CONTROLLED CHEMICAL AND DRUG DELIVERY VIA THE INTERNAL AND EXTERNAL SURFACES OF LAYERED COMPOUNDS

Journal Disp. Sci and Technol. 24, 589 (2003)

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CONTROLLED CHEMICAL AND DRUG DELIVERY VIA THE INTERNAL AND

EXTERNAL SURFACES OF LAYERED COMPOUNDS.

Joseph F. Bringley* and Nancy B. Liebert

Imaging Materials & Media, R&D, Eastman Kodak Company, Rochester, NY 14650-2002, USA

ABSTRACT

We demonstrate, and review the very small, but growing body of literature regarding a recently

discovered application of layered compounds, which involves the ability of layered materials to

sequester and later release molecules of chemical and biological significance. The application

relies upon intercalation chemistry; a reversible process whereby atoms, molecules,

macromolecules, and polymers may be inserted into the interstices of a layered matrix. We

demonstrate that layered materials are able to effectively getter water-soluble atoms and

molecules from aqueous dispersions, and further demonstrate that the absorbed molecules can be

later released from the interlayer region to perform a desired chemical function. Work in our

laboratory involving the application of layered hybrid materials in photographic media is

described in detail and we establish two general release mechanisms whereby intercalated

functional chemistry can be first sequestrated and later delivered via a chemical switch to

perform a desired function. The process has enormous potential as a general method for the

controlled, temporal release of materials of chemical and biological significance.

*Corresponding author. E-mail: [email protected]


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INTRODUCTION

Layered compounds are a class of materials in which strong bonding, i.e., ionic or covalent, is

limited to two-dimensions, or less. In the third dimension, only weak van der Waals type

interactions are present, which we shall see, give rise to a unique and diverse set of chemical and

physical properties. The impetus for work on layered materials has been provided by the

recognition of an extremely broad range of applications, including composites, high-energy-

density battery materials, catalysts, separations materials, bio-medical materials and more

recently, drug and chemical delivery materials.[1-9] Many excellent reviews have appeared on the

general chemistry, structure and physical properties of low-dimensional, or layered, materials

and we direct the reader to the references contained herein.[1-6] In this report, we shall focus,

specifically, on the ability of layered compounds to sequester and later release, compounds of

chemical, biological or industrial interest. We give a short review of the small body of literature

on this subject, and include a detailed description of work performed in our laboratory.

The ability of layered compounds to sequester atoms, or molecules, arises directly from the weak

bonding interactions, which are present between the layers of lamellar materials. Thus, it is

possible to �prop� the weakly bound layers open to insert atoms, molecules, oligomers, or

polymers in a process widely known as intercalation chemistry.[1]. Intercalation is a process in

which a layered material, referred to as the host, swells or opens to accommodate other

molecules or ions, referred to as the guest as in Eq. (1), and depicted graphically in Fig. 1. The

chemistry occurs both naturally and synthetically and a wide variety and large number of

intercalation compounds are known.[1-6]

(1) Host + guest ! Host(guest)x


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layered host solid + guest molecules intercalation compound

Figure 1. An illustration of the intercalation process.

Interactions between the host and guest species, and between neighboring guest species, stabilize

the intercalation complex over the physical mixture. The process is by definition reversible, and

generally occurs through one of three general mechanisms including ion-exchange, acid�base

interaction, and via charge-transfer. Specific examples of intercalation compounds prepared via

these methods are given in Eqs. (2�4).

Ion Exchange

Mg2Al(OH)6.NO3 + C12H24SO4

-Na+ ! Mg2Al(OH)6. C12H24SO4

- + NaNO3 (2)

Acid Base

Zr(HPO4)2.H2O + RNH2 ! Zr(PO4

-)2. 2RNH3

+ + H2O (3)

Charge Transfer

FeOCl + ET ! FeOCl(ET)1/8 (4)

Ion exchange is by far the most common form of intercalation reaction and occurs for a wide

variety of materials including smectic clays,[10] layered double hydroxides,[6] hydroxy double

salts,[11] metal hydrogen phosphates,[4] and others.[1-10] Mg2Al(OH)6.NO3, is a member of a large

class of layered materials known as layered double hydroxides (LDH, vide supra) and may


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undergo intercalation of negatively charged atoms, molecules, or complex species via the

exchange of interlayer anions such as NO3-, Cl-, etc. Because of the exchange, the distance

between adjacent [Mg2Al(OH)6]+ layers swells to accommodate the anionic guest species. The

degree of swelling of the layers is dependent upon a number of factors including the size of the

guest species and the nature of host-guest and guest-guest interactions, but typically varies from

about a few angstroms to as large as 50 Å. For the example shown, dodecylsulfate intercalated

into layered double hydroxide (Mg2Al(OH)6. C12H24SO4), the interlayer distance is 25.7 Å.[12]

Acid-base type intercalation reactions occur for inorganic solids, which have a strongly acidic

interlayer region, as is the case for the metal hydrogen phosphates M(HPO4)2.H2O. Organic bases

such as amines interact strongly with the acidic protons in the interlayer region and are readily

intercalated,[4] (Eq. 3). Charge transfer is a less common form of intercalation reaction but occurs

for a number of layered materials such as the metal oxyhalides,[13] metal dichalcogenides,[14] and

several other layered materials. The driving force for intercalation is provided by a transfer of

charge, usually from guest to host, and very often though π−π stacking interactions of the guest

species within the host galleries. Equation 4 shows an example of such a reaction in which the

organic molecule bis(ethylenedithio)tetrathiafulvalene (BEDT-TTF or �ET�), a molecule used to

prepare organic conductors and superconductors, is intercalated into the host FeOCl.[15]

Intercalation materials prepared via the above methods are beginning to find a wide range of

commercial uses ranging from bio-medical applications,[8] solid state batteries,[16] catalysts,[17]

acid scavengers,[18] and composites,[19] to name just a few. Zr(HPO4)2.H2O has been employed to

getter ammonia in kidney dialysis.[20] Zr(H1-xAgxPO4)2.H2O is sold as an antimicrobial agent in

food contact materials.[21] The layered double hydroxides are sold commercially and used in

polyvinylchloride composites as acid scavenger materials.[20] Various ion-exchanged zeolites

have long been used in catalysis[17] and more recently synthetic clays are finding extraordinary

uses as inorganic-organic polymeric nanocomposites.[22]

Herein, we demonstrate and review the very small, but growing body of literature on a more

recently discovered application of layered compounds, which involves the ability of the materials

to sequester and later release molecules of chemical and biological significance. The application


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relies on the fact that the intercalation process is reversible, and on the fact that the equilibrium

distribution of intercalated versus un-intercalated, or �free� molecules, can be rapidly changed

via access to a chemical �switch�, such as a concentration gradient or change in pH, or even

potentially a physiological change.[9] We demonstrate that layered materials are able to

effectively getter water soluble atoms and molecules from aqueous dispersions, and further

demonstrate that the absorbed molecules can be later released from the interlayer region to

perform a desired chemical function. The process has enormous potential as a general method for

the controlled, temporal release of materials of chemical and biological significance. The article

is devoted mainly to the intercalation chemistry of the layered double hydroxides and to that of

the metal hydrogen phosphates although the general sequester and release concept may be

directly extended to a multitude of other systems.

SEQUESTER AND CONTROLLED RELEASE: SOME GENERAL CONCEPTS

Chemical, and even more so biological, processes are often sequenced temporally to obtain a

desired result. That is to say that the identities, concentrations, and the sequence of reactants may

play a definitive role in determining the outcome of a particular process. In general, the role of

these processes becomes more critical as the complexity of a system increases. There are many

examples of such systems in biological and pharmaceutical processes, wherein a particular

reagent may be toxic to particular components of the system, or acutely concentration dependent

in its effect upon the system. This recognition of the divergent needs of complex systems, and

coincidently many dramatic advances in materials technologies, has provided the impetus and

the tools for the emerging field of controlled drug delivery. The field often relies on the

development of complex dispersion technologies, which allow for the sequential and time-

dependent release of a particular agent to a system. The approach has been pursued most broadly

toward drug delivery, but is not limited to this application. Although chemical examples, because

they are often significantly less complex, are not as well known, some excellent examples do

exist. The photographic process is a remarkable example of such a system in which the processes

of exposure, latent image formation, development, and development inhibition are carefully


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controlled both spatially and sequentially, and through complex chemical feedback loops, to

produce a desired result.[23] Further, the development of complex dispersion technologies,

comprising self-assembled nanoparticulate systems, capable of detecting and responding to

physical (light) and chemical stimuli, have been paramount to the development of the

photographic industry. The self-assembly of sensitizing dyes, and consequent spectral

sensitization of silver halide grains, was first recognized as early as 1873.[24] Complex chemical

feedback loops able to first accelerate and then shut-down a process have long been employed in

the photographic process.[25] Indeed, the photographic process employs a plethora of complex

chemical reactions, sequenced and carefully controlled, to faithfully reproduce images,[25] and

thus serves as a prime example of a non-biological, complex chemical system.

The ability to successfully develop controlled chemical delivery systems relies on the

development of techniques to sequester, and later release upon demand, functional chemistry.

We use the term sequester to emphasize that in many cases it is necessary that the chemistry be

transparent to the system (i.e., unrecognized by other components) until the time that it is

required. This is true because some components may be deleterious, or toxic, to a system when

made available out of sequence. Through the development of polymer dispersion technologies, in

which target molecules are encapsulated within polymeric beads, scientists have been able to

slow that rate of delivery of chemo/biological compounds. However, this method perhaps has the

disadvantages in that it is typically non-specific and that release gradually occurs and may not be

easily controlled. Layered compounds are an interesting alternative, or are complementary to this

technology, in that they are able to effectively sequester complex molecular and even polymeric

species via intercalation chemistry as described above. The intercalated form of a molecular

species is typically unreactive, because it is sequestered in the solid state and cannot diffuse to

the reactive site, and because it is conformationally and sterically hindered by the host layers.

Further, and perhaps more importantly, because they provide several mechanisms, or chemical

�switches�, whereby target molecules may be suddenly released to a system, they allow for at

least some temporal control over concentration. The release mechanisms afforded by

intercalation technology arise from the fact that the intercalation process is inherently reversible,

and from the differential chemical affinities of molecular moieties for the interlayer host

surfaces. The most immediate release mechanism is ion exchange via a concentration gradient,


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in which an abundant system ion is exchanged, and affects the release of, a sequestered

functional molecule (FM).

Host(FM) + ion ! Host(ion) + FM

A second release mechanism is a pH-switched release of an intercalated molecule, which occurs

as the pH is varied about the pKa of the intercalated molecule. This has the effect of neutralizing

the charge on the molecule, and thus it diffuses away from the host since it is no longer

coulombically bound to the host lattice.

pH > pKa

Host-[GuestH+] ! Host + Guest

Some specific examples of these processes and details of their intercalation chemistries, their

ability to sequester in aqueous dispersions, and release mechanism are discussed below to

demonstrate the general concepts.

EXPERIMENTAL

Layered double hydroxide was obtained from Sud Chemie having the composition

Mg0.7Al0.3(OH)2.0.15 CO3

. nH2O. This material was calcined before use at 500°C for 3 h and

cooled in a nitrogen atmosphere, the calcined product is hereafter referred to as c-LDH.

Zr(HPO4)2.H2O was prepared as described in the literature.[26] In a 4.0 l Erlenmeyer flask was

placed 750 mL distilled water and 750 mL 85 % phosphoric acid. The solution was heated to

80°C and a solution of 200.00 g of ZrOCl2.8H2O dissolved in 500 mL of distilled water was


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added drop wise over about 3 h with vigorous stirring supplied by a Teflon coated prop stirrer.

A white gelatinous precipitate appeared and after the addition was complete, the stirring was

continued at this temperature for 18 h. The solid was collected by filtration, washed with 2.0 l of

distilled water and 1.0 l of ethanol and recollected by filtration and dried at room temperature

under flowing nitrogen. The yield was 177.0 g (94.7%). X-ray powder diffraction confirmed that

the product was Zr(HPO4)2.H2O with no apparent impurities.

Preparation of Intercalates

Mg0.7Al0.3(OH)2.0.26 PMT. nH2O. 10.00 g 1-phenyl-5-mercaptotetrazole (PMT) was placed in

250 mL of distilled water and to the stirred suspension under nitrogen was added 8.21 of c-LDH.

After 1 h, the pH was adjusted to 7.5 by the addition of 1 N nitric acid. The mixture was then

stirred at 50°C for 3 h and at 25°C for 4 days. The product was collected by vacuum filtration

and washed with ethyl alcohol. Elemental analysis, with theoretical values in parentheses, gives

C = 19.5 % (18.8 %), N = 11.9 % (12.5 %), S = 7.0 % (7.2 %), in good agreement. The integrity

of the guest molecule is confirmed by UV-VIS spectroscopy, and by de-intercalation and

subsequent GC analysis.

Zr(H0.45PO4)2. [2 CD:2H+]0.55. Into 75.0 g distilled water was placed 2.00 g of Zr(HPO4)2

.H2O.

To the stirred suspension was added 26.6 mL of 0.25 M NaOH. This was allowed to stir for

about 1 h and the contents were degassed with nitrogen. 2.85 g of .color developer [ethanol, 2-(4-

amino-3-methyphenyl)ethylamine, see Fig. 7 inset) were added, along with a small amount

(0.090 g) of Na2SO3 antioxidant. The contents were stirred for 24 h under nitrogen and the solid

recovered by centrifugation and washed 3 times with pure distilled water. Elemental analyses

were consistent with the composition shown above.

Zr(Ag0.75H0.25PO4)2.H2O. Zr(HPO4)2

.H2O (10.00 g, 0.0332 moles) was suspended in 200 mL of

distilled water. 2.5 M NaOH was added drop wise to this suspension until the pH was about 4.

200 mL of a 0.5 M AgNO3 solution was added to the suspension and the pH adjusted to 4.0 with

the addition of 0.25 NaOH, and the contents allowed to stir for 18 h. After this time, the solid


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was separated in a centrifuge, washed with distilled water until no Ag ion could be detected in

the eluent, and finally re-suspended to make a solution containing 3.8 w % gel and 7.5 w %

solids. Elemental analysis showed the composition of the solid to be Zr(Ag0.75H0.25PO4)2.H2O.

Preparation of Photographic Coatings

Experimental photographic films were prepared upon cellulose acetate support. Coatings were

prepared from gelatin dispersions containing silver halide emulsion(s), coupler dispersion and

surfactants. Materials were typically coated onto the support at a laydown of 100 mg/ft2 Ag, 75

mg/ft2 coupler, and 300 mg/ft2 gelatin. The levels of addenda were varied as given. The emulsion

examined in this study in all cases was an undyed sulfur-only sensitized AgBr tabular emulsion,

with average grain dimensions, 2.9 × 0.132 µm.

The sensitometric properties of the coatings were assessed as follows: elements received

identical stepped 365 nm line exposures to allow density (D) versus exposure (log E)

characteristic curves to be plotted. The exposed elements were processed in the Kodak Flexicolor

C-41 color negative process described in British Journal of Photography Annual (1988, pp. 196-

198). The resulting cyan dye images were analyzed using an optical densitometer and plotted as

optical density versus the log relative exposure.

Sequester and Release of Anionic Molecules and Supramolecules

Few host materials are able to accommodate anionic guest species, however, fortunately the

hosts that are able, intercalate a remarkably broad range of anionic molecule, supramolecules,

and polymers. We include a general description of their intercalation chemistry below with an

emphasis on the �reconstruction� method of synthesis and their ability to sequester molecules

from aqueous dispersions.


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I. Layered double hydroxides (LDH):

The layered double hydroxides[6,27-31] are members of a very large class of materials closely

related to the mineral hydrotalcite and represented by the general formula: [M2+1-x M

3+x

(OH)2]An-

x/n�yH2O; or [M1+ M

3+2 (OH)6]A

n-x/n�yH2O; where M1+ = Li, Na, K, Rb or Cs; M2+ =

Ca, Mg, Mn, Co, Ni, Cu, Zn, and Cd; and M3+ = Cr, Fe, Al, Ga, In, Mo; A may be an organic

anion, but is typically an inorganic anion such as NO3-, Cl-, Br-, I-, ClO4

2-, SO42- , or CO3

2-. A

closely related class of materials and having, in general, a very similar intercalation chemistry

are the hydroxy double salts of the general formula: (M2+)5(OH)8. (An-)2/n �yH2O or (M2+)2(OH)3.

(An-)1/n �yH2O; wherein M is typically Zn, Cu or Ni.[32,33] These remarkable materials are closely

related to the mineral brucite, Mg(OH)2, which has a layered structure consisting of sheets of

edge-sharing Mg(OH)6 octahedra. The hydrotalcite structure is derived from brucite by

substitution onto the cation sublattice as in Eq. (5) and the subsequent uptake of an anion into the

interlayer region to preserve charge neutrality.

Derivation of Hydrotalcite from Brucite

Mg(OH)2 + x Al3+ + x anion ---------> [Mg1-xAlx (OH)2]An-

x/n�yH2O (5)

The structure of Mg2Al(OH)6.1/2CO3

.H2O is given in Fig. 2 and shows the interlayer (carbonate)

anions, which may be readily ion-exchanged. The brucite-like [Mg0.7Al0.3(OH)2]+0.3 sheets are

held together only loosely through coulombic attraction to the interlayer anions and via van der

Waals forces.

The preparation and general intercalation chemistry of these materials has been described


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elsewhere.[6,27-31] We include herein, the preparation of intercalation complexes of specific

interest, and describe the preparation of dispersions of the intercalates.

Figure 2. The crystal structure of Mg2Al(OH)6.1/2CO3

.H2O; representing the general structure of

the layered double hydroxides. The [Mg0.67Al0.33(OH)2]+0.3 sheets are shown in blue and the

exchangeable interlayer anions (carbonate) are given in red, H2O = green.

A. LDH Intercalation Chemistry

The intercalation chemistry of LDH is rather unique, because intercalation complexes can be

prepared by one of several methods including ion-exchange, direct precipitation or by a rather

unique method known as �reconstruction�.[29,34] The details of these methods have been reviewed

elsewhere, but we devote some time herein to the reconstruction method because it is ideally

suited for the preparation of aqueous dispersions of intercalation complexes. A schematic of the

reconstruction method is shown in Fig. 3. Layered double hydroxides may be obtained

commercially with the composition Mg2Al(OH)6.1/2CO3

.H2O. When this material is calcined at


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about 500°C, it decomposes to an amorphous solid, which is presumably a mixture of Mg- and

Al-oxides. When the amorphous solid is re-dispersed in aqueous media containing a suitable

organic or inorganic anion, it may �reconstruct� to form the layered intercalation compound of

the new anion. The reaction has the stoichiometry[34] as indicated in Eq. (6) below, and generally

proceeds readily at, or just above, room temperature. The reaction is quite remarkable in that in

many cases it proceeds quantitatively to completion and has no by-products.

1.15 Mg0.62Al0.26O + 0.3/p H+Anion-p -----> Mg0.7Al0.3(OH)2.0.3/p Anion. nH2O (6)

Figure 3. A schematic of the �reconstruction� method of intercalation, wherein the precursor is

calcined to form an amorphous oxide and the oxide later re-dispersed in water with an

appropriate anion to form the intercalation compound.


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To illustrate the ability of this method to form intercalation compounds with complex organic

anions and to demonstrate the ability of this technology to effectively getter the anion from

aqueous solution, we discuss in detail a specific example in which the well-known photographic

inhibitor phenylmercaptotetrazole (PMT, shown below)[25] is intercalated into LDH.

Phenylmercaptotetrazole is a heterocyclic acid, forming a stable anion above about pH 4.0.

1.15 Mg0.62Al0.26O + 0.3 --! Mg0.7Al0.3(OH)2.0.26 PMT. nH2O (7)

PMT

In this reaction a slight excess of PMT and a stoichiometric amount of calcined

Mg2Al(OH)6.1/2CO3

.H2O are stirred together in aqueous solution at about 50°C to form the

intercalation compound of Eq. (7). Elemental analysis indicates a PMT loading of 0.26, slightly

below the stoichiometric value, 0.30. The discrepancy is because steric crowding prevents the

PMT molecules from intercalating at a stoichiometric amount; the periodicity of charge density

of the host lattice is slightly smaller than can be accounted for by close packing of guest

molecules. The powder X-ray diffraction pattern of the product, Fig. 4, indicates a highly

crystalline product with an interlayer spacing of 16.9 Å, which represents an increase of 12.1 Å

over that of the host sublattice (4.8 Å), i.e., the thickness of a single [Mg0.7Al0.3(OH)2]+0.3 layer.

This increase is consistent with an upright orientation of the PMT molecule within the host

layers, which is to say that the long axis of the PMT molecule lies perpendicular to the LDH

layers.


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Figure 4 . Powder X-ray diffraction spectrum for Mg0.7Al0.3(OH)2.0.26 PMT. nH2O. The first

four peaks labeled are interlayer (00l) reflections. The inset shows the approximate orientation of

the guest molecules as derived from the interlayer expansion.

To determine the efficiency of this reaction in gettering PMT from aqueous solution, we

subjected a 10 mg/mL solution of PMT to varying amounts of calcined LDH, and after 18 h of

stirring, centrifuged the reaction contents and analysed the supernatant for the unintercalated

guest. The results of these studies are plotted in Fig. 5, as a function of host loading for the PMT

and other guest anions. The guest molecules studied are common photographic molecules; their

structures and names are given below. In each case, the pH was kept constant between 6.5 and

7.5 and the concentration of guest species was 10 mg/mL.

N

NNN S

N

N NNS


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ascorbic acid (AA) DNB SBPMT

3,5-dinitrobenzoic acid 1-[3-(2-sulfo)benzamidophenyl]

-5-mercaptotetrazole

0

20

40

60

80

100

120

1x 2x 3x 4xEquivalents Calcined LDH

Perc

ent U

ptak

e

PMTDNBAASBPMT

Figure 5. Percent uptake for 10 mg/ml solutions of the guest species as a function of LDH

stoichiometry. The stoichiometry is calculated as per equation 6.


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The data of Fig. 5 show that the ability of LDH to effectively sequester guest molecules from

solution is dependent upon the chemical nature of the guest species itself. The size of the

molecule certainly must play a role as at stoichiometric levels steric crowding will likely prevent

complete uptake of the guest into the host layers. This effect is observed for all the molecules of

interest as a marked increase in uptake is observed upon going from 1x to 2x the stoichiometric

amount. For higher levels of c-LDH, typically greater than 90% of the soluble guest species is

gettered from solution and in some cases 100% of the molecules are effectively gettered from

solution. The variation in uptake will be dependent upon the solubility, the basicity, and the

charge of the guest species. The remarkable simplicity of the synthesis allows for the direct

preparation of dispersions with little or no post treatments, such as filtration to remove by

products, or mechanical energy to reduce particle size. The host need only be combined with an

appropriate quantity of a chosen guest species in aqueous dispersion and allowed to stir, typically

at temperatures between about 25�70°C. The time for the reaction to reach completion increases

as the size of the guest increases and as the solubility of the guest decreases. The particle size

distributions typically vary from about 0.30 to about 2.0 microns for Mg2Al(OH)6:anion

intercalates and may be modified somewhat by suitable choice of host composition. Polymeric

addenda and surfactants (typically non-ionic) may be added if necessary. Some characteristics of

LDH and cationic clay dispersions have been discussed in detail.[35,36] A unique form of

dispersion of layered materials may, in some cases, arise from the exfoliation of the host

lattice.[37-39] Exfoliation refers to a special case in which the individual host layers have been

essentially �solvated� such that they are spread apart by distances so great that there are no

longer interactions between adjacent layers. The layers thus float freely in the dispersing media

and have length scales on the order of microns but thicknesses on the order of 5�10 Å. This

remarkable physical state of layered materials has been reviewed nicely by Jacobson.[5]

Sequester and Release of Bio-molecules

Several authors have shown that relatively simple and genuinely complex bio-molecules can be

incorporated into LDH hosts.[7-9, 40-44] In a remarkable series of papers, Choy et al.[7,8] have


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shown that complex bio-molecules such as adenosine triphosphate (ATP), oligonucleotides

and DNA are readily exchanged into LDH to form bio-LDH nanohybrids. The bio-molecules are

sequestered intact between the host layers and are bound via the interaction of the negative

phosphate functionalities with the positively charged layers. The intercalation complexes were

found to greatly enhance the transfer of bio-materials into mammalian cells, presumably because

the neutral complex formed minimizes electrostatic repulsions, which normally occur between

negatively charged cell membranes and negatively charged bio-materials.[8] A pH type release

mechanism is invoked whereby the guest molecules are released inside the cell membrane. In a

related report, Choy et al. showed that LDH intercalation complexes with molecules having

pharmaceutical, cosmeceutical, and nutraceutical functions could also be prepared.[44] Khan et

al.9 prepared intercalation complexes of a number of cardiovascular and anti-inflammatory

agents and proposed their use as novel �tunable� drug delivery vehicles. The drugs were shown

to be released intact from the interlayer galleries and the rate of release was found to vary, in

some cases, as a function of pH. Fudala et al.[40] reported the intercalation of amino acids into

Zn-based LDH and into cationic montmorillonite clays. The amphoteric nature of such species

allows for the intercalation into hosts having either negative (LDH) or positively charged layers.

Constantino et al.[41] ion exchanged fluoroscein dye into Zn-based LDH and further established a

synthesis whereby dye was absorbed only to the surfaces of the LDH particles. Aisawa et al.[42]

showed the intercalation of amino-acids into a variety of LDH materials and showed a structural

specificity of the hosts dependent upon the molecular structure of the amino acids. Kumar et

al.[43] reported the intercalation of proteins into the interlayer galleries of α-Zr(HPO4)2.H2O and

found that the proteins remained intact and retained activity after intercalation. The retention of

structure and activity are important attributes regarding the application of inorganic

biocomposites. Although research in bio-layered material composites is certainly only in its

infancy, these studies indicate the vast potential and the remarkable array of composite structures

accessible by intercalation methods. The approach is suited to the sequester, release and targeted

delivery of molecules of biological significance and as complex reservoirs for facile gene, DNA

and bio-information delivery.


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Sequester and Release of Cationic Molecules and Supramolecules

A wide variety of layered compounds are able to accommodate cationic guest molecules into

their interlayer spaces, including clay minerals,[10] metal hydrogen phosphates,[4,26] transition

metal dichalcogenides,[14] and layered metal oxides,[3] to name only a few. The vast majority of

these reactions involve the intercalation of amino-functionalized organic molecules via an acid-

base type mechanism. We describe here briefly the intercalation chemistry of the metal hydrogen

phosphates and consequently their application as chemical sequester and delivery vehicles in

photographic media.

Metal Hydrogen Phosphates (MHP)

Zr(HPO4)2.H2O is a member of a class of materials known as the metal hydrogen phosphates and

may undergo reversible intercalation by either ion-exchange or by a Brönsted acid-base

interaction, Eq. (3).[4,26] The X-ray crystal structure of Zr(HPO4)2.H2O was reported by Clearfield

et al.[45] and is given in Fig. 6. The structure consists of sheets of Zr4+ ions octahedrally

coordinated by oxygen atoms, which comprise the corners of PO43- tetrahedra (in green below).

Three of the oxygen atoms in the tetrahedra are bound to three different Zr atoms while the

fourth bonds to a proton and points into the interlayer space. Only weak van der Waals forces

exist between HPO42- groups across the interlayer space. The protons in the interlayer region are

highly acidic and it is these last two factors which give rise to the rich ion exchange and

intercalation chemistry of metal hydrogen phosphates.[4,26] Organic bases such as amines, or

molecules with amine functionalities, may be inserted into the interlayer space where they are

protonated and bound coulombically by the host lattice. In addition, the proton may be readily

ion exchanged for alkali and alkaline earth metals, and some transition metals. The affinity and

selectivity is determined by the charge and size of the metal ion; a very strong selectivity has

been suggested for silver ion.[46,47]


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Fig. 6. Crystal structure of α-Zr(HPO4)2.H2O; zirconium (red), oxygen (blue), hydrogen (white),

phosphorus (not shown) reside at the center of the tetrahedra. Interlayer water is excluded for

clarity.

In our laboratory, we have prepared intercalation complexes of atomic and molecular species of

photographic interest within the interlayer galleries of LDH (vide infra) and metal hydrogen

phosphates. We briefly describe the materials preparation and the ability of the complexes to

sequester the functional chemistry within aqueous dispersions (which often also contain gelatin

and surfactant). We further demonstrate a chemical switch mechanism whereby the sequestered

materials are rapidly released to perform a desired function.


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Sequester and Release of Photographic Molecules via MHP Hosts.

The protons in the interlayer region of MHP are highly acidic and may be readily ion exchanged

for alkali and alkaline earth metals, and some transition metals as is shown in Eq. (8).[26]

Zr(HPO4)2.H2O + 2 NaOH(aq.) ! Zr(NaPO4)2

.5H2O + 2 H2O (8)

The exchange is accompanied by the uptake of an additional four moles of water into the

interlayer space and results in a considerable expansion of the interlayer region. Our synthetic

schemes take advantage of this effect, to later exchange larger organoammonium cations into the

interlayer space according to Eq. (9).

Zr(NaPO4)2.5H2O + 2 RNH3

+X aq.) ! Zr(PO4)2. [2 RNH3]

.nH2O + NaX (9)

Alternatively, the organoammine may be reacted directly with the unexchanged pristine host as

in Eq. (3), although this method is often considerably slower. The functional chemistries to be

intercalated were chosen from modern photographic color developers[23,25] (CD), which are two-

electron reducing agents derived from para-phenylenediamine, some representative examples of

these materials are shown in the inset of Fig. 7. Color developers are responsible for

amplification of the latent silver halide image (which may contain as few as 4-5 silver atoms),

into clouds of colored dye molecules. The amplification factor is on the order of 109 dye

molecules/latent image and is one of several crucial elements of the color photographic

process.[23,25] From Fig. 7, the developer molecules contain both a primary and a tertiary amine.

The pKa of the amine functionalities are about 8 for the tertiary and 4 for the primary. The

reactions were performed under acidic conditions so that the intercalated form of the developer is


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therefore likely to be the diprotonated form according to Eq. (10).

Zr(NaO4)2.5H2O + 2 CD:2H+ ! Zr(H0.45PO4)2

. [2 CD:2H+]0.55 .nH2O (10)

The compounds are non-stoichiometric with the precise stoichiometry driven by the size of the

guest developer molecules (steric crowding) and by the degree of protonation of the amine

substituents. The data of Fig. 7 show powder X-ray diffraction profiles for two color developer

intercalates. The powder patterns are quite similar as is expected since the two molecules differ

in size only slightly. The strong peak near 2θ = 6°, indicates a layer expansion of the host lattice

of about 6.4 Å versus the pristine host and is most consistent with an orientation of the molecular

axis bisecting the amine groups, parallel to the host layers; but with the benzene ring oriented

perpendicular to the host layers. Elemental analysis is in good agreement with the stoichiometry

given in Eq. (9). The primary particle size of the intercalated materials is estimated from SEM at

50�100 nm although considerable agglomerations of aqueous suspensions make them appear

turbid.


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Figure 7. The powder X-ray diffraction patterns for two color developer intercalates having the

approximate composition Zr(H0.45PO4)2. [2 CD:2H+]0.55. The molecular structures of the guest

molecules are shown in the inset, the compounds are N,N-diethyl-2-methyl-1,4-benzenediamine

(left and bottom spectra) and ethanol, 2-(4-amino-3-methyphenyl)ethylamine (right and top

spectra).

The ability of Zr(H0.45PO4)2. [2 CD:2H+]0.55

.nH2O to sequester CD molecules [(ethanol, 2-(4-

amino-3-methyphenyl)ethylamine]) as a function of pH and ionic strength is demonstrated in

Figs. 8 and 9. Experiments were performed by dispersing intercalates at a known concentration,

in aqueous suspensions at the given pH and ionic strength. After about 30 min, the suspensions

were then centrifuged and an aliquot of the supernatants reacted with a known amount of AgBr

and photographic cyan coupler[25] held at pH 10. Any color developer, which had diffused out of

the host layers is quantitatively converted to a cyan dye. The concentration of the dye is

monitored by the appearance of cyan density, and quantitatively by visible spectroscopy. The

fraction of intercalated complex was chosen so that if all of the developer molecules were

quantitatively released, and quantitatively converted to dye molecules, the resulting solution

N

NH2

N

NH2

OH


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23

would have an optical density of 1.0. The data of Fig. 8 indicate that the intercalated color

developer molecules are sequestered well by the host lattice at pH values below about 8, but that

above this value they are readily released from the host layers. At pH 10, essentially all of the

intercalated molecules are released and converted to dye as an optical density near 1.0 is

observed. As we recall from the discussion above, the pka of the tertiary amine moiety on the CD

molecule is about 8.0. The data therefore indicate that the mechanism of release involves a pH

dependent deprotonation of the guest molecules. Once the guest is deprotonated, it is no longer

electrostatically attracted to the host layer surfaces and may quickly diffuse from the interlayer

space to perform a desired function. In a similar fashion, the data of Fig. 9 indicate that the guest

molecules may be released via ion-exchange with sodium ions, albeit less effectively and at

relatively high concentrations. Conversely, the data of Fig. 9 can be viewed as indicating that the

switching mechanism for release of the guest molecules is mainly pH dependent, and may be

expected to be relatively tolerant of electrolyte containing dispersions. The data therefore

strongly support a pH dependent sequester and release mechanism whereby access to the

sequestered molecules can be achieved via a chemical switch. Such a pH dependent chemical

switch is ideally suited to applications in photography, since it takes advantage of the natural

basicity of commercial developer solutions (about pH 10),[25], and is further augmented by the

flux of electrolyte species contained in development and photo-processing solutions.


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Figure 8. Visible absorption spectra of supernatant solutions prepared as described above, showing the stepwise release of color developer molecules from the interlayer spaces of Zr(H0.45PO4)2

. [2 CD:2H+]0.55 .nH2O as a function of pH.

wavelength (nm)

Abs

orba

nce

wavelength (nm)

Abs

orba

nce

400 500 600 700 800

400 500 600 700 800


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25

Figure 9. Visible absorption spectra of supernatant solutions prepared as described above,

showing the stepwise release of color developer molecules from the interlayer spaces of

Zr(H0.45P O4)2. [2 CD:2H+]0.55

.nH2O as a function of NaCl concentration. The curves obtained

for concentrations of 10-3, 10-4 and 10-5 were essentially identical.

Photographic Applications: Sequester and Controlled Delivery

The photographic process, in its most simple form, is comprised of silver halide (capable of

capturing electromagnetic energy and storing it as latent image) and developer chemistry

(capable of converting the latent image into a visible image).[23, 25] These two chemistries,

however, are incompatible, that is to say, unexposed silver halide is thermodynamically unstable

with respect to reduction in the presence of developer molecules (and also to many other

chemistries contained in the development process). The consequence is that the photographic

subsystems must be kept separate, with each function performed in sequence, and thus modern

photography requires multiple steps: exposure, processing, etc. Incorporation of active chemistry

such as developers directly into film formulations has long been a goal in the photographic

industry. A number of authors have reported on methods of improving the stability of

incorporated developers.[48]. While methods have been developed, these have been limited owing

largely to the inability to prevent the slow diffusion and subsequent contact of reactants over

time. We show that direct incorporation of reagents can be achieved via the controlled sequester

and release afforded by the layered hybrids described herein.[49-51] We show that this approach is

ideally suited to conventional photography, because the natural basicity of developer solutions

(pH about 10) allows for facile release of reagents from the host lattices. The molecules are

effectively sequestered by the host lattice until the time of development, at which time a pH

change affects the release of the sequestered developer molecules. The effect is demonstrated in

photographic systems in Figs. 10�13, which show sensitometric curves (optical density vs. light

exposure) for silver halide films containing the compounds of interest and the appropriate

validation experiments.


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Silver ion is known to play an important role in photographic sensitivity and in development

kinetics. The developability of a silver halide emulsion is, in general, proportional to silver ion

activity, however, high activities may lead to increasing emulsion fog (i.e., increased density in

unexposed or minimum density regions).[23, 25] The build-up of fog may be even more

pronounced if excess silver ion is absorbed to emulsion grains prior to exposure and

development. Thus, we have intended to employ the silver ion intercalate of alpha-zirconium

hydrogen phosphate to increase silver ion activity only during the development stage, and to

sequester the added silver ion prior to that stage.[50] Figures 10 and 11 show the sensitometric

data for a series of photographic films containing the silver ion release agent,

Zr(Ag0.75H0.25PO4)2.H2O. From Fig. 10, it is observed that the sensitivity of the emulsion

increases (i.e., requires less exposure to produce the same density) as excess silver ion is

introduced from Zr(Ag0.75H0.25PO4)2.H2O or from AgNO3 (essentially free silver ion). However,

it is seen in Fig. 10, that free silver ion (i.e., from the aqueous soluble AgNO3) also results in a

fogging of the emulsion as the D-min density is significantly increased. From Fig. 11, the

emulsion sensitivity may be increased greatly through sequester/release of silver ion via the

intercalate, indeed, by nearly as much as 0.60 log E or 2 �stops� of photographic efficiency. This

efficiency is realized without a concomitant increase in emulsion fog. The data of Figs. 10 and

11 support our hypothesis that silver ion is sequestered by the intercalate, but is �delivered� to

the process during the development stage.


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Figure 10. Sensitometric data for a AgBr emulsion coating containing 0.35 mg/ft2 excess silver

ion delivered from Zr(Ag0.75H0.25PO4)2.H2O (dotted); 0.35 mg/ft2 excess silver ion delivered

from AgNO3 (dashed) and for the emulsion alone (solid line).

Log Relative Exposure

Opt

ical

den

sity

(arb

. uni

ts)

-3.0 -2.0 -1.0 0.0 1.0

2.0

1.0

0.0


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Figure 11. Sensitometric data for a AgBr emulsion coating containing 0.0 mg/ft2 (solid), 0.1

mg/ft2 (dotted), 1.0 mg/ft2 (dashed) and 2.0 mg/ft2 (dot-dash) excess silver ion delivered from

Zr(Ag0.75H0.25PO4)2.H2O.

Figure 12 shows sensitometric data for a AgBr emulsion and for the same emulsion containing

1.0 mg/ft2 color developer delivered from of Zr(H0.9PO4)2. [2 CD:2H+]0.55

.nH2O. The results

indicate a loss of sensitivity for the photographic emulsion containing intercalated developer, but

also a higher contrast and greater overall optical density (D-max ). The reason for the sensitivity

loss is not clear, but may indicate that a small fraction of intercalated developer is released from

the intercalate prior to development. The increased contrast and D-max are consistent with an

increasing development rate resulting from the release of the guest color developer molecules

from the host. Figure 13 shows sensitometric data for a AgBr emulsion and for the same


Opt

ical

den

sity

(arb

. uni

ts)

-3.0 -2.0 -1.0 0.0 1.0

2.0

1.0

0.0


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emulsion containing 0.1 mg/ft2 phenyl mercaptotetrazole (PMT) delivered from

Mg0.7Al0.3(OH)2.0.3 PMT. nH2O. PMT is a well known photographic inhibitor.[25] An �inhibitor�

is a term that refers to materials capable of slowing the rate of photographic development and are

typically used to �brake� the photographic process in order to control features such as D-min, D-

max and contrast. These features, together with sensitivity, essentially add to comprise the tone-

scale of a photographic film.[25] The addition of an inhibitor to an emulsion while allowing one to

control tone-scale typically results in a significant loss of sensitivity. From Fig. 13 it is observed

that when PMT is introduced into a photographic emulsion via the intercalate no loss of

sensitivity is incurred; and surprisingly a small but measurable sensitivity increase is observed.

The data further show a decrease in contrast in the upper scale resulting apparently from the

release of the PMT inhibitor during the development process. While we cannot yet explain the

small sensitivity increase, the data are consistent with the sequester and release mechanism

Figure 12. Sensitometric data for a AgBr emulsion (solid) and for the same emulsion containing


Opt

ical

den

sity

(arb

. uni

ts)

-3.0 -2.0 -1.0 0.0 1.0

2.0

1.0

0.0


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30

1.0 mg/ft2 color developer (dotted) delivered from of Zr(H0.9PO4)2. [2 CD:2H+]0.55

.nH2O.

Figure 13. Sensitometric data for a AgBr emulsion (solid) and for the same emulsion containing

0.1 mg/ft2 phenyl mercaptotetrazole (dashed) delivered from Mg0.7Al0.3(OH)2.0.3 PMT. nH2O.

CONCLUSIONS

The development of complex materials has undergone an extraordinary acceleration resulting

from supramolecular chemistry, self-assembly, and nanoscience. This has made possible the

fabrication of unprecedented molecular and nanoscale structures having diverse and multiple

functionalities. We present here a new fabrication tool for the development of complex


Opt

ical

den

sity

(arb

. uni

ts)

-3.0 -2.0 -1.0 0.0 1.0

2.0

1.0

0.0


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materials. The tool uses the intrinsic composite nature of layered materials, and we show that

these are able to act as chemical sequestraints that may later release the sequestered chemistry to

perform a desired function. Further, several release mechanisms are accessible and may act as a

chemical switches to provide a temporal release of the functional chemistry. A remarkable array

of complex composite structures are accessible by intercalation methods and guest molecules

may include simple and complex molecules, polymers, macromolecules such as amino acids,

proteins, and even DNA. The approach has potential to be extended to the sequester, release and

targeted delivery of molecules of biological significance and as complex reservoirs for facile

gene, DNA and bio-information delivery. In parallel, we demonstrate the application of layered

nanohybrids containing functional photographic chemistry to the photographic process. Aqueous

dispersions are easily prepared and their ability to sequester and later release active chemistry is

cleanly demonstrated. The method has been used to obtain photographic media with unusual and

carefully tailored sensitometric properties.[49-51] Although in its infancy, the generation of

complex nanohybrid materials via intercalation chemistry, has vast potential for the development

of complex chemical systems, able to detect and respond to the needs of diverse systems.


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CONTROLLED CHEMICAL AND DRUG DELIVERY VIA THE INTERNAL AND EXTERNAL SURFACES OF LAYERED COMPOUNDS

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