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 systematic 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 (216a >144a
9.5 9.5 12.5 6.4 8.1
10
0.51
1160
2.14 2.20 1.26 0.36 0.19 0.00 0.63
0.5 0.5 2 6 4
1270
22.4 21.2 13.2 29.2 10.6 0 15.9
± ± ± ± ±
0.63
11.7 6.8 11.1 29.5 13.1 10.8 31.6 (19.0b)
48
13.7 ± 0.5
3.4 0.7 0.2 1.5 3.0
± 0.5
72
H2O
kinetic constant 6.3 ± 0.5 ± ± ± ± ±
0.8 0.3 0.6 0.2 0.4
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 MIL53 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 recrystallized 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(CO) 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 establishment 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 CO band has previously been associated with interactions involving the 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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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
dx.doi.org/10.1021/cm400798p | Chem. Mater. 2013, 25, 2767−2776
Chemistry of Materials
Article
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 investigating 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 impregnations. 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 ( 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 microporous 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 (dimensionality, 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
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 (
