R2 = 0.9493 R2 = 0.9615
n = 0.6 y = 0.0955x − 0.0065 nd y = 0.3094x − 0.5013 y = 3.2081x + 30.486
R2 = 9907 R2 = 0.9513 R2 = 0.9709
n = 0.5 (Higuchi) y = 0.1051x − 0.0101 nd y = 0.4349x − 0.6603 y = 5.1806x + 27.004
R2 = 0.9736 R2 = 0.9531 R2 = 0.9789
−kt
Mt/M∞ = 1 − e Ionic exchange (Bhaskar) y = 0.0996x − 0.0067 nd y = 0.3726x − 0.6811 y = 0.509x + 0.3448
R2 = 0.9916 R2 = 0.9575 R2 = 0.9808
Mt/M∞ = 1 − e−kt First order y = 0.0688x + 0.0073 nd y = 0.139x − 0.3193 y = 0.0113x + 0.4549
R2 = 0.9942 R2 = 0.9516 R2 = 0.9474

(17% Phe released), the best linearity was obtained for n = 0.8 demon-
strating that the diffusion (non-Fickian type) from the particle to the
medium fluid is controling the drug release [35].
Examinating the correlation coeficient (R2) values in Table 3, the
mechanism of the 3rd and 4th stages of drug release differs from the
1st stage. The best linearity was observed for both release stages when
using the Bhaskar equation. The higher R2 values obtained using the
Bhaskar equation (higher than those of Higuchi kinetic model) suggest
that the Phe diffusion through the LDH is not passive but strictly con-
trolled by the matrix.
At pH 7.5 in PBS both H2PO− 4 and HPO4
2−
anions are generated that
are able to intercalate into the layered matrix. Therefore, the Phe release
in the observed 3rd and 4th release steps may be attributed to an ion-
exchange mechanism.
By comparing the R2 values obtained by fitting the release data using
the Bhaskar model with the first order kinetic model, it may be observed
that the Phe release depends on a diffusion mechanism from the particle
to the medium fluid and not on the drug concentration in the LDH
matrix.
Overall, the release profile of the Phe molecules from the layered
matrix may be well correlated with the obtained results from the
structural characterization of the obtained samples. These are all in-
dicating different host–guest interactions induced by the intercala-
tion or grafting of the Phe anions inside the LDH matrix.
The amount of Phe released in 48 h reaches 0.16 g/g tablet, which
means about 60% from the amount deduced from the thermal analysis.
This behavior was previously reported by other researchers in the case
of drug-intercalated into LDH-type matrix [41]. Ambrogi et al. [41]
attributed this incomplete release of the drugs to a grafting reaction
of the H2PO− 4 anions to the hydroxylic lamellae of the LDH matrix.
In this strongly bond form, the phosphates are no longer movable
and can obstruct the exit of the remaining intercalated drug anions.
These results suggest that the LDH-type materials could be biocom-
patible inorganic hosts for biomolecules and successfully used for the
delayed delivery of drugs.
4. Conclusions
The synthesis of several Mg3Al, Zn3Al and Zn3Fe layered double
hydroxides was performed by coprecipitation, using NaOH and urea
as precipitation agents at constant pH values. The choice of these cat-
ions in the layers was based on their biocompatible character and the
possibility of their use in drug formula.
The introduction of Phe (used as a model organic molecule) between
the layers was approached using three different methods, i.e. the
introduction of Phe in the initial precipitation medium together with
the precursor salts, the anionic exchange and the LDH reconstruction
of the mixed oxide in Phe aqueous solution.
The introduction of Phe on the Zn3Fe samples was more successful
than on the Zn3Al ones. The best results in terms of Phe incorporation
in the LDH were obtained by ionic exchange, while an important
increase of the crystallinity degree of the sample was observed. Also
important increases of the particle size and morphology changes were
observed.
The thermal analysis of the exchanged LDH and the release test in
PBS solution indicated that large amounts of Phe were incorporated in
the sample during the ionic change, the ratio between the trivalent cat-
ion and the Phe being 2.11. These results suggest that the ionic exchange
on Zn3Fe–LDH leads to the development of a solid rich in organic anions,
which could be used for the delayed delivery of drugs.
Acknowledgments
The financial support from MNT Era Net Project No. 09044 SootSens
II and MNT 7-028/2010 granted by CNMP — Romania is greatly ac-
knowledged. E.M. Seftel greatly acknowledges the Fund for Scientific
Research — Flanders (FWO — Vlaanderen) for financial support.
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