Article

pubs.acs.org/cm

Rationale of Drug Encapsulation and Release from Biocompatible

Porous Metal−Organic Frameworks
Denise Cunha,† Mouna Ben Yahia,†,‡ Shaun Hall,‡ Stuart R. Miller,† Hubert Chevreau,† Erik Elkaïm,§
Guillaume Maurin,‡ Patricia Horcajada,*,† and Christian Serre*,†
†
Institut Lavoisier, UMR CNRS 8180, Université de Versailles Saint-Quentin-en-Yvelines, 45 Avenue des Etats-Unis, 78035 Versailles
Cedex, France
‡
Institut Charles Gerhardt Montpellier UMR 5253 CNRS UM2, UM1, Université Montpellier 2, Place E. Bataillon, 34095
Montpellier Cedex 05, France
§
Cristal beamline, Soleil Synchrotron, L’Orme des Merisiers Saint-Aubin, BP 4891192 Gif-sur-Yvette Cedex, France
*
S Supporting Information

ABSTRACT: A joint experimental and computational system-

atic exploration of the driving forces that govern (i)
encapsulation of active ingredients (solvent, starting material
dehydration, drug/material ratio, immersion time, and several
consecutive impregnations) and (i) its kinetics of delivery
(structure, polarity, ...) was performed using a series of porous
biocompatible metal−organic frameworks (MOFs) that bear
different topologies, connectivities, and chemical compositions.
The liporeductor cosmetic caffeine was selected as the active
molecule. Its encapsulation is a challenge for the cosmetic
industry due to its high tendency to crystallize leading to poor loadings (<5 wt %) and uncontrolled releases with a subsequent
low efficiency. It was evidenced that caffeine entrapping reaches exceptional payloads up to 50 wt %, while progressive release of
this cosmetic agent upon immersion in the simulated physiological media (phosphate buffer solution pH = 7.4 or distilled water
pH = 6.3, 37 °C) occurred mainly depending on the degree of MOF stability, caffeine mobility, and MOF−caffeine interactions.
Thus, MIL-100 and UiO-66 appear as very promising carriers for topical administration of caffeine with both spectacular
cosmetic payloads and progressive releases within 24 h.
KEYWORDS: MOFs, encapsulation, release, cosmetic, caffeine

■ INTRODUCTION
Porous metal−organic frameworks (MOFs)1−3 have attracted
during the past two decades increasing attention due to their
numerous potential applications2,4−6 in strategic domains such
as gas storage, separation, catalysis, photonics, and, more
recently, biomedicine.7−9 Their high and regular porosity
combined with their amphiphilic internal microenvironment
have allowed the achievement of record drug loadings and
controlled releases under simulated physiological conditions.10
This concept has been recently extended to surface-engineered
nanoparticles of nontoxic and biodegradable porous iron(III)
polycarboxylates MOFs with very high loadings and progressive
release of challenging antitumoral or antiretroviral drugs
coupled with interesting imaging properties.11 Despite this
growing interest on drug encapsulation into MOFs12−17 there
has been no real effort in order to gain understanding of the
drug adsorption/release processes which makes hazardous
prediction and design of the most suitable MOF for a given
drug and administration route. To the best of our knowledge,
the only rationale attempt reported so far in this domain was
realized by some of us dealing with the quantitative structure
activity relationship (QSAR) study of experimentally caffeine
loading within a series of functionalized porous flexible
iron(III) terephthalates of MIL-88B topology (MIL = Material
of Institut Lavoisier)18 and functionalized rigid zirconium
terephthalates UiO-66.19 Interestingly, the most correlated
QSAR descriptors related to caffeine uptake were the polarity,
polarizability, and H-donor capacity of the grafted functional
groups on the organic spacer.
In this context, there is thus a strong need for a systematic
and rationale study to gain a deeper understanding of the main
parameters that govern active ingredient encapsulation as well
as the delivery kinetics from MOFs. As a first step,
encapsulation of the active cosmetic molecule caffeine using a
relatively large range of biocompatible porous metal carbox-
ylates MOFs7,20 with different topologies and compositions
(structure, porosity, flexible network, functional groups, ...) was
undergone. Caffeine-containing solids were then characterized
using joint experimental and modeling approaches. Finally,
their caffeine release kinetics was investigated under two
Received: March 11, 2013
Revised: June 12, 2013
Published: June 19, 2013

© 2013 American Chemical Society 2767 dx.doi.org/10.1021/cm400798p | Chem. Mater. 2013, 25, 2767−2776
Chemistry of Materials
different simulated physiological conditions (phosphate buffer
solution and water).
To that purpose four different MOF architectures were
selected (Figure 1): (i) the cubic-zeotype mesoporous MIL-
Figure 1. Schematic representation of MIL-100, UiO-66s, MIL-127,
and MIL-53s structures and caffeine molecule. Iron and zirconium
polyhedra and carbon atoms are in orange, blue, and black,
respectively. Hydrogen atoms have been omitted for a better
understanding.
100, based on trimers of iron(III) octahedra and trimesate
anions leading to a very important porosity (SBET ≈ 2400
m2·g−1, Vp ≈ 1.2 cm3·g−1) associated with two types of
mesocages (25 and 29 Å) accessible through microporous
windows (∼4.7*5.5 and 8.6 Å);21 (ii) the cubic structure Soc-
MOF(Fe) or MIL-12722,23 based on trimers of iron(III)
octahedra and 3,3′,5,5′-azobenzenetetracarboxylate anions
resulting in two types of pores (an accessible 1D channel
system (∼6 Å) and cages of around 10 Å accessible through
windows of ∼4 Å, allowing only adsorption of small molecules
such as H2O or H2 (SBET ≈ 1400 m2·g−1, Vp ≈ 0.7 cm3·g−1));
(iii) the cubic UiO-66 solids (UiO for Oslo University), based
on zirconium oxoclusters and terephthalate anions bearing
different functional groups on the aromatic benzyl ring (UiO-
66_X for X = H, Br, or NH2); these latter solids possess
octahedral (∼11 Å) and tetrahedral cavities (∼8 Å) accessible
through microporous triangular windows (∼5−7 Å; SBET ≈
1200 m2·g−1, Vp ≈ 0.5 cm3·g−1),24−26 and. finally, (iv) the MIL-
53 materials built up from corner-sharing chains of iron(III)
octahedra related together via functionalized terephthalates
(MIL-53_X, X = H, Br, or NH2),27−29 creating a three-
dimensional structure with a microporous 1D pore system;
MIL-53 exhibits a flexible structure30−32 able to reversibly adapt
its pore size in the presence of different stimuli (temperature,
guest adsorption, pressure)33−35 from a closed form (unit cell
volume Vu.c. ≈ 900−1000 Å3; Ø ≈ 4 Å) to an open form (Vu.c.
≈ 1400−1500 Å3; Ø ≈ 8.5 Å).36
Amphiphilic caffeine (or 1,3,7-trimethylxanthine) was
selected as the active molecule due to its small and simple
structure (Figure 1) as well as its large interest for therapeutic
and cosmetic applications.37,38 In fact, caffeine acts directly on
adipose cells, promoting lipolysis, inhibiting phosphodiesterase,
and increasing cyclic adenosine monophosphate (cAMP) and
triglyceride lipase enzyme activity. Caffeine also possesses a
stimulating effect on cutaneous microcirculation.39 However,
due to its poor skin penetration, caffeine is usually employed in
cosmetic formulations such as emulsions,40 hydrogels,41 or
liposomes.42,43 In addition, due to its high tendency to
crystallize, the payloads into these formulations are often very
poor, not exceding 2−5 wt %, leading to lower efficacies.44
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Therefore, better control of caffeine release is strongly desired
in order to avoid several topical reapplications and an optimal
local concentration during the whole day, with a more effective
slim effect.39,45 Indeed, encapsulation and controlled release of
caffeine still remains a real challenge to be addressed.
■ EXPERIMENTAL SECTION
Synthesis of MOFs. Synthesis of starting materials was performed
under hydrosolvothermal conditions as previously re-
ported.21−23,28,46,47 In a typical synthesis, the metal source and linker
were dispersed in a polar solvent, placed in a Teflon-lined autoclave,
and heated at different temperatures (see details in the Supporting
Information, Table S1). Resulting solids were recovered by filtration
and washed with deionized water and acetone. Then, activation was
carried out to remove the remaining free linker and/or solvent into the
pores by exchange (see details in the Supporting Information; Table
S1).
Caffeine Encapsulation. Caffeine encapsulation was performed
by simple impregnation, suspending the (dried or hydrated) MOFs
powder into water or ethanol caffeine solutions for rigid and flexible
materials, respectively, under stirring at room temperature for 72 h
(for more details see the Supporting Information).
Caffeine Release. Drug release was carried out by soaking the
drug-loaded powder material in a phosphate buffer solution (PBS; 0.04
M, pH 7.4) or distilled water at 37 °C under bidimensional continuous
stirring (120 rpm, incubator Multiton Orbitale, Infors HT, France). At
different incubation times, an aliquot of supernatant was recovered by
centrifugation and replaced with the same volume of fresh medium at
37 °C. The amount of encapsulated and released caffeine was
determined by combining high-performance liquid chromatography
(HPLC), thermogravimetric analysis (TGA), and elemental analysis
methods (see the Supporting Information).
X-ray Powder Diffraction (XRPD). XRPD routine patterns were
collected in a SIEMENS D5000 diffractometer (θ−2θ) using Cu
Kα1,α2 radiation (λ = 1.54051, 1.54433 Å) from 5° to 15° (2θ) and a
step size of 0.04° and 4 s per step in continuous mode.
The XRPD and structure solution for hydrated UiO-66-NH2 was
carried out using a Bruker D8 powder diffractometer equipped with a
Lynx-eye detector. Data collection was performed at room temper-
ature in Debye−Scherrer geometry, with the sample in a 0.5 mm glass
capillary, with 2θ of 3.75−90°, with a 0.01° step width, and using
monochromated radiation with a wavelength of 1.5409 Å (see the
Supporting Information).
The synchrotron powder diffraction experiment has been carried
out for the caffeine-containing MIL-53_Br sample at the Cristal
beamline, Soleil Synchrotron (Gif-sur-Yvette, France). A monochro-
matic beam was extracted from the U20 undulator beam by means of a
Si(111) double monochromator. Its wavelength of 0.79176 Å was
refined from a LaB6 (NIST Standard Reference Material 660a)
powder diagram recorded just before the experiment. High angular
resolution is obtained, in the diffracted beam, with a 21 perfect crystals
Si(111) multianalyzer (see the Supporting Information).
Thermogravimetric Analysis. Samples were analyzed under
oxygen flow (20 mL·min−1) using a Perkin-Elmer Diamond TGA/
DTA STA 6000 running from room temperature to 600 °C with a
heating rate of 2 °C·min−1.
Nitrogen Adsorption Porosimetry. N2 isotherms were obtained
at 77 K using a Belsorp Mini (Bel, Japan). Prior to analysis,
approximately 40−60 mg of activated rigid samples was evacuated for
12−24 h at 200 °C under vacuum for bare materials or 80 °C for
caffeine-loaded materials and after caffeine release solids.
Molecular Simulations. A force-field-based Monte Carlo strategy
was first conducted to provide an estimation of the optimal caffeine
uptake for the different rigid and flexible MOFs, starting with their
crystal structures, a microscopic model for the drug, and a suitable
description of the caffeine/MOF interactions including van der Waals
and Coulombic contributions. All computational details are reported
in the Supporting Information.
dx.doi.org/10.1021/cm400798p | Chem. Mater. 2013, 25, 2767−2776
Chemistry of Materials Article

Table 1. Pore Volume and BET Surface Areas before and after Caffeine Encapsulation, Together with the Caffeine Loadings and
Release Times in PBS and Aqueous Media
caffeine release
36
time for total = Kt
prior encapsulation after encapsulation loading capacity release (h) (H2O)
Vp SBET Vp SBET Caf/MOF kinetic
material (cm3·g−1) (m2·g−1) Ø (Å) (cm3·g−1) (m2·g−1) theor (wt %) exp (% wt) (mol/mol) PBS H2O constant
MIL- 0.82 1790 25, 29 0.30 570 65.8 (46.4b) 49.5 ± 1.9 1.70 0.5 48 6.3 ± 0.5
100
UiO-66 H 0.48 1230 7.5, 12 0.22 570 11.7 22.4 ± 3.4 2.14 0.5 48 9.5 ± 0.8
Br 0.30 640 0.11 270 6.8 21.2 ± 0.7 2.20 0.5 48 9.5 ± 0.3
NH2 0.35 930 0.22 580 11.1 13.2 ± 0.2 1.26 2 48 12.5 ± 0.6
MIL-53 H 0.60c 1000c 8.6c 29.5 29.2 ± 1.5 0.36 6 >216a 6.4 ± 0.2
Br 13.1 10.6 ± 3.0 0.19 4 >144a 8.1 ± 0.4
NH2 10.8 0 0.00
MIL- 0.63 1270 10 0.51 1160 31.6 (19.0b) 15.9 ± 0.5 0.63 72 48 13.7 ± 0.5
127
a
Uncompleted release. bSimulated values considering only the accessibility of the large cages (MIL-100) and the 1D channels (MIL-127). cValues
obtained from the MIL-53 solid based on chromium since, contrary to its iron analogue, shows an open porosity when dehydrated.

Periodic density functional theory calculations were performed on
the MIL-53_X, X = H, Br, and NH2, solids in the absence and
presence of caffeine with the aim to (i) determine the magnitude of
pore contraction upon encapsulation and (ii) elucidate the geometries
of the drug molecules within the porosity and the resulting interaction
energy. Initial atomic coordinates of the open pore form for each MIL-
53 structure were taken from our previous studies,26 and we further
considered incorporation of one caffeine per pore in a simulation box
consisting of a (1,1,2) primitive cell. Note that such models probed at
least three different starting configurations for the drug and that the
optimization always converged toward the same positions. Full
geometry optimizations (atomic positions and unit cell volumes) of
these structures were realized using the PBEsol GGA functional48 and
pseudopotentials described by the projector-augmented wave method
(PAW)49,50 as implemented in the Vienna ab initio simulation package
(VASP).51−54 A plane wave cutoff of the calculations was set to 600 eV
to ensure convergence, while a k-point mesh of 4 × 4 × 6 was
considered to represent the Brillouin zone of each system. We
employed a DFT+U approach as formulated by Dudarev et al.55 to
overcome the strongly correlated character of the Fe d orbitals. To that
purpose, Ueff was fixed at 5 as this value was previously shown to
reproduce the structural, electronic, and magnetic properties of the
MIL-53(Fe) solid.56 Finally, the interaction caffeine/MIL-53_X energy
was further obtained by the difference between the energy of the
caffeine-containing MIL-53_X system and the energy sum of the single
constituents.
caffeine doses with reduced amounts of excipient (in this case,
the MOF).
Analysis of the Drug-Loaded MOFs. Crystalline structure
of all solids was checked by XRPD, confirming not only that the
impregnation step does not alter their crystalline structure but
also, in accordance with a significant change in the Bragg peaks
relative intensity, the filling of the pores by caffeine molecules
(Figure S1, Supporting Information). Remarkably, no recrystal-
lized caffeine is observed whatever the MOF, as confirmed by
XRPD (Figure S1, Supporting Information).
Fourier transform infrared spectroscopy (FTIR) confirmed
encapsulation of the caffeine in all loaded solids after
impregnation through the presence of vibrational bands at
around 1770 and 1658 cm−1 characteristic of the ν(CO)
groups of the caffeine (Table S3 and Figure S7, Supporting
Information) as well as a shift to higher wavelengths of these
bands in comparison to the pure caffeine, suggesting establish-
ment of weak interactions between the caffeine moieties and
the hybrid framework which induce only a lower electron
delocalization in the two carbonyl groups. Furthermore, in
similar molecules to caffeine-bearing urea groups (ethyleneurea
and propyleneurea), the negative shift of the CO band has
previously been associated with interactions involving the

■ RESULTS AND DISCUSSION

Caffeine Encapsulation. Caffeine encapsulation was
carried out by a simple impregnation method by suspending
the powder MOFs into nontoxic and environmentally friendly
aqueous or ethanol caffeine solutions (see Experimental
Section). Optimal caffeine loadings were reached by suspending
the previously dehydrated powder solids (material:caffeine ratio
= 1:2 and 5:3 for rigid and flexible solids, respectively) into
aqueous (10 mg·mL−1 for rigid MOFs) or ethanol (3 mg·mL−1
for flexible MIL-53 solids) caffeine solutions at room
temperature under magnetic stirring for 72 h (see section
below). MIL-100, MIL-53, UiO-66, and MIL-127 materials
showed exceptionally high caffeine payloads (up to 50, 30, 24,
and 16 wt %, respectively; Table 1). Such caffeine loadings are
among the highest reported so far (2−5 wt %).41 These porous
MOFs as well as the previously reported MIL-88B solids (up to
22 wt %)18 represent new promising candidates for formulation
of caffeine that would allow administration of important
2769
oxygen atoms of the carbonyl group, whereas positive shifts
were associated with coordination through the nitrogen
atom.57,58 Therefore, based on the remarked positive shifts of
this band in the caffeine-containing solids, one can assume that
the N3 atom of the caffeine present between the two carbonyl
groups (see Figure 1) is involved in the interactions between
caffeine and the MOF materials.
Force-field-based Monte Carlo simulations were first
employed to evaluate the theoretical caffeine uptake for each
investigated MOFs in order to check if the maximum loading
has been experimentally achieved. Table 1 shows that for the
flexible MIL-53_X, the simulated values are in very good
agreement with the experimental payloads, which emphasizes
that caffeine has been optimally entrapped in the −H and −Br
forms, the predicted uptake for the −NH2 version being similar
to those obtained for MIL-53_Br. Further, one can observe that
the so-obtained caffeine encapsulation in the nonfunctionalized
material is very similar to the performance of the Cr analogue,
ca. 30 wt %.36
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Chemistry of Materials
Regarding MIL-100, the theoretical loading (65.8 wt %)
estimated by assuming a full accessibility of both small and large
cages is much higher than the experimental one (49.5 wt %). In
contrast, if one assumes that the pentagonal windows (∼4.7 ×
5.5 Å) are nonaccessible to caffeine (∼7.6 × 6.1 Å), leading to
selective adsorption within only the larger cavities, the
predicted (46.4 wt %) and experimental uptakes are in very
good agreement. This hypothesis is supported by a simple
structural analysis: taking into account the effective volume of a
caffeine molecule (165.5 Å3) and considering the volume of
each small and large cage (∼8200 and 12 750 Å3) present in a
1:2 ratio, the maximum caffeine cargo would be around 1.10 g
of caffeine per gram of MIL-100. The important discrepancy
between the theoretical and experimental loading values (1.10
vs 0.49 g·g−1) is again consistent with the preferential filling of
the larger cages, with a predictable occupation of ca. 77 caffeine
molecules, which corresponds to ca. 0.48 g·g−1, in accordance
with the experimentally observed capacity. Such predictions are
validated by the presence of a significant residual porosity
accessible to nitrogen after caffeine impregnation evidenced
from adsorption isotherm measurements at 77 K on the loaded
sample (see Table 1, pore volume = 0.30 g·cm−3, BET surface
area = 570 m2·g−1).
The presence of residual pore volume and BET surface area
also holds true for MIL-127 and might be associated again to
steric hindrance of caffeine within the porosity of this material
that would not allow its accommodation within all the
accessible volume for nitrogen. To confirm such findings,
optimal uptakes have been calculated considering either the full
accessibility of the cages (∼10 Å) and the 1D channel (∼6 Å)
or only the 1D channel assuming that the windows giving
access to the cages are too narrow (∼4 Å) to be crossed by
caffeine. Table 1 shows that the predicted value (19 wt %)
assuming the accommodation of caffeine only the 1D channel is
very close to the experimental data (16.5 wt %), which supports
only a partial occupancy of the available volume in MIL-127.
Finally, regarding UiO-66s, except for the amino form,
simulations based on the assumption of a rigid framework
significantly underestimate the experimental payloads. Such a
discrepancy is not surprising as it was previously evidenced that
in such a narrow windows MOF type the dynamics of the
phenyl ring strongly affects the adsorption/diffusion processes
of small gas molecules.59,60 However, these predictions cannot
indeed be valuable to check the encapsulation efficiency in the
nonfunctionalized and the −Br forms, one can already argue
that for the −NH2 version a good agreement between the
experimental uptake and the simulated one using this
inadequate rigid framework suggests that the encapsulation is
not optimized at least for UiO-66_NH2. In the later case, the
steric hindrance of caffeine is most probably induced by
coadsorption of the solvent, i.e., water, that tends to form
hydrogen bonding with the amino group that further prevents
the accessibility of the tetrahedral (∼8 Å) and octahedral cages
(∼11 Å) for caffeine.
In order to gain a deeper understanding of the role of the
interaction between water and the polar functional group of
modified UiO-66 solids, the crystal structure of hydrated UiO-
66_NH2 was solved from XRPD data (see Figure S2,
Supporting Information). It appears that within the tetrahedral
cages an ordering of the hydrogen bondings occurs highlighting
the strong affinity of water molecules for the free amino groups
of the framework. Figure S3, Supporting Information, shows
the organization of one of the two independent (Ow1) free
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water molecules within a tetrahedral cage, illustrating the
network of hydrogen bondings. This is in agreement with
interatomic distances between two consecutive water molecules
of 2.69 or 3.06 Å, while Owi−Nj distances are 3.06 or 3.47 Å.
Thus, any encapsulated drug molecule will have to break these
intramolecular interactions in order to diffuse within the
tetrahedral cages. This explains why caffeine, as not being
capable of providing strong H-donor or -acceptor hydrogen
bondings, exhibits a lower loading within the NH2, NO2, or
2OH derivatives of UiO-66.19
Further, it has been shown by a joint XRPD and DFT
approach that caffeine preferentially occupies the more
confined tetrahedral cages,61 leaving empty or only partially
occupied the octahedral cages. Such a statement provides an
explanation of the relatively high N2 residual porosity obtained
after encapsulation (Table 1) and thus suggests that
optimization of the encapsulation performance could be
achieved at least for the −H and −Br forms that are not
expected to show a high affinity for the solvent.
Analysis of the Drug Loading Parameters. The
conditions of caffeine encapsulation were studied by investigat-
ing the influence of different parameters such as the nature of
the solvent, initial state of material hydration, drug/material
ratio, immersion time, and number of consecutive impregna-
tions.
Role of Solvent. Nontoxic water and ethanol (rat oral lethal
dose 50%, LD50 = 10.6 g·kg−1)65 were first selected as solvents
because of the high caffeine solubility (∼10 or 3 mg·mL−1,
respectively) and their easy removal at low temperatures (<120
°C). Remarkably, the nature of the solvent used during the
impregnation step drastically affects the caffeine encapsulation
rate. For the rigid porous materials based on oxocentered
trimers of iron(III) octahedra, i.e., MIL-100 and MIL-127
materials, very low capacities (1 and 0 wt %) were obtained
when caffeine/ethanol solutions were used in comparison to
caffeine aqueous solutions (50 and 16 wt %). This is likely to be
due to the preferential adsorption of ethanol against caffeine for
such solids. These MOFs exhibit indeed a significant amount of
iron-unsaturated Lewis metal sites (CUS),21,23,66 i.e., up to two
CUS per trimer, that could lead to formation of a direct
coordination adduct of the polar solvent molecules on the iron
CUS located on the border of the windows.67 For instance, in
the case of MIL-100, in comparison to water coordination, the
geometry-optimized structures in the presence of ethanol
coordinating the CUS sites show that the free diameters of both
the pentagonal (1.7 vs 4.5 Å) and the hexagonal windows (4.1
vs 8.2 Å; Figures S10 and S11, Supporting Information)
considerably decrease (ΔØ ≈ 3−4 Å), leading to more
restricted accessibility for the caffeine. Considering the caffeine
dimensions (∼7.6 × 6.1 × 1.8 Å), these poor caffeine uptakes
using ethanol solutions could therefore be a consequence of the
blocking of both microporous windows. Furthermore, as
discussed above, one can argue that the active molecule will
be preferentially adsorbed only within the larger cages.
Further, higher caffeine payloads were achieved in UiO-66
when using caffeine aqueous solutions in comparison to ethanol
ones (22.4 vs 2.5 wt %). This solid also possesses zirconium
CUS,25 able to coordinate polar solvents. Similarly to MIL-100
and MIL-127 solids, one can speculate that ethanol could be
coordinated to the zirconium metal sites, decreasing the
accessibility of the triangular windows. In addition, adsorption
of ethanol seems to be energetically more favored than water in
iron trimer-based materials (MIL-100 and MIL-127) and UiO-
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Chemistry of Materials
66. Finally, the different caffeine concentration in both solvents
might also have an influence (see below part drug:material
ratio).
In contrast, caffeine loading was higher when the flexible
MIL-53 was suspended in ethanol caffeine solutions than in
aqueous ones. This observation is consistent with a full pore
opening of the structure in the presence of ethanol (Vu.c. ≈
1500 Å3), whereas a narrow pore form is observed in liquid
water (Vu.c. ∼ 990 Å3).29,68,28 Therefore, the larger pore size of
the ethanol form (∼ 8.5 vs 6.0 Å) would play in favor of
caffeine insertion. Interestingly, a higher encapsulation rate was
achieved in ethanol when starting from the anhydrous instead
of the hydrated form of MIL-53 (29.3 vs 12.7 wt %). As
recently reported,69 the pore content of the ethanol open form,
when starting from the hydrated solid, consists of a mixture of
alcohol and water moieties rather than pure alcohol guests.
Consequently, the caffeine−matrix interactions might not be
strong enough to replace ethanol and water guests from the
MIL-53 pores, leading to lower drug entrapping when hydrated
materials are used. Accordingly, the adsorption enthalpy for
ethanol is lower than for water, which might favor replacement
of ethanol over water.70,71
In light of such findings, caffeine entrapping was carried out
in aqueous solutions and ethanol ones for the rigid and flexible
materials, respectively, starting from the dehydrated flexible
materials.
Drug:Material Ratio. The active molecule:MOF ratio
parameter was then investigated by modifying the starting
solution concentration for 72 h, considering the maximum
solubility values of caffeine in both solvents (∼10 or 3 mg·mL−1
in water or ethanol, respectively). Hence, adsorption isotherms
of caffeine onto MIL-100, UiO-66, and MIL-53 solids revealed
a loading improvement proportional to the concentration
increase up to a plateau, where an equilibrium was achieved
(Figure 2 (left) and Table 2). The maximum loadings, attained
Figure 2. Room-temperature caffeine adsorption isotherms (left) and
kinetics of encapsulation (right) for MIL-100, UiO-66, and MIL-53.
Table 2. Caffeine Encapsulation Loadings in Different
Hydration State and Solvents
caffeine encapsulation (wt%)
material hydration state water (10 g·L−1) ethanol (3 g·L−1)
MIL-100 anhydrous 49.5 ± 1.9 1.2 ± 0.2
MIL-127 anhydrous 15.9 ± 0.5 0 dynamics of the caffeine throughout the pores.
MIL-53 hydrated 3.4 ± 1.2 12.7 ± 4.8
anhydrous 2.2 ± 0.9 29.3 ± 1.5
UiO-66 anhydrous 22.4 ± 3.4 2.5 ± 1.4
at the equilibrium concentration, were 20 and 27 wt % for UiO-
66 and MIL-53 using initial caffeine solution concentrations of
10 and 1.6 mg·mL−1, respectively. At the considered caffeine
aqueous concentrations, the equilibrium was not reached for
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MIL-100, suggesting that higher encapsulation rates than 50 wt
% as suspected from molecular simulations are feasible.
However, the poor stability of the caffeine aqueous solution
at concentrations higher than 10 mg·mL−1 led to an important
inaccuracy in the caffeine payload estimation which rules out
such encapsulation tests. Nevertheless, to further optimize the
caffeine loadings, repeated impregnations were performed for
MIL-53 and MIL-100; however, they did not lead to any
significant increase in the loading capacity. This indicates that
the maximum caffeine loadings were reached at the selected
caffeine concentrations, pointing out that the pores were
completely filled or that the caffeine/solvent packing did not
allow any accommodation of additional caffeine molecules.
One can estimate the affinity of each solid by calculating the
caffeine partition coefficient between the solvent and the MOF
(or encapsulation efficiency = adsorbed drug/drug amount in
the starting solution). At low concentrations (<1.2 g·L−1), more
than 90% of the caffeine present in the starting ethanol solution
is adsorbed on the flexible MIL-53, indicating a strong affinity.
Lower efficiencies were found for the UiO-66 and MIL-100
solids in the same domain of concentrations (1 g·L−1; 40 and
55%, respectively), suggesting lower affinities. If the efficiency is
normalized by the maximum caffeine payloads of both solids,
the affinity of UiO-66 is twice as big as that of MIL-100 (2.0 vs
1.1, respectively). Among others, this could be explained by the
more hydrophobic environment of UiO-66 and its smaller
cavities, which may lead to a higher confinement of caffeine
moieties.
Kinetics of Encapsulation. The kinetics at which the active
molecule is entrapped within the pores is another interesting
point to be addressed (see Figure 2 (right)). All solids showed
very fast kinetics of encapsulation, with, for instance, caffeine
loadings higher than 26, 43, and 9 wt % during the first hour of
the immersion for MIL-100, MIL-53, and UiO-66, respectively,
which corresponds to around 89%, 87%, and 40% of their total
caffeine capacities, consistent with a relatively high drug−MOF
affinity. Nevertheless, strong host−guest interactions are usually
associated with a slower diffusion at the molecular level
throughout the pores. Consequently, the fast encapsulation
kinetics of caffeine might indicate indeed a moderate strength
of the host−guest interactions, in concordance with the absence
of highly active functional groups on the caffeine able to
strongly interact with the surface of the hybrid solid.
Note also that UiO-66 exhibits slower kinetics than MIL-100
and MIL-53 (2 vs 1 h). This fact might not be a consequence of
either the dimensionality of the pore system (interconnected
3D in both MIL-100 and UiO-66 rigid solids, 1D channels in
MIL-53) or the pore size (MIL-100, UiO-66, and the open
form of MIL-53−4.7 × 5.5−8.6, 5−7, and 8.5 Å, respectively)
but more likely to the competitive adsorption of the caffeine/
solvent (ethanol or water) mixture within these solids. Indeed,
diffusion of water within the slightly more hydrophobic
character of UiO-66 might be enough to slow down the
Impact of the Ligand Functionalization. Following our
previous studies,18,19 which evidenced the key factors that
govern caffeine uptake into a series of functionalized MIL-88B
and UiO-66 solids, the effect of grafting the organic linker on
the caffeine encapsulation and release performance of MOFs
was investigated for both the flexible MIL-53 and the rigid UiO-
66 solids bearing either hydrophilic and protic NH2 groups and
highly polarizable −Br atoms (Figure 1).
dx.doi.org/10.1021/cm400798p | Chem. Mater. 2013, 25, 2767−2776
Chemistry of Materials
First, it appears that the MOF functionalization strongly
impacts the loading capacity of caffeine (Table 1). The bare
MIL-53 showed a caffeine capacity almost twice as big as that of
MIL-53_Br (0.36 vs 0.19 mol·mol−1), whereas MIL-53_NH2
did not show any significant encapsulation rate. On the
contrary, in comparison with the bare UiO-66 solid, caffeine
encapsulation into UiO-66_Br was only slightly higher (2.20 vs
2.14 mol·mol−1) but significantly lower into UiO-66_NH2
(1.16 vs 2.14 mol/mol) (Table 1). Indeed, functionalization
of UiO-66 and MIL-53 can act in two different ways: (i) the
steric hindrance of the functional group that reduces the pore
size and/or pore accessibility; (ii) formation of specific
interactions between the adsorbate (active ingredient and
solvent) and the functional group.
Considering the case of MIL-53, the deviation in the
encapsulation rates can be explained by different factors. First,
the absence of encapsulation within the amino form is most
probably due to a stabilization of the framework in its narrow
pore form due to establishment of strong intraframework
interactions between the amino group of the linkers and the
oxygen atoms from the iron octahedral that cannot be
overcome upon adsorption as previously reported for the Fe
analogue,28 which would prevent any caffeine adsorption.
Second, the presence of bulky and heavy bromine atoms (van
der Waals radius ≈ 1.85 Å) within the 1D pore system of MIL-
53_Br induces a significant decrease in the pore accessibility
and/or rotation ability of the phenyl rings to let the guest
molecules diffuse throughout the channels, resulting in a
significant decrease of the caffeine uptake.
Regarding UiO-66, the situation significantly differs. Despite
the presence of the bulky bromine atoms, these electronegative
and polarizable atoms could enable formation of additional
electrostatic interactions between the caffeine and the frame-
work, which seems to favor adsorption of caffeine. Similarly to
the bromine form, amino−terephthalate groups can a priori
interact with the caffeine moieties. However, the lower
encapsulation of caffeine within UiO-66_NH2 could be here
related to the protic and high hydrophilic character of the
−NH2 group, which can form preferentially hydrogen bonds
with water molecules (used as solvent for impregnation)
instead of caffeine, as previously evidenced by XRPD, leading to
a coencapsulation of both water and caffeine, reducing the
loading of the cosmetic molecule.
XRPD is a very useful technique to analyze the sorption of
guest within highly flexible solids such as MIL-53. Here, XRPD
first confirms that the crystalline MIL-53_X (X = H, Br, NH2)
structures are kept intact after the impregnation step (Figure
S1, Supporting Information). Note that the loaded MIL-
53_NH2 XRPD patterns did not show any change, in
agreement with the absence of any active molecule within the
pores (0 wt %; Table 1). Interestingly, the position of the main
Bragg peaks after encapsulation in the flexible MIL-53 and
MIL-53_Br solids is strongly affected, consistent with a
different pore opening due to the caffeine entrapping inside
the pores. Unit cell parameters of the caffeine-loaded MIL-
53_Br solids were indexed using Dicvol and its graphical
interface Winplotr. A monoclinic cell (C2/c (no. 15) with a =
19.75 Å, b = 10.84 Å, c = 6.96 Å, ß = 114.6°, V = 1388 Å3) was
estimated (Figure S4, Supporting Information). To confirm
such findings, DFT calculations were then performed on the
bare MIL-53 and MIL-53_X (X = Br, NH2)/caffeine systems.
As a validation step of the methodology employed (functional,
pseudopotential, ...), the initial open pore forms of each MIL-53
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solid were fully geometry optimized (atomic position and cell
parameters) in the absence of caffeine, and their resulting
crystallographic features were further compared to those
previously reported by XRPD.28 As shown in Table S5,
Supporting Information, very good agreement is obtained
between the experimental and the simulated unit cell volumes
(relative error < 0.5%) and one can also notice that the b
parameters, which are related to the pore opening of the
structure, are very well reproduced which emphasizes that the
method employed (DFT+U, PBE functional, pseudopotential,
...) is accurate enough to describe such solids. The caffeine-
containing MIL-53_Br system was further geometry optimized.
This calculation confirmed that drug incorporation induces a
significant contraction of the pore, the unit cell parameters and
volumes matching remarkably the experimental data mentioned
above (a = 19.749 Å, b = 10.844 Å, c = 6.956 Å, ß = 111.2°, V =
1388.7 Å3). As the indexing of the caffeine-containing MIL-53
was not possible due to the presence of a mixture of different
structural phases corresponding to different pore opening, a
plausible structure model was proposed using our DFT
approach with the following unit cell parameters (a = 19.395
Å, b = 10.115 Å, c = 6.878 Å, ß = 107.4°, V = 1289.3 Å3)
corresponding to a more significant contraction of the pore
than its −Br analogue (19% vs 11%), consistent with what has
been previously reported upon water adsorption.28 Such a trend
can be explained by a steric hindrance caused by the Br atom
that prevents a more pronounced closure of the structure.
Finally, the hypothetical MIL-53_NH2 structure in the
presence of caffeine has been also predicted resulting in a
pore contraction very similar to the nonmodified material (a =
19.506 Å, b = 9.965 Å, c = 6.877 Å, ß = 107.15°, V = 1275.4
Å3), here again similar to its behavior upon immersion.28
A further step consisted of understanding the origin of such
structure contractions by analyzing the caffeine−MOFs
interactions in terms of geometries and resulting energies. It
has been shown that the drug is not aligned along the direction
of the tunnel but adopts an orientation at a slight angle to the
channel axis. The most likely interaction for caffeine in the bare
MIL-53 involves relatively strong hydrogen bonding between
the oxygen atom of its carbonyl group (C4; Figure 1) and the
μ2-OH group present at the MOF surface (d(O4caf−Hμ2‑OH) =
1.70 Å). Such predominant interactions seem at first sight
contradictory with IR observations; however, one should keep
in mind that such calculations are conducted in the presence
only of the drug, while experimentally, the presence of some
residual ethanol (coming from the impregnation) coordinated
to the iron would tend to replace the OH groups and thus
preventing O4caf−Hμ2‑OH interactions. In addition, weaker van
der Waals or CH−π interactions were found between the other
carbonyl and the methyl groups of the drug molecule and the
organic/inorganic part of the matrix (Figure 3a). However, one
observes that the interacting distance between the methyl
group that bears N1 and the oxygen atom of the framework is
relatively short (2.32 Å), which supports that N1 is indirectly
involved in the interactions with the pore wall, as might be
suggested by IR measurements mentioned above. We also
observe a weak interaction between the N1 atom of the caffeine
and the organic part (d(N1caf−Horganic) = 2.50 Å; Figure 1). The
resulting binding energy of −62.6 kJ·mol−1 is higher than those
we previously obtained for ibuprofen in the same MOF (−57.4
kJ·mol−1). In the MIL-53_Br solid, one observes that while the
main hydrogen-bonding interactions between the drug and the
μ2-OH group remains almost unchanged (d(O4caf−Hμ2‑OH) =
dx.doi.org/10.1021/cm400798p | Chem. Mater. 2013, 25, 2767−2776
Chemistry of Materials
Figure 3. DFT-optimized structures of MIL-53_X (X = H (a), Br (b),
and NH2 (c)) in the presence of caffeine. Characteristic caffeine/MOF
interacting distances are reported in Angstroms (in green, the main
hydrogen bonding O4caf−Hμ2‑OH; in blue, the additional interactions
between caffeine and the organic/inorganic part of the MOF; in
purple, the interactions induced by the presence of the grafted
function).
1.75 Å) compared to the nonmodified material, the −Br atom
grafted on the organic linker leads to additional interactions
with caffeine via its aromatic hydrogen atom (d(Br−Hcaf) =
2.70 Å) and its carbonyl oxygen (d(Br−Hcaf) = 3.25 Å)
resulting in a higher binding energy of −67.1 kJ·mol−1. Finally,
the amino-functionalized MIL-53 also shows very similar
strength of hydrogen-bonding interactions (d(O4caf−Hμ2‑OH)
= 1.72 Å) with the drug; however, one can notice that the
−NH2 functional group serves as an additional anchoring point
for caffeine leading to relatively strong interaction with the
oxygen atom of the second carbonyl function (d(HNH2−O2caf)
= 2.20 Å) as well as the methyl group (d(HNH2−Hcaf) = 2.10
Å), resulting in a significantly higher binding energy of −69.4
kJ·mol−1. Assuming that the initial stage of the delivery process
occurs without any degradation of the MOFs, such an
enhancement of the drug/matrix interactions when the solid
is functionalized would be expected to lead to an increase of the
energy barrier required to be passed prior to triggering the
delivery process, thus leading to a slower initial step of drug
release in the case of the amino and bromine versions.
Caffeine Release. As a further step, caffeine release was
evaluated at 37 °C using either a simulated serum fluid
(phosphate buffer solution (PBS) 0.04 M at pH = 7.4) or pure
water (pH = 6.3), considering that for cosmetics (slim and
microcirculation effect) topical applications are envisaged. Note
that PBS seems to be a good and simple simulated serum fluid
since similar release kinetics were achieved using other more
complex phosphate media (cell culture medium supplemented
with fetal bovine serum).72 The caffeine-containing MOFs were
in both cases soaked in solution under continuous bidimen-
sional stirring (see Supporting Information) in order to avoid
external diffusion phenomena (Figure 5).
Release in PBS Media. Caffeine delivery was first followed
into PBS (Figure 4). The amount of released caffeine was
quantified by HPLC, and the solids were fully characterized
after caffeine delivery (see Supporting Information).
Except for MIL-127, caffeine release was very fast, in less
than 6 h. The total amount of caffeine was released in 0.5, 2, 2,
4, and 6 h from MIL-100, UiO-66, UiO-66_Br, UiO-66_NH2,
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Figure 4. Caffeine release from different porous MOFs in PBS (left)
and in deionized aqueous (right) media at 37 °C.
MIL-53_Br, and MIL-53, respectively (Figure 5 and Table 1).
Moreover, except for the MIL-127 and MIL-53 materials, most
of the caffeine (53%, 68%, 79%, 93%, and 100% for MIL-53_Br,
UiO-66_NH2, MIL-100, UiO-66, and UiO-66_Br, respectively)
was delivered through a burst effect, i.e., within the first 30 min.
In order to understand the origin of this fast release,
degradation of the solids on their constitutive metal and
organic linker was also analyzed via quantitative release of the
organic linker (HPLC), XRPD, FTIR, and N2 adsorption
porosimetry (see Supporting Information). Note that we
recently demonstrated the lack of toxicity and direct removal
by the urine and feces of both metal and ligand of several iron
carboxylates MOFs.20 It was concluded that apart from MIL-
127, complete caffeine release is associated with a total
amorphization of the solids (Figure S1, Supporting Informa-
tion) and a significant release of the organic linker. After the
first 30 min of the assay, up to 18%, 31%, 22%, 3%, 78%, and
81% of the linker was released for, respectively, MIL-53, MIL-
53_Br, UiO-66_NH2, MIL-100, UiO-66, and UiO-66_Br, in
agreement with degradation of the framework (Figure S9,
Supporting Information). PBS medium leads to a framework
collapse of the metal polycarboxylates MOFs due to
replacement of the carboxylate linkers by phosphate groups
present in the PBS solution and/or formation of iron oxide
considering the pKa of the carboxylic functions (∼4−5)
rendering less favorable formation of stable metal carboxylate
bonds at several pH units above their pKa. Accordingly, FTIR
(Figure S7, Supporting Information) revealed the presence of
ν(PO4−3) bands characteristic of the phosphate groups at
around 1000 cm−1, and N2 adsorption measurements showed
no residual porosity after caffeine release for all these solids
(Figure S6, Supporting Information). Therefore, one can
estimate that under PBS conditions the main parameter driving
drug release is degradation of the MOF. Indeed, the kinetics
profiles of caffeine delivery and MOF degradation (Figures 5
and S9, Supporting Information) almost overlap, confirming
undoubtedly that MOF degradation governs caffeine release,
particularly when the MOF degrades rapidly in PBS.
A more progressive caffeine release to the PBS medium was
however evidenced from the MIL-53 and MIL-127 solids, with
complete release after 6 and 72 h. Interestingly, despite the
significant decrease of the crystallinity of MIL-53 after 2 h, only
5% and 20% of the cosmetic agent were, respectively, delivered
after 30 min and 1 h. The release kinetics from the MIL-53
solid was fitted from 0 to 4 h to a zero-order kinetics ([caffeine]
= −2.008 + 23.115t; R > 0.99; where [caffeine] corresponds to
the concentration of released caffeine and t to the release time),
predictable and independent of the caffeine concentration. As
previously shown for the ibuprofen drug,36 this controlled zero-
order release could be related with its hydrophobic 1D pore
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Chemistry of Materials
system, maintaining the same aperture throughout the entire
delivery process.
For MIL-127, despite an initial burst effect of ca. 40%
caffeine delivered in the first 30 min, caffeine release of caffeine
was completely achieved after 72 h (Figure 4). This remarkable
result might be the consequence of the higher stability of this
solid under the PBS conditions, as it has been evidenced not
only by the XRPD (Figure S1, Supporting Information) but
also by the absence of release of the constitutive ligand (<limit
of detection (1.25 mg·L−1), corresponding to 0.08% of
degradation) and the presence of a significant remaining
porosity after caffeine release (SBET = 870 m2·g−1, Figure S6 and
Table S2, Supporting Information). In fact, reduction of the
MIL-127 porosity could be associated with partial degradation
and/or the presence of heavier phosphate anions adsorbed on
the porous framework after the delivery tests. Hence,
progressive caffeine release from MIL-127 solid would be
mostly governed by a controlled diffusion of the caffeine
through the slightly amphiphilic 1D pores as well as by
formation of significant host−guest interactions.
Such a different kinetics of release profile is however only
related to differences in terms of MOF stability in PBS. Indeed,
the kinetics of degradation of MIL-53 perfectly fits with the
caffeine release profile (Figure 5). To explain such a difference
Figure 5. Caffeine (black) and organic ligands (red) release from
different caffeine-containing MOFs under PBS conditions.
in terms of stability, one could argue that MIL-53 bears chains
of iron octahedra that are likely to be less hydrolyzed than
trimers of iron octahedra. MIL-127 is nevertheless built up
from molecular building units (trimers) but possesses four
carboxylate groups per spacer that increase the complexing
strength of the linker and thus would make removal of the
linker less favorable compared with MOFs built up from di- or
tricarboxylates. Note that the highly water stable UiO-66 MOF
degrades very fast in PBS, probably due to the strong affinity of
Zr atoms for phosphate groups and/or formation of Zr oxide,
strongly favored out of the very acidic or basic conditions for
such high-valence cation.
Release in Deionized Water. The study of caffeine release
using water medium was performed not only to better mimic
cutaneous release but also to rule out the influence of the
degradation, allowing a better understanding of the effect of
other parameters (polarity, interactions, flexibility, structure,
etc.) on delivery of the therapeutic molecule.
Remarkably, caffeine delivery profiles were much slower in
pure water than under PBS conditions. This is in agreement
with the much higher stability of the MOFs in deionized water
(Figure 4). XRPD confirmed the stability of all solids, although
a broadening of the diffraction peaks was observed in the case
of MIL-53 solids, which might be explained by the presence of
a distribution of forms bearing slight differences in terms of
pore opening and/or to partial degradation after long time
periods (up to 9 days; Figure S1, Supporting Information).
Additionally, after caffeine delivery in water, N2 adsorption
measurements confirmed the absence of any severe degrada-
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tion, as evidenced by maintenance of porosity comparable to
the starting solids (see Figure S6 and Table S2, Supporting
Information). Moreover, no release of the ligand to the water
medium was detected by HPLC under this delivery condition.
Caffeine release rates could be classified as follows from the
faster to the slower kinetics: MIL-100 > UiO-66_Br ≈ UiO-66
> MIL-127 > UiO-66_NH2 ≫ MIL-53_Br > MIL-53. As one
could expect, faster release was observed from the larger pores
MIL-100 solid, showing however two different delivery steps:
the first one characterized by an important “burst” release with
ca. of 60% of the caffeine released in the first 30 min and the
second one with a progressive release of the remaining 40%
within the following 48 h. Taking into account that most likely
caffeine is accommodated into the large cages, as previously
discussed, these two different stages could correspond to the
different location of the caffeine within this cavity. During the
first step (1 h), this would correspond to the departure of the
molecules at the center of the cages with no interaction with
the surface of the pores. In contrast, the second delivery step
(1−48 h) would be associated to release of drug molecules
present at the surface of the pore walls interacting through
specific interactions (van der Waals and π−π interactions).
Taking into account the surface of one large cage (∼2640 Å2)
and considering that the maximum surface in contact with the
wall might be one-half of the surface of one caffeine molecule
(∼102 Å2), one can estimate that around 34% of the caffeine
(ca. 26 molecules per cage) could be in direct contact with the
wall of the cavity, which is in reasonable agreement with the
second release step of around 40%.
Very slow caffeine delivery rates were observed for the
flexible MIL-53_Br and MIL-53 solids, with a partial release of
around 70% of the cosmetic within, respectively, 6 and 9 days
after the delivery assay. This very long delivery time with a total
progressive release might pave the way for interesting
applications in the sustained release of active compounds. As
discussed previously for ibuprofen,36 this result is due to (i) the
1D pore system, which restrains diffusion to only one direction,
(ii) the flexible porosity that adapts the pore size to the guest
molecule, optimizing the confinement effect, reducing the
diffusion rate, and improving the host−guest interactions, and
(iii) the relative hydrophobic character of the framework, which
slows down water diffusion, which favors a slow exchange and
release of the caffeine. This could also explain why release is
faster from MIL-53_Br compared with MIL-53 (6 vs 9 days),
bromine atoms increasing the hydrophilic character, even if
additional bromine caffeine electrostatic interactions and the
steric hindrance of the bromine atom might play in favor of a
slower delivery rate.
Full caffeine release was achieved after 48 h from MIL-127,
UiO-66, and UiO-66_Br solids. Here, considering the micro-
porous character of the solids, unlike for mesoporous MIL-100,
all caffeine molecules are mainly interacting in some extent with
the MOF framework. Interestingly, the kinetics of caffeine
delivery can here be empirically adjusted with regression factors
> 0.99 to a Higuchi model ([caffeine] = Kt1/2; Table 2).73,74
Therefore, caffeine release is here mainly governed by a
diffusion process, predictable by the Higuchi equation and
dependent on several factors such as the structure (dimension-
ality, interconnectivity, flexibility, pore size) and composition
(polarity, interactions). Considering that the external diffusion
process is avoided by constant stirring during the assays, the
diffusion process is only due to drug motion through the
windows of the cages. Caffeine bears no highly reactive
dx.doi.org/10.1021/cm400798p | Chem. Mater. 2013, 25, 2767−2776
Chemistry of Materials
functions that might strongly interact with acidic or basic metal
or functionalized groups. One expects that using active
molecules bearing stronger sites, longer deliveries and/or
significant differences in terms of kinetics of delivery would be
expected from these solids.
■
CONCLUSION
The challenging cosmetic caffeine was successfully entrapped
within porous MOFs, achieving exceptional payloads up to 50
wt % together bearing very fast kinetics of encapsulation.
Release of caffeine strongly depends on the release media. In
serum-simulated physiological media (PBS pH = 7.4, 37 °C),
very fast release occurs that is mainly governed by the MOF
degradation, except when a sufficient chemical stability is
reached. Noteworthy, when other topical simulated conditions
(distilled water pH = 6.3, 37 °C) are evaluated that do not
degrade the MOFs architectures, progressive releases can be
achieved that are mainly governed by the degree of caffeine
mobility and MOF−caffeine interactions. Considering that a
typical cosmetic administration typically requires controlled
releases within 8−24 h, MIL-100 and UiO-66 appear thus as
very promising carriers for topical administration of caffeine
with both spectacular cosmetic payloads and progressive
releases. Indeed, slower releases could even be expected
under cutaneous conditions since on the upper layer of the
skin only partial pressures of vapor water will be usually
reached. Besides, the influence of other components of the
stratum corneum mainly involving a lipid matrix75−77 and the
natural moisturizing factor (aminoacids, lactates, urea, inorganic
salts, sugars, ...)78,79 could either accelerate or slow down the
caffeine release rate.
■
ASSOCIATED CONTENT
*
S Supporting Information
Synthesis, encapsulation, and delivery details, XRD data, FTIR,
TGA, HPLC, elemental analysis, N2 adsorption porosimetry,
and simulation methodology. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail: horcajada@chimie.uvsq.fr, serre@chimie.uvsq.fr.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
This work was supported by EU funding through the ERC-
2007−209241-BioMOFs ERC (C.S., P.H., D.P., G.M.) and the
Region Languedoc Roussillon through the award “Chercheur
d’Avenir” 2009 (G.M.). The authors gratefully acknowledge F.
Ragon and T. Baati for their help in, respectively, material
preparation and HPLC method development.
■
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