Journal of Controlled Release 169 (2013) 28–39

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Journal of Controlled Release

journal homepage: www.elsevier.com/locate/jconrel

Review

Layered double hydroxides as drug carriers and for controlled release of

non-steroidal antiinflammatory drugs (NSAIDs): A review
Vicente Rives ⁎, Margarita del Arco, Cristina Martín
GIR-QUESCAT, Departamento de Química Inorgánica, Universidad de Salamanca, 37008 Salamanca, Spain

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

Article history: Non-steroidal anti-inflammatory drugs constitute one of the groups most widely currently used, but show several
Received 14 February 2013 problems for administration due to low solubility and delivery control. For this reason, several matrices have been
Accepted 30 March 2013 tested to support them in order to overcome these drawbacks. Among them, layered double hydroxides have been
Available online 11 April 2013
used in recent years. The aim of this review is to update the current knowledge and findings on this hybrid system,
namely, layered double hydroxides intercalated with different NSAIDs. The basic nature of the matrix introduces
Keywords:
Layered double hydroxide
an additional advantage, i.e., to decrease ulceration damages. We have focused our review mostly on the prepara-
Drug intercalation tion procedures, as these control, define and determine the performance of the systems in vitro and also in living
Controlled delivery organisms.
Organic–inorganic nanohybrids © 2013 Elsevier B.V. All rights reserved.
NSAID

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
2. Intercalation and controlled release of non-steroidal antiinflammatory drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
3. Conclusions and further studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

1. Introduction
Layered double hydroxides (LDHs) constitute a broad family of
lamellar solids which in the last decades have deserved an increasing
interest because of their applications in different fields [1,2]. They are
sometimes named as anionic clays due to the similarities shared with
cationic clays, or hydrotalcite-like materials, as derived from the natural
hydroxycarbonate of Mg and Al discovered in Sweden in 1842. Their
properties have been reviewed in recent years in different books and
monographs [2–4].
Their structure is similar to that of brucite, Mg(OH)2, where hydroxyl
anions are hexagonally close packed and magnesium cations are filling
all octahedral sites every two layers; consequently, edge-sharing octahe-
dra of magnesium cations are surrounded by six hydroxyl groups
⁎ Corresponding author. Tel.: +34 923 294489; fax: +34 923 294574.
E-mail address: vrives@usal.es (V. Rives).
forming infinite sheets; these layers are stacked on top of each other
and held together by weak hydrogen bonds. Some of the cations can be
isomorphically substituted by others with similar size, but with higher
valence, developing a positive charge in the sheets. Charge balance is
recovered by intercalating anions between the layers, Fig. 1, where
water molecules also exist. The brucite-like layers can be stacked in
different ways, leading to different structures [5], the most typical ones
being rhombohedral (3R symmetry) and hexagonal (2H symmetry).
Divalent/divalent isomorphical substitution is also possible, as well as
the trivalent/trivalent one; the most commonly found cations in the
layers are Mg2+, Zn2+, Co2+, Ni2+, Cu2+ or Mn2+, and Al3+, Cr3+,
Co3+, Fe3+, V3+, Y3+ or Mn3+. With the exception of Al3+ (0.50 Å),
all these elements have similar ionic radii as that of Mg2+ (0.86 Å)
thus accounting for the isomorphic substitution without a substantial
distortion of the structure. Other LDHs containing monovalent and tetra-
valent metal cations have been also synthetised [6–9], as well as systems
containing three or even four different metal cations [10–17].
There are no strict limitations to the nature of the interlayer anions,
and systems with many different anionic species are known: simple

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 V. Rives et al. / Journal of Controlled Release 169 (2013) 28–39
described in the literature [37–39]. Selection of one or another greatly
depends on the specific material to be prepared. The most widely
used are the following:
Fig. 1. Idealised structure of a layered double hydroxide, with interlayer carbonate an-
ions.
Reprinted from Coordination Chemistry Reviews, Vol. 181, V. Rives and M.A. Ulibarri,
Layered double hydroxides (LDH) intercalated with metal coordination compounds
and oxometalates, pp. 61–120, Copyright (1999), with permission from Elsevier.
inorganic anions (carbonate, nitrate, halides, etc.) [18], organic anions
(terephthalate, acrylate, lactate, etc.) [19–21], coordination compounds
[22,23], polyoxometalates [24–28], biomolecules such as nucleoside
monophosphates (AMP, CMP, GMP or ATP) or even DNA fragments
[29–31] have been successfully intercalated.
The only restriction concerning the nature of the anions to be inter-
calated makes reference to their size/charge ratio, as large anions with
low charge are unable to balance properly (homogeneously) the posi-
tive charge in the layers. Kwon and Pinnavaia [32] claimed that
polyoxometalates (POMs) with the Keggin structure with a charge
less than −4 are unable to be intercalated between brucite-like layers
will be outlined below.
with a M2+/M 3+ molar ratio close to 2, since these molecules are not
spatially able to balance the host layer charge.
The M2+/M3+ molar ratio usually ranges between 2 and 4, both in all
natural occurring LDHs and in most of the synthetic ones. The synthesis
of these sorts of solids with molar ratios outside this range has been
sometimes claimed [33], although it is difficult to know the accurate
layer composition, since for such extreme ratios formation of dispersed
amorphous oxides cannot be discarded.
These materials have deserved a great interest in recent decades
in different fields because of their specific properties, namely:
- Acid–base properties. LDH solids are basic materials with surface
basic hydroxyl groups; the basicity of carbonate-intercalated
LDHs has been related to the electronegativity of the layer cations
[34,35]. The mixed oxides formed upon thermal decomposition of
LDHs are more basic than the original LDHs, due to the presence of
strong oxide basic sites. Moreover, the intercalation of different
species can give rise to the development of acid sites providing
systems with unique acid–base properties.
- Homogeneous mixtures containing well dispersed elements in layer
and interlayer domains in a wide range of composition and ratios
can be prepared, allowing to tailor the properties of these solids.
- The so-called memory effect [32,36], i.e., the ability to recover their
original layered structure when mixed oxides, previously obtained
upon calcination of some LDHs at moderate temperatures (usually
29
not exceeding 500 °C) are put in contact with solutions containing an-
ions.
- A good anion exchange capacity (AEC), associated to the non-divalent
layer cation, usually higher than that shown by cationic clays, and
ranging between 2 and 4 mEq/g.
Many different synthetic procedures to prepare LDHs have been
- Coprecipitation, consists of the slow addition of a solution containing
salts of the metal cations in the required molar ratio into a reactor
containing water; simultaneous addition of an alkaline solution
keeps the pH within a selected, narrow range, to precipitate the
mixed hydroxide.
- Anionic exchange is largely applied to obtain LDHs intercalated with
anions of different nature. Strictly speaking this is not a proper syn-
thesis method, but a post-synthesis modification, since it is necessary
to have a LDH precursor, usually a carbonate-free LDH. The feasibility
of exchanging the anions in LDHs depends on the electrostatic inter-
actions between the layers and the interlayer anions. The equilibrium
constants increase as the ionic radius of the anion decreases. The
rate-determining step is the diffusion of the in-going anions within
the interlayer. Exchange reactions are usually carried out by stirring
the LDH precursor in a solution containing an excess of the anion to
be intercalated; ultrasounds have been also applied to speed up the
exchange process [40].
- The reconstruction method is based on the above mentioned memory
effect [32,36]. First a LDH with the desired metal cations in the
brucite-like layer, commonly intercalated with carbonate (which is
released as CO2) is first prepared. Then the solid is calcined at or
just below 500 °C (preferable under dynamic inert gas atmosphere
to remove CO2) [41,42]. Finally, the mixed oxide formed is stirred
in an aqueous solution of the anions to be intercalated, usually in a
concentration several times higher than that required for a stoichio-
metric reaction.
- Hydrothermal and microwave treatments have been applied to pro-
cess LDHs, improving the crystallinity and other properties of the
LDHs, especially upon microwave treatment [43–51].
The fields of applications of LDHs are very broad. Only a few of them
- Materials Science. LDHs are used as additives in polyvinyl chlo-
ride polymer (PVC), as they improve its strength and retard
darkening of the polymer [52,53]. LDHs enhance the mechanical
properties of polymer matrices and may provide them with
other properties such as colour [54], flame retardant [55,56] or
barrier effect [57], and others [58,59]. Hydrotalcite-type mate-
rials have been used as electrode surface modifiers. They are
more stable under high temperature and oxidizing conditions
than organic polymers [60,61].
- Water decontamination. The large AEC together with the memory
effect exhibited by hydrotalcite-type solids, make them good adsor-
bents for the removal of harmful species in anionic form; hydrotalcites
and their calcined products can be used at pH values close to those at
which pollutants are usually found in the environment [62]. Layered
double hydroxides were proposed as adsorbents for the capture of
inorganic anions such as arsenate, chromate or phosphate from
waste water [63–65], and in recent years their use has been extended
also for removal of organic toxic species, such as phenolic compounds,
pesticides or even nuclear residues. This issue has been recently
reviewed [66].
- Separation processes. O'Hare and Lotsch [67] have reported the use of
these materials for separation or purification of isomeric com-
pounds, due to the differences of affinity shown by the isomers for
the LDH. The intercalated isomer can be recovered by treatment
30 V. Rives et al. / Journal of Controlled Release 169 (2013) 28–39
with an aqueous carbonate solution, due to the strong affinity of
carbonate for LDH materials; the material can be regenerated
by calcining the carbonate-intercalated solid and hydrating the
resulting product.
- Catalysis. LDHs are very widely used in catalysis, as they can include
a wide number of elements homogeneously dispersed with con-
trolled proportions, thus allowing the synthesis of tailored catalysts
[68–70]. Hydrotalcites can be used in heterogeneous catalysis as
synthesised [71], as catalyst supports [72,73] and as catalyst precur-
sors. Oxides prepared by calcination of hydrotalcites show wide
compositional ranges, homogeneous dispersion of the elements,
preserved even after moderate thermal treatments or reduction,
high specific surface areas (100–130 m 2/g) or memory effect,
making them more attractive than other oxides obtained through
conventional methods. They have been used in basic catalysed
reactions and to prepare fine chemicals and intermediates [74].
Other reactions studied include oxidative steam reforming of meth-
anol for selective production of hydrogen for fuel cells [75], as seeds
for the catalytic synthesis of carbon nanotubes [17], gas phase hy-
drogenation of acetonitrile [76] and selective hydrogenation of acet-
ylene to ethylene [13,14]. Catalysis by LDHs has been reviewed by
Jacobs et al. [77] and more recently by Centi and Perathoner [78],
and basic catalysis processes by LDHs have been also summarised
by Tichit and Coq [79] and Figueras [80] for several reactions. The
application of LDHs with intercalated polyoxometalates in different
catalytic processes has been recently reviewed by some of us [81].
- Medicine. LDHs are able to intercalate biologically-active molecules,
a property which has opened their applications in Medicine and
Pharmacy. Due to their high adsorption ability, they are used in
cosmetics to remove inflammatory exudates, as found in acne
vulgaris, to encapsulate organic molecules, or for protection
against solar damage of the skin, providing as well protection
against degradation by light, heat or oxygen of labile molecules.
For instance, p-amino benzoic acid intercalated in Mg, Al or Zn,
Al hydrotalcites avoids skin reactions such as irritation, urticaria,
contact dermatitis, etc., avoiding degradation to carcinogenic
nitrosamines and extending its photostability, and increasing
the protection in the UV-A range [82]. No cytotoxic results
were found when doses lower than 100 mg/kg were injected in
Sprague–Dawley mice [83,84]; the safety profile of LDHs and
their biocompatibility have led to the use of LDH–DNA hybrids for
gene transfer and storage [85–89]. LDHs have been also used as ma-
trices to store active principles with cytotoxic activity [90–95]. Due
to their low price, stability, versatility and adsorbing ability, LDH-
biosensors are also being developed to immobilise enzymes for
selective detection of molecules such as urea [96–99], ascorbic acid
[97], cyanide [100], nitrite [101], etc. They have been also used for
treatment of peptidic ulcers [102,103]. On comparing different
antacids, it has been shown that hydrotalcites show a larger
neutralisation capacity than conventional antacids and a prolonged
buffer effect in an optimum pH range [104,105]; no dangerous in-
crease of aluminium levels on serum was observed when using
LDHs [105]. Hydrotalcite can be found in different commercial
drugs, such as Talcid© or Almax©. MgAl-LDHs have been also used
to adsorb intestinal phosphate to prevent hyperphosphatemia [106].
Hydrotalcite-type materials have been also proposed for the con-
trolled release of intercalated drugs. LDHs have the advantage of ease
of preparation, low cost, good biocompatibility, low cytotoxicity, and
full protection of the loaded drug. It has been reported that drug inter-
calation into LDH matrices does not only reduce stomach irritation but,
in some cases, an increase in drug solubility is also observed [107–110].
Choy et al. [111] proposed to use LDH materials as non-viral vectors for
DNA release inside the cell. The ion exchange capability of LDHs allows
encapsulating functional negatively charged biomolecules such as anti-
sense DNA to form bio-LDH nanohybrids, a system where the hydroxide
layers protect the intercalated molecules from degradation: once the
LDH–DNA hybrids have entered into the cell through endocytosis, the
hydroxide layers are dissolved in the lysosome, with a slightly acid
pH, and the encapsulated biomolecules are released inside the cell.
The use of these supports or matrices aims to improve the release
of NSAIDs whichever the clinical stage of the patient or disease, as
with its use we will be able to maintain high, constant levels of the
drug because of an improved pharmacokinetics behaviour; as a result,
dosage will be more easily improved and the dosing intervals could
be expanded.
In this review we collect the information published, roughly from
2000, on the intercalation of non-steroidal antiinflammatory drugs
(AINEs) in different layered double hydroxides, as well as their con-
trolled release. This is the family of drugs in which insertion in and
controlled release from LDHs have been most widely studied recently.
We concentrate our efforts on the experimental procedures, as it is
clearly concluded from the literature here cited that minor changes
in the experimental procedures may lead to important differences
in the performance of these systems. On preparing this report, we
have put together those studies concerning a given family of drugs
for a specific illness or symptom.
One of the first reviews on this subject was published by
Costantino and Nocchetti in 2001 [102], and some other studies
have appeared [112,113], highlighting the relevance of the subject,
and the need for further studies, both fundamental and applied.
Khan and O'Hare [114] published in 2002 a short review on the inter-
calation chemistry of LDHs, where they stressed the promising future
of these systems, in particular the work on the intercalation of biolog-
ically active guests, foreseeing “… that LDHs will move from being
used as simple low-cost ion exchange materials to be used as part
of a sophisticated drug or gene delivery system in patient care or
therapy”; a clear statement which ten years after has been demon-
strated to be true. Xu and Lu [87] reviewed the use of LDHs as cellular
drug delivery agents; these authors concluded that in addition to the
huge information then available on the structure and preparation
procedures of LDHs, as well as the first works on their ability to inter-
calate biomolecules, studies about the interaction of LDHs and cells
were still lacking, and need further exploration; a similar conclusion
was reached in a subsequent review on the same specific subject
[115].
2. Intercalation and controlled release of non-steroidal
antiinflammatory drugs
Non-steroidal antiinflammatory drugs (NSAIDs) are aromatic or-
ganic compounds with easily ionizable carboxylic groups, thus permit-
ting their intercalation as anions between the layers of LDHs. Most of
these compounds, however, are scarcely soluble in water, thus limiting
their dissolution and absorption by living organisms. On intercalation of
NSAIDs in inorganic matrices, such as hydrotalcite, their solubility is
increased, and their controlled release is also possible, while negative
effects on the gastrointestinal tract are simultaneously diminished.
Fenbufen is used to improve the symptoms of arthritic rheumatism
and osteoarthritis, and is also applied for treatment of gout; however,
its use is limited because of its frequently observed negative effects on
the gastrointestinal tract and the central nervous system and because it
decreases the concentration of leucocytes and increases aminotransfer-
ase. Controlled delivery of this drug may, however, decrease significantly
these systemic negative effects.
Evans et al. [116] have intercalated fenbufen in Mg, Al and Al, Li
hydrotalcites by coprecipitation from aqueous solutions of the metal
nitrates in a basic solution of the drug. These authors have pointed out
that the intercalation process depends on the chemical composition of
the hydrotalcite and the pH of the reaction medium. If the reaction is
carried out at pH 8 a thermally stable phase is obtained; however,
when the reaction is carried out at pH 13 the interlayer spacing is larger,
 V. Rives et al. / Journal of Controlled Release 169 (2013) 28–39
and these authors have claimed formation of a bilayer of intercalated
molecules weakly bonded to the brucite-like layers. Release of fenbufen
from hydrotalcite was studied at pH 7.8, as fenbufen is only dissolved
and completely absorbed at this pH value. Release from the Al, Li sample
is very large and fast in the initial stages of the process (10 min) and
reaches an almost constant release level after 20 min. The maximum
amount of released fenbufen is 40% of the initially intercalated amount.
Release from the Mg, Al sample is also very fast during the first 15 min,
but significantly slower afterwards; it increases linearly after the initial
step, reaching ca. 59% of the initially adsorbed amount after 120 min
release. These results indicate that the LDH-Mg, Al-fenbufen system is
more effective than the LDH-Al, Li-fenbufen system, and suggest that
the former system can be used for controlled release of this drug.
Del Arco et al. [117] have studied also the intercalation of fenbufen in
Mg, Al and Mg, Al, Fe hydrotalcites prepared following three different
routes, namely, coprecipitation, ion exchange from hydrotalcites with
chloride anions in the interlayer, and reconstruction from a starting
hydrotalcite containing carbonate, but calcined at intermediate temper-
atures to yield a mostly amorphous mixture of metal oxides. According
to these authors, fenbufen is effectively intercalated between the layers
of the Mg, Al system following any of these three methods, although
more than a single crystalline phase is obtained; element chemical
analysis data suggest the presence of small amounts of chloride or
carbonate in the interlayer, where they are required for an electric
balance of the solid. However, when using the Mg, Al, Fe matrix the
drug is intercalated only by coprecipitation or ion exchange, but not by
reconstruction. The sample prepared by ion exchange also contains
small amounts of chloride as an interlayer impurity. From the value of
the interlayer spacing, it is concluded that the drug molecules form a
bilayer, somewhat tilted within the interlayer, with the carboxylate
groups pointing towards the brucite layers. These authors have also
studied the effect of hydrotalcite (well as an additive or as a hosting
matrix) on the solubility of fenbufen at different pH values. They find
that the presence of Mg, Al-LDH as an additive increases the solubility
by 51, 62, and 21%, respectively, at pH 1.2, 4.5, and 6.8; the increases
were 128, 99, and 98% of intercalated fenbufen when the LDH was
used as a matrix. Studies on the release of fenbufen from the Mg,
Al-LDH and Mg, Al, Fe-LDH systems show that the dissolution rate is
slower when fenbufen is intercalated: while 2 h is required for a total
release from the Mg, Al matrix, only 93% is released from the Mg, Al, Fe
matrix in a slower process. The presence of a residual amount of non-
released fenbufen in the solid matrix is confirmed from analysis of
the solid residues after the release studies: two different residues
are obtained from sample Mg, Al, Fe-LDH-fenbufen; a dense LDH-
phosphate (from the buffer used) phase, which precipitates at the
bottom of the reaction flask, while the other remains floating and corre-
sponds to the unreleased phase. However, only a single phase, corre-
sponding to the LDH-phosphate, is obtained from the Mg, Al matrix.
Evans et al. [118] have studied the release of fenbufen from LDH
systems covered with a Eudragit S-100® film; only 67% of the initial
amount of drug is released, suggesting that the interaction between the
carboxylate groups of the polymer and the surface of the LDH crystallites
inhibits the release of the drug and the dissolution of the polymer.
However, in similar studies carried out by del Arco et al. [117], where
the samples are covered by simple dispersion and immobilization in
microspheres, total release of the intercalated drug is observed; disper-
sion is not enough for a total effective covering, while preparation of
microspheres guarantees a total covering of the particles, suitable for
delayed colonic release of the drug.
O'Hare et al. [119] have intercalated naproxen, diclofenac, gemfibro-
zil, 4-biphenylacetic acid, ibuprofen, 2-propylpentanoic acid and
tolfenamic acid in an Al, Li hydrotalcite by ion exchange at 60 °C,
starting from a sodium salt of the drug and a hydrotalcite containing
chloride as the interlayer anion. From the height of the interlayer
space measured by PXRD, these authors conclude that the drug mole-
cules are located in the interlayer forming bilayers. The amount of
31
intercalated drug was determined by ion exchange of the drug with car-
bonate and by acid treatment with aqueous HCl to dissolve the
hydrotalcite crystallites, the drug precipitating in its acidic form. Release
studies carried out at 37 °C with a phosphate buffer and at pH 4 or 7
indicate that, except for gemfibrozil, for which release is identical at
both pH values, release is faster at pH 4 than at pH 7 for all other
drugs tested; the time needed for release of 50 and 90% of the initial
amount of drug is reported.
Duan et al. [120] have intercalated naproxen by ion exchange in a
Mg, Al hydrotalcite containing nitrate in the interlayer, at pH 8 and
70 °C under a nitrogen atmosphere (to avoid carbonation), and the
stability of the host–guest composite has been studied following differ-
ent techniques. According to these authors, the experimental conditions
during exchange allow a complete nitrate/naproxen exchange, although
a small contamination by carbonate cannot be avoided. From PXRD
experiments, the basal spacing corresponds to a gallery height of
1.86 nm, with the naproxen molecules located with the naphthalene
double ring perpendicular to the brucite-like layers and the carbox-
ylate groups pointing alternatively to the top and bottom layers
forming an intercalated monolayer; water molecules are located be-
tween the naproxen and the brucite-like layers (Fig. 2).
FT-IR spectroscopy, PXRD and thermogravimetric analysis are ap-
plied to check the stability of this system, and the results are com-
pared to those measures for pure naproxen; intercalation increases
the thermal stability of naproxen, as decomposition starts at 250 °C
while bulk naproxen decomposes at 170 °C.
Berber et al. [121] have intercalated naproxen in a Mg, Al hydrotalcite
and have studied the effect of the inorganic matrix on the drug solubility
at pH 2 (although under this strongly acidic condition dissolution of the
layers is strongly expected). The LDH–drug systems were prepared by
coprecipitation, by adding the metal chlorides solution on a naproxen
solution at pH 8, and also by reconstruction, starting from a calcined
carbonate sample, at pH 8 in nitrogen flow at 80 °C. According to these
authors, the coprecipitation method is better than the reconstruction
one, as the amount of naproxen fixed in the interlayer space was 52%
following the first method, but merely 23% by reconstruction; this poor
performance of the last sample can be due to the simultaneous
(and competitive) presence of naproxen and carbonate in the reac-
tion medium; actually, the PXRD diagrams show the major presence
of the LDH-carbonate phase, with only weaker diffraction maxima
due to the LDH-naproxen phase. These differences can be also concluded
from the thermogravimetric study reported, where the mass loss is
much larger in the sample prepared by coprecipitation, due to the com-
bustion of a larger amount of naproxen in this sample. From the position
of the basal maxima in the PXRD patterns, these authors have proposed
that naproxen molecules are located perpendicular to the brucite-like
layers, with the carboxylate groups in a staggered interdigitated shape.
Intercalation in this matrix leads to an important increase of naproxen
solubility, from 8·10 − 3 to 26·10 − 3 g/L in simply 1 min, and from
30·10 −3 to 146·10 −3 g/L after 1 h, on comparing the values for pure
and intercalated naproxen.
Del Arco et al. [122] have intercalated naproxen in a Mg, Al
hydrotalcite following three different routes, namely (a) ion exchange
from the LDH in the nitrate form, (b) reconstruction, from a calcined
carbonate LDH, and (c) coprecipitation, by addition of an aqueous solu-
tion of the metal cations to a basic solution of naproxen. The drug load-
ings were rather similar for the exchange (44.2%) and coprecipitation
(46.5%) samples, but somewhat lower (38.4%) for the reconstruction
sample, probably due to a minor contamination by carbonate, arising
from incomplete removal during calcination or carbonation during
preparation of the sample. Such contamination is evident from the
PXRD patterns, where maxima due to the LDH-carbonate phase are
undoubtedly recorded, and also from the 13C CP/MAS NMR spectra,
where a peak at 170 ppm due to carbonate is recorded. The 13C CP/
MAS NMR spectra of the other two samples are similar to that for
the bulk drug, with only minor shifts in the positions of the signals,
32 V. Rives et al. / Journal of Controlled Release 169 (2013) 28–39
Fig. 2. (A) Structure of naproxen; (B) schematic representation of the possible arrange-
ment for naproxen/LDH.
Reprinted from the Journal of Solid State Chemistry, Vol. 177, M. Wei, S. Shi, J. Wang, Y. Li, X.
Duan, Studies on the intercalation of naproxen into layered double hydroxide and its ther-
mal decomposition by in situ FT-IR and in situ HT-XRD, pp. 2534–2541, Copyright (2004),
with permission from Elsevier.
due to the ionic state of the drug upon intercalation. The dissolution
rate of naproxen intercalated in the Mg, Al-LDH [123] or the Mg, Al,
Fe-LDH system [124] has been also studied by these authors, and the re-
sults have been compared with dissolution results for pure naproxen
and for mixtures of naproxen and LDH-carbonate. The dissolution pro-
files of these two last systems are rather similar to each other, while
the dissolution rate is much slower when the drug is intercalated in
any of both matrices. Both the dissolution rate and the total amount of
released drug are larger from the Mg, Al-LDH than from the Mg, Al,
Fe-LDH one (Fig. 3).
The data can be fitted to an order 1 process and also to the Weibull
model [125], with an important role played by interparticle and
intraparticle diffusion in the Fe-free sample, but only interparticle diffu-
sion for the Mg, Al, Fe-LDH system.
The intercalation of naproxen in a Zn, Al-LDH system has been
studied by Hou and Jin [126]. These authors prepared their samples by
contacting solutions with different concentrations of the drug with a
given amount of Zn, Al-LDH, well with chloride or nitrate in the
interlayer space, and studied the effect of different factors, namely,
contact time, composition of the matrix, charge density, specific surface
area of the LDH sample, and pH of the solution, on the total amount of
intercalated naproxen and on its release rate. According to these
authors, the time required to reach the adsorption equilibrium is
160 min, whichever the specific LDH used, and the adsorption
isotherms can be fitted to a Langmuir model. The monolayer capacity
Fig. 3. Naproxen release evolution: (triangle) drug, (circle) physical mixture, (square)
intercalated drug.
(Left) Mg, Al-LDH, modified from Microporous and mesoporous materials, Vol. 130, D.
Carriazo, M. Del Arco, C. Martín, C. Ramos and V. Rives, Influence of the inorganic ma-
trix nature on the sustained release of naproxen, pp. 229–238, Copyright (2010), with
permission from Elsevier; (right) Mg, Al, Fe-LDH, modified from Applied Clay Science,
Vol. 42, M. Del Arco, A. Fernández, C. Martín, V. Rives, Release studies of different NSAIDs
encapsulated in Mg, Al, Fe-hydrotalcites, pp. 538–544, Copyright (2009), with permission
from Elsevier.
(mmol m −2), as calculated from the Langmuir fitting, increases as the
charge density of the LDH does, due to a large adsorption of naproxen,
much larger for the chloride-containing samples than for the carbonate-
containing samples, but decreases when the pH is increased. The release
rate decreases when the charge density of the structure is increased,
probably because the large electrostatic interactions between naproxen
anions and the hydroxyl layers inhibit the exchange between naproxen
anions and those originally existing in the reaction medium, HPO42− and
H2PO4−, from the buffer solution.
Intercalation of flurbiprofen by coprecipitation and reconstruc-
tion in a Mg, Al-LDH has been studied by Berber et al. [121]. The sol-
ubility at pH 2 was compared to that for the pure, unintercalated
drug. The findings reported by these authors demonstrate that a
single crystalline phase is obtained by the coprecipitation method,
while by reconstruction the major phase contains carbonate anions
in the interlayer. The amount of intercalated flurbiprofen corre-
sponds to 49 and 21%, respectively, for the samples prepared by
coprecipitation and reconstruction.
The solubility of this hardly soluble drug is markedly increased
upon intercalation. The initial dissolution rate is rather slow, due to
the electrostatic interactions between the drug and the LDH layers,
but after 4 min the solubility is four times larger when the drug is in-
tercalated than when it is not; it reaches a value five times larger after
5 h and then it reaches a constant value for pure flurbiprofen,
720 mg/L after 24 h (Fig. 4).
The improvement in naproxen and flurbiprofen solubilities and
their dissolution rates depends on the properties of the LDH–drug
composites; the high molecular arrangement of the drug within the
interlayer space prevents its recrystallization, while the hydrophilic
nature of the LDH–drug composites favours water penetration into
these composites, as well as the acidic medium in which the protons
attack and destroy the layered materials, leading to the drug release.
Perioli et al. [127] have studied the effect of the Mg, Al LDH on the
biopharmaceutical properties of flurbiprofen. The drug was inter-
calated by ion exchange at 60 °C for 7 days in a water–alcohol
solution. Solubility studies at pH 1.2 (where the layered structure
has been completely destroyed, releasing the drug) show that the
concentration of flurbiprofen changes from 4.46 mg L − 1 for
the pristine compound to 38.51 mg L − 1 when intercalated, after
15 min. This result is related to the lack of crystallinity of the
 V. Rives et al. / Journal of Controlled Release 169 (2013) 28–39
Fig. 4. Solubility data of flurbiprofen: (A) before intercalation, and (B) after intercala-
tion with hydrotalcite.
Reprinted from the European Journal of Pharmaceutical Sciences, Vol. 35, M.R. Berber,
K. Minagawa, M. Katoh, T. Mori and M. Tanaka, Nanocomposites of 2-arylpropionic acid
drugs based on Mg–Al layered double hydroxide for dissolution enhancement, pp. 354–360,
with permission from Elsevier.
intercalated flurbiprofen, which is straightforward released to the
reaction medium in a “molecular” state due to the fast destruction
of the layers in the acidic medium. This increase in the observed
solubility could be also related to the energy barrier for solvation
of the drug molecules and the formation of a saturated solution,
which has been identified as the dissolution limiting step.
Studies of dissolution at pH values close to that of gastric fluid
show that the percentage of released drug is approximately twice
when the drug is intercalated than when it is in the crystallized, iso-
lated, form. Permeability studies have demonstrated that the pres-
ence of hydrotalcite in some sort of way favours permeability of
flurbiprofen through the gastric mucous, due to the increase of pH
due to the basicity of the LDH layers. Release in the intestine takes
place through ion exchange with phosphate and carbonate anions
existing in the medium, and is slower than for the corresponding
physical mixture (where the drug is not intercalated), but faster
than in Froben® during the first 5 h of the test; this is a consequence
of the increased solubility by ion exchange, as mentioned above.
Ambrogi et al. [128] have intercalated diclofenac in a Mg, Al-LDH
in the chloride form by ion exchange in a water–alcohol dissolution
(50% vol/vol) of the sodium salt of diclofenac at 60 °C for 3 days in
an orbital incubator. The solid thus obtained contained up to 55% of
drug. The gallery height, as measured from PXRD, is 1.88 nm, and
these authors proposed that interdigitated bilayers of diclofenac are
formed, the main symmetry axis of the molecules being perpendicu-
lar to the layers. Release studies at pH 7 and 7.5 show that the process
is much slower than for a drug and hydrotalcite physical mixture (for
which complete dissolution is reached in 15 min) at both pH values.
The release rate and the total amount of drug released are larger at
pH 7.5 than at pH 7 (99 and 70%, respectively, of the initial amount
of intercalated drug). Release of the drug actually occurs via an ion
exchange process, with phosphate anions of the buffer solution. The
solid residue isolated after the exchange at pH 7.5 corresponds to a
phosphate-intercalated hydrotalcite, while at pH 7 a mixture of
diclofenac- and phosphate-intercalated hydrotalcites is obtained.
These differences arise from the relative concentration of H2PO4−
and HPO42− in the reaction medium at the different pH values tested.
The data can be fitted to the Higuchi model [129], confirming that
diffusion is the dissolution rate limiting step, and that the concentra-
tion of drug has no effect on the release rate.
These authors have extended this study for Eudragit®-encapsulated
LDH-diclofenac [130]. The main reason for this sort of studies is that
the LDH matrix is dissolved in the acidic medium on the stomach and
thus the drug cannot reach the colon. A Mg, Al carbonate LDH was
prepared by homogeneous coprecipitation and the carbonate species
exchanged by chloride; diclofenac was then intercalated [128]. The
encapsulated microcapsules were prepared by an oil-in-oil solvent
evaporation method [131] using Eudragit® S100 and L100 in an
33
acetone/ethanol mixture. Powder X-ray diffraction confirmed intercala-
tion of the drug, although a small amount of carbonate remained interca-
lated. From a d-optimal design these authors conclude that the main
factors affecting the quality of the encapsulated microparticles are the
addition order of the LDH and Eudragit® to the solution, the acetone/
ethanol solution volume and the LDH/polymer ratio; better results
were obtained at a high stirring speed (1000 rpm), adding the LDH be-
fore than Eudragit®, and when low LDH/polymer ratios and large vol-
umes of solution were used; Eudragit® L produced slightly better
results than the S form. SEM showed non aggregated spherical particles
with a smooth surface and a high homogeneity; the outer polymer shell
was more compact, less porous and less irregular than the core. The
gastroresistance of the microparticles was confirmed by treatment at
37 °C with a pH 1.2 solution; no traces of Mg2+ nor diclofenac were ob-
served in the medium, indicating a good stability of the microparticle.
As expected, drug release was observed at pH 6.8 (above that for solu-
bilization of Eudragit® L) or 7.5 (Eudragit® S solubilizes at pH 7). For
the nanoparticles prepared with Eudragit® L no further diclofenac re-
lease was observed when the pH was increased to 7.5, probably because
of grafting of dihydrogen phosphate species (from the buffer solution),
which caused difficulty in diffusion of diclofenac from the interlayer. Re-
lease from Eudragit® S was faster, probably because of its thinner coat-
ing and the prevalence of monohydrogen phosphate, which does not
graft onto the brucite-like layers.
Perioli et al. [132] have intercalated diclofenac in nanosized Zn, Al
hydrotalcite by an ionic exchange procedure; the aim of the study
was to analyse the effect of the particle size on the release rate of
diclofenac. The starting hydrotalcite material, with bromide anions
in the interlayer, was prepared by addition of a CTAB microemulsion
to an aqueous solution of Zn and Al nitrates; total exchange was
achieved under these conditions, reaching a final diclofenac content
of 41.8% (w/w).
The morphology of the nanohybrid particles was determined by
SEM and TEM; small hexagonal platelets were observed, with a diam-
eter close to 200 nm, together with some larger platelets (around
350 nm), likely due to the formation of aggregates.
Release of the drug was carried out in three different media: phos-
phate buffer at pH 7.5 or 7.0 and at pH 7.0, but containing NaCl and
Na2CO3. The highest release rate and largest amount of drug released
(100% of drug was released) were reached at pH 7.5. The process was
slower at pH 7, when only 72% of the initial drug amount had been
released after 24 h; no significant difference was observed after addi-
tion of sodium chloride and carbonate to the reaction medium. These
authors conclude that phosphate concentration is the most important
parameter on the release rate and on the amount of drug released, as
H2PO4− reacts with hydroxyl groups from the brucite-like layers,
forming Zn and Al hydroxyphosphate by a solid grafting reaction.
The strong bonds between the grafted phosphates and layers are
able to stop the ion exchange mechanism and to cause the obstruc-
tion of HTlc galleries, entrapping the diclofenac anions into the inter-
nal part of interlayer region.
Wang et al. [133] have studied the intercalation, by coprecipitation, of
diclofenac in a Zn, Al hydrotalcite; the nanohybrid formed was compared
with sodium diclofenac on auricular tumescence induced by xylene in
mice.
Diclofenac was incorporated by ion exchange in the interlayer space
of a Mg, Al hydrotalcite by Sanmartino et al. [134], and the hybrid thus
formed was incorporated into polycaprolactone, and processed as films
of 0.15 mm thickness. The resulting compound showed better properties
than the original polymer. Release of the drug takes place in two steps, a
first, fast, one releasing a small amount of drug, followed by a much
slower second step.
Gunawan and Xu [135] have studied the possible relationship
between the crystalline morphology and the aggregation state of
an ibuprofen–LDH system and their effect on the drug release. Ibuprofen
was intercalated in a Mg, Al LDH (Mg/Al molar ratio of 2) by
34 V. Rives et al. / Journal of Controlled Release 169 (2013) 28–39

coprecipitation using two different solvents (water, and a 1:1 ethylene

glycol:water mixture) under two reaction conditions (ambient pressure
or hydrothermal treatment for 18 h at 150 °C). PXRD patterns and FT-IR
spectra showed that coprecipitation and ageing (both under ambient or
hydrothermal conditions) lead to intercalation of the drug, although a
small amount of carbonate is simultaneously intercalated; ethylene
glycol is not intercalated. From the molecular size of ibuprofen and the
gallery height measured by PXRD, it is concluded that the ibuprofen
anions are tilted with respect to the brucite-like layers, forming an
antiparallel bilayer, with the carboxylate groups bonded to the inorganic
layers. The crystallinity of the samples is not dependent on the nature of
the solvent used, but is highly dependent on the ageing conditions; a
larger crystallinity is observed after hydrothermal treatment at 150 °C
for 18 h than after ambient pressure ageing at 70 °C for 3 days. This
effect is clearly concluded from TEM and SEM images, Fig. 5, which
show somewhat rounded platelets and irregularly shaped particles
with an average diameter of 200 nm, when the samples were aged at
ambient pressure. The surface of the hydrothermally treated crystallites
is smoother and the nanoplatelets are regularly oriented with a larger
packing density (face-to-face and border-to-border); however, for the
ambient pressure-aged samples the compacity of the crystals is lower
and the surface is porous and shows a certain degree of roughness.
These differences can be related to the presence of ethylene glycol,
which would act as a dispersing agent, limiting the agglomeration of
the particles during the hydrothermal treatment. It can be also a conse-
quence of an Ostwald ripening during hydrothermal treatment.
Studies on release of the drug at pH 7 show that release is complete
in all samples, although the release rate depends on the crystallinity
and aggregation degrees; the slowest release rate is observed for the
hydrothermally treated samples prepared in ethylene glycol. The diffu-
sion rate of the anions from the hydrotalcite aggregates can thus be con-
trolled by the characteristics of the solid, namely, porosity, aggregation
degree and crystallinity of the LDH platelets. For a dense powder formed
by well oriented particles, as obtained in the presence of ethylene glycol
and submitted to hydrothermal treatment, the length of the path
followed by diffusing anions and the resistance to diffusion is much
larger, due to the large size of the aggregates and their rigid structure.
As a result, the release rate of ibuprofen is slower.
Diclofenac and ketoprofen have been intercalated in LDHs containing
Zn or Mg and Zn, together with Al, in the brucite-like layers [136] by
coprecipitation from addition of a metal salt solution into an ethanolic
solution of the drug at pH 9 under nitrogen atmosphere at room
temperature and stirring for 24 h. The divalent/Al3+ molar ratio was in
all cases slightly lower than the expected value of 2, probably by a partial
dissolution of the divalent cations and formation of coordination
compounds with the organic anions. However, it should to be noticed
that the presence of Mg leads to values closer to 2.0 than the exclusive
presence of Zn2+ as the divalent cation. The interlayer spacings were
ca. 23 Å in both cases; from the molecular sizes of the drug it can be
concluded that a slightly tilted bilayer perpendicular to the brucite-like
layers is formed. The ketoprofen sample contained a small impurity of
nitrate, as concluded from element chemical analysis and the X-ray
diffraction patterns, as well as from the FT-IR spectrum, which displays
a sharp band at 1367 cm−1 (mode ν3) and another at 1066 cm−1, due
to mode ν1, inactive for the free anion (D3h symmetry), but activated in
the restricted symmetry situation within the interlayer. Thermal decom-
position proceeds at a higher temperature than for the free drugs, prob-
ably because of the enhanced stabilization due to the strong electrostatic
interactions with the layers.

Fig. 5. TEM images of as-prepared Mg2Al-Ibp-LDH samples using two different types
of solvent systems (EG/W = ethylene glycol and water; W = water) at atmospheric
(C) or hydrothermal (H) conditions: (A) EG/W–H; (B) W–H; (C) EG/W–C; (D) W–C.
Reprinted from the Journal of Pharmaceutical Sciences, Vol. 97, P. Gunawan and R. Xu,
Direct control of drug release behaviour from layered double hydroxides through
particle interactions, pp. 4367–4378, with permission from Wiley Interscience.
 V. Rives et al. / Journal of Controlled Release 169 (2013) 28–39
Ambrogi et al. [137] have also studied the ion exchange intercalation
of ibuprofen in a Mg, Al LDH with chloride anions in the interlayer. The
drug loading was very high, 50%, and the molecules are forming a mono-
layer in the interlayer with the main molecular axis perpendicular
to the inorganic layers, interaction taking place through the carbox-
ylate groups. These authors relate their release results with those of
commercial Neo-Mindol® and a physical mixture of the
hydrotalcite and ibuprofen. The release rate at pH 7.5 is much
slower from the interlayer (in the hybrid) than in the commercial
product and the physical mixture, as in the first case it proceeds
via ion exchange with phosphate anions of the buffer solution.
DeLeon et al. [138] have prepared and characterised polymer
nanocomposites with poly-L-lactic acid (PLLA) and LDH–ibuprofen,
studying the effect of the presence of the LDH and the LDH–ibuprofen/
PLLA ratio on the release rate of the drug. This was incorporated into
the interlayer space of the hydrotalcite by ionic exchange in a Zn,
Al-nitrate hydrotalcite, and observed a practically complete exchange
(only 0.06% N was identified in the final solid), final ibuprofen loading
being 40.9% (w/w). The composites with PLLA were prepared by spin
casting and the results are compared with a similar composite, but
formed exclusively by PLLA and ibuprofen, without the inorganic phase.
Intercalation was confirmed by PXRD, as a basal spacing of 24.7 Ǻ
was measured for the hydrotalcite–ibuprofen sample, with a weak
swelling to 26.59 Ǻ after dispersion in the PLLA matrix.
The release studies were carried out in a phosphate buffer (pH = 7.4)
at 37 °C for 10 days. In the absence of hydrotalcite, only 5% release was
observed and in the very early stages of the process; probably it corre-
sponds to ibuprofen adsorbed on the surface of the matrix. However, a
two-step release process was observed from the nanocomposites, a first
fast one lasting 15 h, followed by a slower second step along 50 h. In
this second step, both the release rate and the amount of drug released
increase as the amount of LDH–ibuprofen in the PLLA matrix increases
(a maximum loading of 70% of LDH–ibuprofen was tested). Changes in
pH along the release process were also studied: pH increased during the
first 10 h and then slowly decreased until a limiting equilibrium value
was reached for the LDH-containing composites. However, such a pH
decrease was larger in the LDH-free samples, probably due to dissolution
of ibuprofen from the polymer surface, without a maintained release.
Ay et al. [139] have studied the intercalation of ibuprofen and glucu-
ronic acid in a Mg, Al-LDH, supported on a magnesium ferrite core; this
had been prepared by calcination of a non-stoichiometric Mg, Fe-CO3
LDH. The drugs were intercalated by ion exchange with nitrate-LDH
precursors, once supported on the magnetic core. Drug loadings of 45%
(ibuprofen) and 25% (glucuronate) were achieved. The nanocomposites
would be hopefully suitable for magnetic targeted delivery, i.e., magnetic
field-controlled delivery of a drug to the targeted organ and its subse-
quent release, as previously reported by other authors with other differ-
ent drugs: Duan et al. [140] intercalated 5-amino salicylic acid in a Zn,
Al-LDH, and diclofenac on a Mg, Al-LDH coated onto a magnesium ferrite
core [141], while Carja et al. [142] intercalated aspirin in a Mg, Al-LDH
supported on FeOx/Fe-LDH.
Ketoprofen, tiaprofenic acid and indomethacin are scarcely soluble
drugs. Ambrogi et al. [110] have intercalated these drugs in a Mg, Al
LDH by ion exchange of originally intercalated chloride or hydroxide
anions, and have studied the effect of the inorganic matrix on their solu-
bility at gastric pH (1.2). All data (PXRD, thermogravimetric analysis,
FT-IR spectroscopy and SEM) confirm that the drug has been effectively
intercalated. Solubility studies with the pure drug, a LDH–drug physical
mixture and the hybrid samples were carried out at pH 1.2 and 37 °C.
Values below 2 mg mL−1 were determined for pure indomethacin and
its physical mixture with the drug, while for intercalated indomethacin
the value was 12 mg mL−1 after 1 min, and 14 mg mL−1 after 15 min.
This much larger solubility has been related by these authors to the
non-crystalline nature of indomethacin in the interlayer, so being imme-
diately released in an ionic form by the easy dissolution of the inorganic
matrix in the strongly acidic medium. Similar results were obtained for
35
the other drugs tested in this study; although the differences were not
as sharp as for indomethacin, it was found that the simultaneous
presence of the inorganic matrix enhances the drug solubility, much
larger when intercalated than when merely mixed. In addition, these
authors also highlight the beneficial role of hydrotalcite to improve the
stability of the drug, delaying its hydrolysis and decarbonation.
Del Arco et al. [107] have also intercalated indomethacin in a Mg, Al
LDH, and have reported in vivo studies using Swiss mice (25 g weight),
to whom indomethacin, the physical mixture and the intercalation
product were supplied; the aim of the study was to check the effect of
the simultaneous presence of the inorganic matrix on ulcer formation,
as measured from the ulcerated area of mice stomach. Intercalation
was carried out by coprecipitation or reconstruction in a basic medium.
Coprecipitation yields a hybrid with 60% drug loading, indomethacin
molecules forming a bilayer in the interlayer space with the carboxylate
groups pointing towards the brucite-like layers; however, a biphasic
system is obtained by reconstruction, with components LDH-carbonate
and LDH–indomethacin, where an intercalated monolayer is formed,
with the molecules somewhat tilted from the perpendicular orientation;
moreover, only 18% drug loading was reached; for this reason, the
pharmacological studies were carried out with the high-loaded sample,
prepared by coprecipitation. Oral doses of 80 mg kg−1 of pure indo-
methacin led to gastric hemorrhagic damage in 88% of the mice, while
using the LDH–indomethacin system ulcer formation was observed
only in 70% of the mice, Fig. 6; the ulcerated surface also decreased
from 0.40 to 0.106% when using indomethacin or the hybrid, respectively.
This value was 0.215% for the physical mixture, confirming not only the
positive role of the use of hydrotalcite because of its basic nature, but
also the additional positive effect of the intercalated drug.
Coprecipitation, reconstruction and ion exchange were used by del
Arco et al. to intercalated mefenamic and meclofenamic acids in a Mg,
Al hydrotalcite [143]. Total chloride exchange was achieved, with drug
loadings of 52 and 58%, respectively, for mefenamic and meclofenamic
acids. PXRD patterns suggest formation of a bilayer between the LDH
layers, with the carboxylate groups pointing towards the brucite-like
layers. These authors have also studied [144] the effect of the LDH on
the solubility of mefenamic acid. Solubility is highly increased, especially
when the acid is intercalated, the best results being achieved at pH values
1.2 and 6.8, but being low at pH 4.5. The inorganic matrix is dissolved
under acidic conditions and the residue is the pure drug, while at
pH 6.8 a fast ion exchange takes place with the buffer anions. The release
rate is very high for the pure drugs and their physical mixtures with
hydrotalcite. As expected, the release rate decreases upon intercalation,
and up to 90 min is required, despite the release rate decreases with
time. The release is fast in the first 30 min, and then it reaches an almost
constant value; total release of mefenamic acid was not, however,
achieved.
When a partial Al3+/Fe3+ substitution is made in the composition of
the brucite-like layers, forming a Mg, Al, Fe-LDH, a decrease in the release
rate and in the total amount of drug released is observed [124], in com-
parison with the results obtained for the Mg, Al-LDH. The release data
can be fitted to order 1 and Weibull models [125], interparticle and
intraparticle diffusion predominating in the iron-free systems, but only
intraparticle diffusion for the iron-containing systems.
3. Conclusions and further studies
The amount of information concerning intercalation of NSAIDs into
LDHs is very large; probably, this is the family of drugs in which in-
tercalation has been more widely studied. From the literature here
summarised some conclusions and proposals for further studies
can be reached.
Among the different procedures applied to intercalate NSAID
molecules in the interlayer space of LDHs, larger drug loadings are
reached when using coprecipitation (direct synthesis) or anionic ex-
change; in this last case, however, a small amount of the anion (generally
36 V. Rives et al. / Journal of Controlled Release 169 (2013) 28–39
Fig. 6. Photographs of extracted stomachs after treatment with (A) pure indomethacin
(In), and (B) sample LDH–indomethacin (InD) prepared by coprecipitation. (C) Ulcer-
ation degree (%) after administration of 80 mg active ingredient/kg weight of mouse
(n = 17).
Reprinted from the Journal of Pharmaceutical Sciences, Vol. 93, M. Del Arco, E.
Cebadera, S. Gutiérrez, C. Martín, M.J. Montero, V. Rives, J. Rocha, M.A. Sevilla, Mg, Al
layered double hydroxides with intercalated indomethacin: synthesis, characterization
and pharmacological study, pp. 1649–1658, with permission from Wiley Interscience.
chloride or nitrate) in the original precursor usually remains, so it is
recommended to use a chloride precursor to avoid the presence of toxic
nitrate species. The reconstruction method also permits intercalation of
NSAIDs, but the effectiveness of the method depends on the nature of
the layer cations, and a biphasic system is usually obtained (LDH–carbon-
ate and LDH–NSAID) or lower drug loadings are achieved, due to incom-
plete removal of carbonate during calcination of the precursor or
carbonation during the preparation due to the strong competition be-
tween carbonate and the anionic drug, because of the high basicity of
the calcined solids. Intercalation leads to an increase in the thermal stabil-
ity of the drug, due to the strong electrostatic interactions developing be-
tween the drug and the layers.
The NSAID loading in the interlayer depends on several factors,
namely, chemical composition of the matrix, method and synthesis
experimental conditions, charge layer density, etc. All of them are able
to modify the orientation of the NSAID molecule in the interlayer, its
release rate and the amount of released drug. In most of the cases the
drug molecules form bilayers in the interlayer inorganic space, forming
antiparallel bilayers, sometimes slightly tilted, with the carboxylate
groups pointing towards the inorganic layers. In some cases, an orienta-
tion of the molecules perpendicular to the layers has been claimed, with
the water molecules located between the drug molecules and the
layers.
The LDH, well as an additive or as a matrix for the drug, gives rise to
an increase in the usually poor NSAID solubility, in a larger extent when
the drug is intercalated. These differences are related to the crystalline
nature of the intercalated NSAID. Release is fast at low pH because of
dissolution of the matrix, while at pH values around 7 release takes
place via anionic exchange with the anions existing in the liquid
medium. The basic nature of the LDH might be also responsible for the
larger solubility of the drug, even when they are simply mixed and
not intercalated.
The release rate depends on the particle size, crystalline morphology
and aggregation state of the particles, which can be modified or even
tuned by using different solvents during preparation. The release rate
and the amount of drug released depend on the chemical composition
of the matrix and on the synthesis variables mentioned above. Release
is slow when the drug is intercalated, as it proceeds via anionic exchange
with the anions in the medium, and depends on the pH as well, release
being usually faster for low pH values. When release takes place at pH
provided by phosphate buffers, the release rate is determined by the con-
centration of H2PO4− and HPO42− species, as the former is irreversibly
grafted to the layers via reaction with its hydroxyl groups, obstructing
the galleries and preventing the drug release.
When the LDH–NSAID systems are covered by polymers in which
stability depends on pH, the quality of the encapsulated particles de-
pends on the precise preparation procedure (for instance, order of the
reactants has been added, type and concentration of solvents used,
and LDH/polymer ratio). Formation of microspheres guarantees a better
covering than simple dispersion.
Nevertheless, despite the numerous advantages that intercalation of
NSAIDs in LDHs exhibits, these cannot be used as matrices for controlled
release in oral administration, as they are very sensitive to the acidic
medium, unless they are covered with a polymer film which preserves
them from being acidically degraded. So, this is a field where new in-
sights are still required, although some studies are already available in
the literature; for instance, several papers have already reported the
use of Eudragit® or polylactic to cover and to protect the LDH–drug
hybrid from degradation. This encapsulation has been also applied to
other systems containing antibiotics or antihypertensive drugs, which
hybrids have been covered with poly(ε-caprolactone) or xyloglucan.
Even the use of mixed natural polymers has been proposed, such as
sodium alginate and zein, a prolamine protein found in maize; quite
surprisingly these two last polymers are unable to act as release control-
lers when combined with the drug, but by using the ternary system
drug–LDH–polymer release systems at a controlled pH will be prepared.
Another very interesting field where developments are expected
are those related to the use of LDH–drug composites, together with
a magnetic nucleus for precise delivery in locations of the body
where the action is required. This procedure will permit a faster
action of the drug, as well as decreasing the total dose, thus avoiding
undesired side-effects.
Acknowledgements
Financial support from MICINN (grant MAT2009-08526) is greatly
acknowledged.
 V. Rives et al. / Journal of Controlled Release 169 (2013) 28–39
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