Applied Clay Science 36 (2007) 22 36

www.elsevier.com/locate/clay

Use of clays as drug delivery systems: Possibilities and limitations

C. Aguzzi a , P. Cerezo b , C. Viseras b,, C. Caramella a
b

a
Department of Pharmaceutical Chemistry, University of Pavia, Italy
Department of Pharmacy and Pharmaceutical Technology, University of Granada, Spain

Received 28 February 2006; received in revised form 15 June 2006; accepted 21 June 2006
Available online 9 October 2006

Abstract
The need for safe, therapeutically effective and patient-compliant drug delivery systems continuously leads researchers to
design novel tools and strategies. Clay minerals are widely used materials in drug products both as excipients and active agents.
When administered simultaneously, drugclay interactions have been observed and studied, but until recently were not considered
as a possible mechanism to modify drug release. In recent years, and based on their high retention capacities as well as swelling and
colloidal properties, clays have been proposed as very useful materials for modulating drug delivery. This paper first reviews the
studies on drugclay interactions, and then those focused on the applications of natural clays and their semi-synthetic or synthetic
derivatives to carry out specific functions in new drug delivery systems. In particular, clays are used to delay and/or target drug
release or even improve drug dissolution. Finally, new strategies are reported for increasing drug stability and simultaneously
modifying drug delivery patterns through the use of clay minerals.
2006 Elsevier B.V. All rights reserved.
Keywords: Clays; Special excipients; Modified drug release; Bioavailability; Cation-exchange

1. Introduction
The main concept in modified delivery technology is
that any pharmaceutical dosage form should be designed
to provide therapeutic levels of drug to the site of action
and maintain them throughout the treatment (Ding et al.,
2002). These goals may be achieved by modifying the
rate and/or time and/or site of drug release in comparison
with conventional formulations. Such modification in
release of active substances is provided to reduce toxic
effects or for some other therapeutic purpose (Quality of
Corresponding author. Departamento de Farmacia y Tecnologa
Farmacutica, Universidad de Granada, Facultad de Farmacia, Campus
de Cartuja, s/n, 18071 Granada, Spain. Tel.: +34 958 249551; fax: +34
958 248958.
E-mail address: cviseras@ugr.es (C. Viseras).
0169-1317/$ - see front matter 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.clay.2006.06.015

Prolonged Release Oral Solid Dosage Forms, Directive

75/318/EEC, November 1992).
Clays are common ingredients in pharmaceutical
products both as excipients and active substances. In the
1960's it was observed that oral absorption of several
drugs was reduced by co-administration of clay-based
intestinal adsorbents or by the presence of clay stabilizers (e.g., suspending or emulsifying agents) in liquid
formulations. Specifically, it was found that the absorption of promazine, an antidepressant agent, decreased
when the drug was administered in association with
antidiarrhea mixtures containing attapulgite (Sorby,
1965; Sorby and Liu, 1966). Many studies have reported
a decrease in bioavailability of several drugs by coadministration with antacid (Mg trisilicate), antidiarrheal
(attapulgite, kaolin) and suspending agents (talc, bentonite) (Thoma et al., 1966; El-Nakeeb and Yousef, 1968;

C. Aguzzi et al. / Applied Clay Science 36 (2007) 2236

El-Masry and Khalil, 1974; Khalil, 1974; Bowman

et al., 1975; Albert et al., 1978a,b; Kahela et al., 1978;
Khalil and Iwuagwu, 1978; Alestig et al., 1979; Ganjian
et al., 1980; McElnay et al., 1980, 1982; Bucci et al.,
1981; Thoma and Lieb, 1983; Khalil et al., 1984;
Naggar, 1985; Fredj et al., 1986; Moustafa et al., 1986;
Khalil et al., 1987a,b; Moustafa et al., 1987; Hashim and
El-Din, 1989; Iwuagwu and Jideonwo, 1990; Iwuagwu
and Aloko, 1992; Jain and Kakkar, 1992; Arayne and
Sultana, 1993; Vatier et al., 1994). It was soon realised
that the effects of such interactions in the concomitant
administration of clay minerals with active substances
might not be purely negative, but could also be used to
achieve technological and biopharmaceutical benefits.
This was the starting point in the use of clays in modified
drug delivery systems.
2. Modified Drug Delivery Systems (MDDS)
MDDS cover a wide range of products, including
delayed release, extended release, site-specific
targeting and receptor targeting dosage forms (Ding
et al., 2002). Delayed-release systems are those in which
drug release is delayed for a finite lag time, after which
release is unhindered (e.g. enteric coated oral tablets).
Extended-release (or prolonged-release) dosage forms
include any system in which the drug is made available
over an extended period of time after administration.
Expressions such as repeated and sustained release
(or action) have also been used to describe such dosage
forms, but the terms extended release (USP 29, 2006a)
and prolonged release (EP 5.0 Suppl. 5.3, 2006) are
those used for pharmacopeial purposes. Site-specific and
receptor targeting systems are those that deliver the
active substance at the desired biological site, e.g. the
diseased organ or tissue (site-specific targeting), or the
particular drug receptor within an organ or tissue (receptor targeting). Systems providing some actual therapeutic temporal and/or spatial controls of drug release are
considered controlled delivery systems, so, controlled release cannot be considered equivalent to extended release (Ding et al., 2002). Some of the more
common controlled-release drug delivery systems are
summarised in Table 1, according to the classification
proposed by Chien and Lin (2002). On the basis of the
technological approach applied, four main groups have
been distinguished: rate-preprogrammed systems (those
controlling molecular diffusion of drug molecules in
and/or across a polymer barrier), activation-modulated
systems (in which drug release is activated and then
modulated by some physical, chemical or biochemical
input), feedback-regulated systems (in which drug re-

23

lease is activated in the body via some feedback mechanisms) and site-targeting drug delivery systems (Chien
and Lin, 2002).
Most of these strategies assume a new concept of
excipient. Thus, excipients (and among them clay
minerals) are not only inert ingredients, but they can
also be used by formulators to provide targets of a
biopharmaceutical (decreasing or increasing dissolution
rate, delaying and/or targeting drug release), pharmacological (prevention or reduction of side effects),
technological (taste masking) or chemical (increasing
stability) nature.
2.1. Mechanisms of claydrug interactions
Among the several approaches proposed to achieve
controlled release formulations, the ion exchange process has received considerable attention from researchers
in recent years (Vikas et al., 2001). It may take place by
mixing solid substrates (namely ion exchangers) with
ionic drugs in solution. In biological fluids, counterions can displace the drug from the substrate and deliver
it into the body. The exchanger may be then eliminated or
biodegraded (Fig. 1).
Clay minerals are naturally occurring inorganic
cationic exchangers and so they may undergo ion exchange with basic drugs in solution. Smectites, especially montmorillonite and saponite, have been the more
commonly studied because of their higher cation
exchange capacity compared to other pharmaceutical
silicates (such as talc, kaolin and fibrous clay minerals).
Nevertheless, there are several mechanisms that may be
involved in the interaction between clay minerals and
organic molecules, as summarised in Table 2. The
relevance of a specific mechanism depends on the clay
mineral involved (Browne et al., 1980) as well as on the
functional groups (Lagaly, 2001) and the physical
chemical properties (Tolls, 2001) of the organic
compounds.
Wai and Banker (1966) investigated the interaction
between montmorillonite and four alkaloids, finding
some differences in bonding mechanisms depending on
molecule size and basicity. In some cases (methapyrilene and triethylamine) drug molecules were quantitatively bound to the clay mineral via cation exchange;
besides ion exchange other mechanisms contributed to
drug adsorption of larger molecules (brucine); and niacinamide was not bounded to the clay, because it mainly
occurred in the neutral form. McGinity and Lach (1976)
confirmed that basic molecules bonded strongly to
montmorillonite; on the other hand, complexes with
anionic and non-ionic drugs exhibited much weaker

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C. Aguzzi et al. / Applied Clay Science 36 (2007) 2236

Table 1
Types of controlled-release drug delivery systems (Chien and Lin, 2002)
Group

Drug delivery system

Drug release control mechanism

Marketed examples

Rate-preprogrammed
systems

Polymer membrane
permeation systems
Polymer matrix systems
Polymer (membrane/
matrix) hybrid systems
Microreservoir partition
systems
Osmotic pressureactivated systems
Hydrodynamic pressureactivated systems
Vapor pressure-activated
systems
Mechanical forceactivated systems
Magnetic-activated
systems
Sonophoresis-activated
systems
Iontophoresis-activated
systems
Hydation-activated
systems
pH-activated systems
Ion-activated systems
Hydrolysis-activated
systems
Enzyme-activated
systems
Bioerosion-regulated
systems
Bioresponsive-regulated
systems
Self-regulating systems

Diffusion

Ocusert, Progestasert IUD, TransdermNitro, Norplant Sudermal Implant,

Nitro-Dur, Compudose Implant
Catapres-TTS, TransdermScop

Activation-modulated
systems

Feedback-regulated
systems

Nitrodisc, Syncro-mate-C Implant

Modulation of the activation input

Alzet osmotic pump, Acutrim tablet

Infusaid
Nasal metered dose nebulisers

Syncro-Male-B implant, Valrelease tablet

Pennkinetic, Tussionex
Lupron-Depot, Zoladex

Concentration of the activating

substance in the body

Site-targeting
systems

interaction bonds and more rapid desorption kinetics.

Bonding via adsorption (Carstensen and Kenneth, 1971)
and iondipole interactions (Kenneth and Carstensen,
1972) of acidic and non-ionised molecules with montmorillonite were previously reported. The crucial effect
of the ionisation degree of drug molecules on their
interaction with smectites was then corroborated by
Castela-Papin et al. (1999), using dioctahedral smectite
as the adsorbent substrate.
Besides smectites, other silicates were investigated to
vehicle bioactive compounds. Fibrous clay minerals
(attapulgite (USP 29, 2006b) (palygorskite) and magnesium trisilicate (USP 29, 2006c) (sepiolite)) and kaolinite
in particular were considered because of their large
surface area and/or widespread pharmaceutical application. Adsorption studies of benzoic acid and crystal
violet on kaolin suggested that anionic species (benzoic

acid) were adsorbed on the edge faces of the mineral, and

cationic (crystal violet) on the basal plane surfaces
(Armstrong and Clarke, 1971; Clarke and Armstrong,
1972). The adsorption isotherms of some -blockers
(including propranolol, acebutolol, metoprolol, nadolol,
oxprenolol) (Al-Gohary et al., 1987, 1988) and mebeverine (Al-Gohary, 1991) with fibrous clay minerals and
kaolinite were investigated, at different pH and temperature. Viseras et al. (2003a) used a factorial design to
concomitantly investigate the influence of some critical
parameters (drug concentration, temperature and adsorption time) on the interaction between timolol and
sepiolite. The adsorption isotherms of 5-aminosalicilyc
acid with halloysite and sepiolite samples were investigated by Viseras et al. (2004a, 2005).
Several studies aimed to improve understanding of
the physicalchemical aspects of drugclay complexes.

C. Aguzzi et al. / Applied Clay Science 36 (2007) 2236

25

Fig. 1. Idealization of claydrug complexation and in vivo drug release mechanisms (clay mineral surface charge ();compensating cations (a+);
cationic drug (X+); drug associated anions (Y); in vivo counter ions (A+); anions associated with the counter ions (B)).

X-ray diffraction was a useful tool to test the penetration

and possible orientation of cationic drugs (e.g. tetracyclines (Porubcan et al., 1978; Viseras et al., 2003b),
chlorpheniramine (Snchez-Camazano et al., 1980a), blockers (Snchez-Martin et al., 1981; Sanchez et al.,
1983; Vicente et al., 1984; Cerezo, 2003), quinidine
(Sayalero et al., 1984), papaverine (Sayalero et al., 1984,
1985; Forni et al., 1985), hydralazine (Sayalero et al.,
1984; Snchez-Martin et al., 1988), promethazine,
buformin and benzalkonium (Fejr et al., 2002)) in the
interlayer space of smectites, by revealing changes in the
basal spacing of the clay minerals. Spectroscopic (UV

VIS, IR) and thermal (TGA) analyses were also

successfully used to reveal cation exchange (Porubcan et
al., 1978; Snchez-Camazano et al., 1980a; SnchezMartin et al., 1981; Sanchez et al., 1983; Forni et al., 1985;
Sayalero et al., 1985; Del Hoyo et al., 1996a; Viseras et al.,
2003b, 2004b) as well as chemical bonds to active sites of
the clay minerals (Del Hoyo et al., 1996b; Cerezo et al.,
2002; Lin et al., 2002; Cerezo et al., 2003; Viseras et al.,
2003c; Sevim and Tanil, 2005) and changes in the spectral
characteristics (Lach and Bornstein, 1965, 1966; Bornstein
and Lach, 1966) or in the acid-base equilibria of drug
molecules (Ismail Mohamed, 1998; Abdel-Mohsen et al.,

Table 2
Interactions between clay minerals and organic compounds (adapted from http://esd.lbl.gov/sposito)
Mechanism
Hydrophobic interactions (van der Waals)

Mineral examples

Any clay with neutral sites

(e.g., kaolinite, smectites)
Hydrogen bonding
Any clay with oxygen surfaces
(e.g., kaolinite)
Protonation
Aluminosilicate edge sites, Fe
and Al oxides, allophane, imogolite
Ligand exchange
Aluminosilicate edge sites, Fe
and Al oxides, allophane, imogolite
Cation exchange (permanent charge sites) Smectite, vermiculite, illite
pH-dependent charge sites (anion exchange Aluminosilicate edge sites, Fe
usually, cation exchange rarely)
and Al oxides, allophane, imogolite
Cation bridging
Smectite, vermiculite, illite
Water bridging

Organic functional groups involved

Uncharged, non polar (e.g., aromatic, alkyl C)
Amines, carbonyl, carboxyl, phenylhydroxyl, heterocycle N
Amines, heterocycle N, carbonyl, carboxylate,
Carboxylate, Phenolate
Amines, ring NH, heterocyclic N
Carboxylate for anion exchange, amines, ring NH, heterocyclic
N for cation exchange
Carboxylate, amines, carbonyl, alcoholic OH

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C. Aguzzi et al. / Applied Clay Science 36 (2007) 2236

2001). Fejr et al. (2001) used X-ray diffraction and FT-IR

analysis to study desorption of cationic drugs differing in
molecular size from loaded montmorillonite. Small molecules (buformin) were weakly bound to the clay mineral
and no significant changes in the basal spacing and in the
IR spectra of the complexes were observed after desorption, whereas for promethazine important modifications in the X-ray and IR patterns were reported.
To widen knowledge on the spatial arrangement of
organic host molecules in their complexes with clay
minerals, novel techniques (e.g., molecular modelling)
have recently been introduced to support the more common spectroscopic, thermal, and XRD analysis. Lee and
Kim (2002) pointed out a discontinuous increase of the
basal spacings in complexes of montmorillonite with a
cationic surfactant. Previously, Karaborni et al. (1996)
observed a similar behaviour in montmorillonite delamination in aqueous medium. Molecular dynamics simulation studies were also performed with other cationic
(Pospsil et al., 2001) or neutral (Pospsil et al., 2002)
substrates and some aminoacids (Kollr et al., 2003).
Rytwo et al. (2002) used a computer model to investigate
adsorption of some organic cations on sepiolite from
Yunclillos, considering both neutral and charged sites of
the clay mineral.
Other studies focused on clarifying the role of some
key parameters (e.g., drug concentration, pH, tempera-

ture, electrolyte concentration and valence, dielectric

constant) in drug-clay adsorption-desorption processes,
e.g. smectites (McGinity and Hill, 1975; SnchezCamazano et al., 1980b, 1982; Snchez-Martin et al.,
1983; Stul et al., 1984; Sayalero et al., 1984; Vicente et
al., 1984; Cameroni et al., 1985; El-Mowafi et al.,
1985a,b,c,d,e; Forni et al., 1985; Sayalero et al., 1985;
Vicente et al., 1986; Aguzzi et al., 2003a; Figueroa et al.,
2004), kaolin (Armstrong and Clarke, 1973; El-Mowafi
et al., 1985a,d; Al-Gohary et al., 1987, 1988; Figueroa
et al., 2004), halloysite (Viseras et al., 2004a, 2005) and
fibrous clay minerals (McGinity and Hill, 1975; AlGohary et al., 1987, 1988; Cerezo, 2003).
On the basis of these interactions, but also because of
their special swelling properties, clay minerals are effectively used to delay (extended-release systems) and/
or target (site-specific release systems) drug release or
even improve drug solubility. Finally, new strategies are
focused on increasing drug stability and simultaneously
modifying drug delivery patterns (particulate delivery
systems) (Table 3).
2.2. MDDS based on claydrug interactions
2.2.1. Preparation of claydrug complexes
Different technological procedures have been reported for obtaining drugclay interaction products.

Table 3
New Drug Delivery Systems based on clay minerals
Issue

Target parameter

Delivery system

Mechanism

Excipients

Original clay

Release
Pattern

Dissolution rates

Extended
Release Systems

Clay mineraldrug interaction

Natural clay
minerals with
high cation
capacity values
Synthetic clay
minerals
Modified clay
minerals

Smectites,
Fibrous clay
minerals

Site of release

Clay swelling
Improved Drug
Adsorption
Solubility Systems
Site-specific
Enteric coated
systems
Bioadhesion

Drug Stability
Hydrophilic ambient
Microparticles
and Targeting (sensible molecules)
nanoparticles
and Distribution Profiles

LDH,
hydrotalcites
Acid/thermal
Bentonite or
activated
kaolinite
Pillared
Montmorillonite
layered structures and others
smectites
Swelling clays
Smectites
Montmorillonite
Montmorillonite
and LDH(oral release)
Smectite and halloysite
(Local release)
Halloysite
Porous-hollow
nanoparticles

Encapsulation
Surface
precipitation,
inclusion, others.
Clay-polymer
Clay-polymer
interaction
nanocomposites

Porous silica from clay

minerals, halloysite
Montmorillonite

C. Aguzzi et al. / Applied Clay Science 36 (2007) 2236

Commonly, clay particles are dispersed in aqueous drug

solutions, dispersions are allowed to equilibrate for a
suitable time, and finally solid phases are recovered and
dried. The influence of the method applied to disperse
the clay and of the equilibrium time on drug loading in
smectite suspensions was investigated by Aguzzi et al.
(2005a). They found that time was crucial to increase the
amount of drug retained by the smectite particles,
especially when mild agitation was carried out for the
dispersion of the smectite.
Nennemann et al. (2001) described a way to entrap
bioactive molecules by inducing coagulation in montmorillonite dispersions.
Dry procedures (specifically helpful for poorly soluble molecules) were also reported, consisting in grinding
the clay and the drug together or putting them in contact
at the melting temperature of the drug (Del Hoyo et al.,
1996a,b).
2.2.2. Extended-release systems
2.2.2.1. Clays and clay minerals. Pharmaceuticalgrade clay minerals (including smectites, kaolinite and
fibrous clay minerals) have been extensively applied for
prolonged release, especially of basic drugs. Smectites
in particular have been the most commonly used substrates, as they can retain large amounts of drug due to
their high cation exchange capacity.
Forni et al. (1987) developed a system based on the
surface deposition of papaverine on papaverinemontmorillonite complex. This system was able to deliver the
complexed papaverine according to zero order kinetics,
after the release of an initial priming dose of surface
deposed drug. The ability of montmorillonite to modify
drug release from polymeric matrices containing cationic drugs was also reported (Forni et al., 1986, 1989).
Formulations of salbutamol (Sayed et al., 1991) and
chlordiazepoxide (El-Sayed et al., 1993) with montmorillonite were described. Aguzzi et al. (2003b,c) examined drug release in different media magnesium
aluminium silicate (blend of montmorillonite and
saponite (USP 29, 2006d) loaded with natural or semisynthetic tetracyclines and found a significant decrease
in dissolution rate for all the complexes compared to
their physical mixtures. In vivo experiments of smectitebased formulations has also been reported. The effectiveness of montmorilloniteamphetamine complexes
in reducing drug bioavailability in human volunteers
was reported by McGinity and Lach (1977). Kahela and
Hurmerinta (1979) found that the absorption of
spironolactone in dogs was successfully reduced by
administration of its complex with bentonite. Formula-

27

tions based on phenformin-loaded bentonite were effective for 1011 h in reducing blood sugar levels in rabbits
(Maheshwari et al., 1988). Microencapsulation of
terbutalinesaponite complexes with cellulose acetate
butyrate provided sustained responses in human patients
suffering reversible chronic air flow obstruction (ElGindy et al., 2000). Abdel-Mohsen et al. (2001) observed an extended duration of the anaestethetic activity
of lidocaine in rabbits from topical buffered poloxamer
gels containing lidocainemontmorillonite complexes.
Kaolin (Delgado et al., 1994) and fibrous clay minerals (Cerezo, 2003) were successfully used to prolong
the dissolution rates of amylobarbitone and timolol.
Levis and Deasy (2003) studied drug release from halloysite loaded with two basic antihypertensives differing
in aqueous solubility (diltiazem and propranol). Propranolol (less soluble) showed a more prolonged release
effect, while for diltiazem drug-loaded halloysite tubes
were coated with different polymers (including chitosan
and cross-linked chitosan) to further reduce the dissolution rate.
2.2.2.2. Layered double hydroxides. Synthetic layered
double hydroxides (LDH, anionic clays) can also be
used as host compounds because of the positively
charged layers and the presence of interlayer anions,
these compounds are especially helpful for retention of
negatively charged biomolecules.
Choy et al. (1999, 2000) studied the intercalation of
nucleosides and DNA into LDH, to develop possible
applications of these complexes as gene delivery carriers. The intercalation of ibuprofen with synthetic hydrotalcite was investigated by Ambrogi et al. (2001).
Hydrotalcite intercalated diclofenac sodium via anion
exchange (Ambrogi et al., 2002). In vitro drug release
from ibuprofen and diclofenac-loaded hydrotalcites
showed that hydrotalcite may be used to prepare
extended release formulations of these anti-inflammatory agents (Ambrogi et al., 2001, 2002). The interaction
of diclofenac sodium (Suzuki et al., 2001) and indomethacin (Yoshiteru et al., 1994) with synthetic mica
has also been reported. Li et al. (2004a) studied in vitro
dissolution of fenbufen from its complexes with
different LDH (Mg/Al, Zn/Al, Fe/Al, Li/Al), finding
that drug release was effectively prolonged, especially
in the case of Mg/Al materials.
2.2.2.3. Modified clays. In the development of claybased extended release formulations, modulation of the
properties of the clay mineral (specific surface area,
porosity, hydrophilic character, kind of exchangeable
cations) may be needed to improve its affinity with the

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C. Aguzzi et al. / Applied Clay Science 36 (2007) 2236

bioactive molecules. Both thermal and chemical (mineral acid dissolutions, intercalation with inorganic or
organic compounds) treatments have been reported to be
useful for this purpose.
Heat-treated sepiolite showed controlled-release of
antifungal and antibacterial isothiocyanates for sanitary
protection in kitchens and food preservation (Corma
Canos et al., 2000). Bojemueller et al. (2001) found that
adsorption of metolachlor onto bentonite was enhanced
by calcinating the clay mineral, because of the enrichment of Al3+ ions at the edges of the silicate.
In acid-treated clay minerals, depopulation of octahedral sheets and formation of amorphous silica was
observed, providing materials with increased surface
area, high porosity and acid character (Vicente-Rodrguez et al., 1996; Dkny et al., 1999). Some authors
reported that acid-treated bentonites were more effective
than the natural ones to reduce the release rate in
extended release formulations (Fernndez-Prez et al.,
1999, 2000; Villafranca-Snchez et al., 2000).
The clay mineral may also be modified with organic
and inorganic compounds, acting as pillars, by permanently holding apart the silicate layers. Inorganic and
organic pillared clays, belong to the general class of
pillared layered structures (PLS), including clay minerals, phosphates and layered double hydroxides (Van
Damne et al., 1995). The great advantage of these
materials is that by a suitable choice of pillar agent, it is
possible to modulate the porosity as well as to change the
surface character from hydrophilic to hydrophobic.
When the hydrophobicity of the clay mineral surface is
increased, the adsorption of hydrophobic molecules is
expected to increase and attain extended release in
aqueous solutions. Thus, organic modified smectites are
widely used as adsorbents of non-polar bioactive substances (Meier et al., 2001). The success of this approach
was shown with alachlor (El-Nahhal et al., 1998),
norflurazon (Undabeytia et al., 2000) and hexazinone
(Celis et al., 2002). Finally, surfactant modified
montmorillonites also showed higher affinity for anionic
species, such as Cr(VI) derivatives, compared to the
unmodified clay minerals (Krishna et al., 2000).
2.2.3. Site-specific systems
2.2.3.1. Colon targeted systems. Site-specific drug
delivery to the colon is attracting increasing attention,
both for therapy of colon-related diseases as well as
systemic drug delivery. For this purpose it is necessary to
incorporate the drug in a formulation able to minimize
premature release in the upper part of the gastrointestinal
tract, and then to optimize drug release into the colon.

Most traditional colon targeted formulations are based

on polymeric materials but inorganic systems have also
been described. Drug release from metronidazolemontmorillonite complexes and their corresponding physical
mixtures was studied by Shrivastava et al. (1985), showing that at acidic pH, both complexes and mixtures were
effective in inhibiting drug release. It has been suggested
that drug diffusion was hindered by the three-dimensional (house-of-cards) network formed by clay mineral particles via edgeface interactions. Lin et al. (2002)
attempted to develop a novel oral delivery formulation of
5-fluorouracil, by using montmorillonite as slow release
vehicle for the treatment of colo-rectal cancer. LDH
loaded with the anti-inflammatory fenbufen and coated
with Eudragit S 100 or Eudragit L 100 (to prevent
gastric release) provided promising in vitro release profiles for colon targeted administration (Li et al., 2004b).
2.2.3.2. Periodontal systems. Aguzzi et al. (2005b)
have checked the suitability of two tetracycline loaded
laminar clay minerals as novel products in the sitespecific treatment of periodontitis, finding promising
release profiles as well as good antibacterial activities.
Incorporation of these complexes in chitosan solutions
resulted in bioadhesive semisolid systems capable of
providing therapeutic levels of drug (tetracycline) compatible with once-a-week administration (Aguzzi et al.,
2005c). Kelly et al. (2004) developed a thermoresponsive gel for periodontal application, consisting of
suspension of chitosan-coated drug-loaded halloysite
tubes in a suitable thermoresponsive vehicle and showing good antibacterial activity in dogs.
2.3. Hydration-activated extended release systems
Smectites successfully act as disintegrant agents in
tablet formulations because of their hydrophilic and
swelling properties (Wai et al., 1966; Fielden, 1996;
Viseras et al., 2001). However, at high clay concentration
tablet disintegration becomes hindered by the rapid
hydration of the silicate, preventing moisture penetration
within the tablets. So, high amounts of smectite may be
employed in prolonged release tablet formulations.
In this case the active substance is not be preadsorbed
onto the clay mineral. McGinity and Harris (1980a)
prepared extended-release tablets by direct compression
of sodium sulphatiazole and magnesium aluminium
silicate (30% wt/wt) and observed the progressive formation of a viscous gel layer around the tablets during in
vitro dissolution tests. They found that drug release was
not significantly affected by tablet hardness but increased with rising stirring rate (because the removal of

C. Aguzzi et al. / Applied Clay Science 36 (2007) 2236

the gel layer around the tablet was facilitated) and pH

(since the clay mineral hydrated more readily at these
conditions). Harris and McGinity (1982a,b) studied
kinetics and drug release mechanisms from the tablets as
a function of a number of key factors (e.g., ionic strength
and surface tension of the dissolution medium, particle
size of drug and montmorillonite). Later, a second order
factorial design was used to produce tablets with the
desired technological and biopharmaceutical characteristics (Harris et al., 1985).
2.4. Particulate delivery systems based on clay minerals
Entrapping of drug molecules in micro- and nanoparticulate systems is a helpful strategy for protecting
drugs against chemical and enzymatic degradation
(especially proteins, peptides and nucleic acids), enhancing aqueous solubility, taste and odor masking,
reducing dissolution rate and/or targeting drug release
(Brigger et al., 2002; Burgess and Hickey, 2002; Fattal
and Vauthier, 2002; Panyam and Labhasetwar, 2003).
2.4.1. Microparticles
Zhu and Adjei (2002) recently patented modulated
release microparticulates for administration of macromolecules into lungs, containing silicates (e.g., amorphous silica, bentonite, attapulgite, kaolin and talc) as
the encapsulating agents both for protecting the active
substance and modulating release into the body.
Halloysite was employed as natural low cost vehicle
for microencapsulation and extended release of both
hydrophilic and lypophilic molecules (Price et al., 2001;
Levis and Deasy, 2002). Kaolinite and halloysite were
used to produce microporous pellets as novel extended
release oral delivery systems (Byrne and Deasy, 2005).
Halloysite-based systems showed slower drug release
because the microtubes created a more tortuous matrix
within the pellets.
2.4.2. Nanoparticles
Nanotechnology has recently been defined as being
the study, design, creation, synthesis, manipulation,
and application of functional materials, devices, and
systems through control of matter at the nanometer scale
and the exploitation of novel phenomena and properties
of matter at that scale (Salamanca-Buentello et al.,
2005). In drug delivery, nanotechnology focuses on
developing submicron carriers (nanospheres, nanocapsules, micellar systems,) for incorporation of small
molar mass substances as well as macromolecules.
Pharmaceutical nanoparticles are often made of organic
polymers (biodegradable or not) but inorganic systems

29

are receiving much attention in the pharmaceutical field.

In particular, clay minerals can provide spontaneous
submicron dispersions in aqueous media, resulting in
low cost and biocompatible systems with large surface
area and high inclusion capacity.
Hollow silica nanoparticles are versatile materials
for a wide range of applications including heavy metal
and gas adsorption, catalysis, coating, and enzyme
immobilization. Additionally, they are now being
considered for delivering drugs, proteins and genetic
materials. Porous silica particles can be easily prepared
by heating silicates at high temperature or by treating
them with acids, alkali or organic solvents. However,
for encapsulation of any heat- or chemical-degradable
active agent (such as enzymes, peptides, proteins and
nucleic acids) the use of these techniques should be
avoided. Naturally occurring nanotubular clay minerals
such as halloysite may be beneficially exploited for
these purposes. Veerabadran et al. (2005) have used
halloysite as nanotubular adsorbent for delivery of
furosemide and dexamethasone. Loading of DNA
oligomers onto halloysite tubes for gene delivery has
also been reported (Veerabadran et al., 2005). Rakesh
Kumar et al. (2005) have described a novel method to
synthesise hollow silica nanoparticles at room temperature under mild chemical conditions. These nanoparticles retained the catalytic activity of the entrapped
enzyme.
Other techniques to prepare hollow nanoparticles for
pharmaceutical use include surface precipitation and
layer-by-layer assemblies. Nanoparticles based on the
surface precipitation of silica on calcite cores (Zhang and
Li, 2004) were proposed as carriers for drug delivery of
cefradine, exhibiting a delayed release effect in acidic
medium (Chen et al., 2004). The layer-by-layer
technique consists in the alternate adsorption of oppositely charged polyelectrolytes (Lvov et al., 1996). It
was recently applied to prepare an assembly for
supplying the NADH cofactor (loaded into halloysite
tubes) to immobilised alcohol dehydrogenase in polyion
films (Lvov et al., 2002).
Polymer/clay nanocomposites are a new class of
hybrid systems in which inorganic or organo-clay
nanoparticles (often montmorillonites) are dispersed in
a polymer matrix. They have some interesting advantages compared to the pure polymer, such as enhanced
mechanical (Chang et al., 2003; Cypes et al., 2003; Lee
and Fu, 2003; Kiersnowski and Pig3owski, 2004; Lee
and Chen, 2004; Puttipipatkhachorn et al., 2005) and
rheological properties (Pongjanyakul et al., 2005a).
These benefits along with the good intercalation capacity offered by the clay mineral particles have been used

30

C. Aguzzi et al. / Applied Clay Science 36 (2007) 2236

to develop new controlled release systems, as documented by a number of patents (Greenblatt et al., 2004;
Nagasaki et al., 2005; Zhong, 2005). Nanocomposites
based on poly(ethylene-co-vinyl acetate) (EVAc) and
three different organo-silicates (one montmorillonite
and two synthetic micas) have been developed by
Cypes et al. (2003), providing slow release of dexamethasone (a corticosteroid agent widely used to reduce
inflammatory diseases), as well as enhanced mechanical properties (Youngs modulus) in comparison with
the free polymer. Nanocomposite hydrogels for mucoadhesive applications were synthetised by Lee and
Chen (2004), by performing photopolymerization of
acrylic acid (AA), poly(ethylene glycol) methyl ether
acrylate (PEGMEA) and an organo-modified bentonite.
The gels showed increased Youngs modulus with
increasing bentonite content while the adhesive force
did not decrease with an increase of the amount of the
clay. In vitro release studies of differently charged
drugs from N-isopropylacrylamide-montmorillonite
(Lee and Fu, 2003) and poly(AA-co-PEGMEA)-bentonite (Lee and Chen, 2004) nanocomposite gels showed
that the amount released was lower when the drug and
hydrogel were oppositely charged. Conversely (drug
and hydrogel showing the same sign of charge), the
amount released was higher. The influence of the
amount of the organic agent intercalated into montmorillonite on the physical properties and drug release
behaviour from N-isopropylacrylamide-montmorillonite nanocomposites was investigated by Lee and Jou
(2004).
Pongjanyakul et al. (2005a) showed that rheological
properties (such as viscosity and flow behaviour) of
sodium alginate or poloxamer 407 gels were improved by
incorporation of magnesium aluminium silicate (MAS),
while less influence was observed for HPMC gels. Drug
release of these composite materials was significantly
decreased in comparison with the pure polymeric gels,
due to both clay-polymer interactions, and drug adsorption onto clay particles (Pongjanyakul et al., 2005a).
Magnesium aluminium silicate has also been applied to
improve physical properties in alginate beads (Puttipipatkhachorn et al., 2005) and to prepare novel composite
films as coating material for modifying drug release from
tablets (Pongjanyakul et al., 2005b). Takahashi et al.
(2005) have developed a new nanocomposite system by
combining Laponite (a synthetic hectorite-type clay
mineral) with a block copolymer containing poly
(ethylene glycol) and polyamine segments. These
nanoparticles were capable of sustained release of
pyrene (hydrophobic model drug molecule) over a
period of 20 days. Flocculation-resistive properties of

these hybrid particles at high ionic strength have also

been reported (Takahashi et al., 2005) whereas clay
mineral dispersions normally tend to coagulate in salt
solutions, as has been widely documented (Lukham and
Rossi, 1999; Ma and Pierre, 1999; Abend and Lagaly,
2000). Dong and Feng (2005) have designed a drug
delivery system, consisting of poly(D,L-lactide-co-glycolide)-montmorillonite nanoparticles, for oral delivery of
paclitaxel. Nanoparticles were prepared by the emulsionsolvent evaporation technique where montmorillonite
was also employed as coemulsifier. The clay mineral did
not affect drug release from paclitaxel-loaded particles
but it promoted the cellular uptake efficiency of the
PLGA nanoparticles in Caco-2 and in HT-29 cells.
3. Use of clay minerals to improve drug dissolution rate
Improving dissolution of poorly water-soluble drugs
remains one of the more important challenges for
pharmaceutical technologists. Among the several approaches applied, the surface adsorption of drug
molecules onto finely divided solids greatly increases
the surface area available to the dissolution medium.
Monkhouse and Lach (1972a,b) first described this
strategy using silica and silicic acid as the adsorbent
agents. Smectites were found to effectively enhance the
in vitro dissolution rate of non-ionic and acidic insoluble
drugs. Drug release from the clay surface is promoted by
the weak bonding between them and concomitantly
drug wettability is enhanced due to the hydrophilic
properties of the clay (McGinity and Harris, 1980b,c;
Kreuter, 1981; Boraie et al., 1983; Takahashi and
Yamaguchi, 1991a,b; Lagadic et al., 2005). Tablets
prepared by direct compression of hydrochlorotiazideveegum adsorbates showed complete dissolution
(100%) of the drug in 10 min while commercial tablets
only released 50% of the dose over the same time
(Boraie et al., 1986). Phenytoin-montmorillonite adsorbates were able to improve the bioavailability of the
drug in humans in comparison with phenytoin sodium
capsules (Koeleman et al., 1990). Ito et al. (2001)
reported that blood levels of indomethacine in rats from
transdermal patches based on drug-montmorillonite
composites were higher compared with control compounds containing crystalline indomethacine.
4. Concluding remarks
As documented by a large number of papers and
patents, clay minerals play a crucial role in modulating
drug delivery. Suitable choice of the clay mineral is the
first step to provide therapeutically effective systems.

C. Aguzzi et al. / Applied Clay Science 36 (2007) 2236

Naturally occurring clays and clay minerals may be

suitable to effectively modulate drug release. However,
sometimes it is necessary to use modified or synthetic
clay minerals and/or polymeric additives. The investigation of claydrug interaction and release mechanisms
is an essential contribution for the formulation of claybased drug delivery systems. The possibilities of such
systems depend on the amount of drug retained by the
clay as well as on the release kinetics and the total
amount released in regard of the therapeutic regime.
The therapeutic advantages of these technologically
advanced drug products make this field of investigation
a high-priority development area.
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