Unraveling the Energetics and Dynamics of Ibuprofen in Mesoporous

Sep 29, 2009 - A computational study is reported to investigate the microscopic behavior of ibuprofen (IBU) in two mesoporous metal−organic framewor...
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J. Phys. Chem. C 2009, 113, 18287–18291

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Unraveling the Energetics and Dynamics of Ibuprofen in Mesoporous Metal-Organic Frameworks Ravichandar Babarao and Jianwen Jiang* Department of Chemical and Biomolecular Engineering, National UniVersity of Singapore, Singapore 117576 ReceiVed: July 8, 2009; ReVised Manuscript ReceiVed: September 5, 2009

A computational study is reported to investigate the microscopic behavior of ibuprofen (IBU) in two mesoporous metal-organic frameworks (MOFs), MIL-101 and UMCM-1. Both host structures possess remarkably large pore volumes and surface areas. The predicted maximum loading of IBU is in good agreement with experimental measurement and approximately four times greater than that in silica MCM-41. The lowest-energy conformation of IBU in MIL-101 is preferentially located near the metal-oxide. From the highest-occupied molecular orbitals (HOMOs) and band gap, a coordination bond is found to form between the carboxylic group of IBU and the exposed metal site of MIL-101. IBU exhibits a stronger binding energy and a smaller mobility in MIL-101 than in UMCM-1. These factors are crucial for the delayed release of IBU from MIL-101, which was observed experimentally. This work unravels the energetics and dynamics of IBU in MOFs at the molecular level and provides useful insight into the interactions of drug with host MOFs. I. Introduction With emerging nanotechnology, interest in novel nanoporous materials for drug delivery has increased tremendously over past years. The capacity and release of drug in a porous carrier are primarily governed by a variety of factors including pore size, pore volume, surface area, and interaction with host.1-4 In traditional materials such as inorganic silica, carbonaceous materials, and polymeric matrixes, drug loading capacity is usually not sufficiently large and encapsulated drug is difficult to release specifically.5-7 To achieve a large loading and a controlled release of drug, materials possessing high and regular porosity are desired. As a new class of hybrid inorganic-organic materials, metal-organic frameworks (MOFs) have unprecedentedly high porosities and well-defined pore structures.8 With the judicious choice of metal connectors and bridging ligands, the pores in MOFs can be readily tuned in the dimensions of several angstroms or nanometers. As a consequence, MOFs provide a wealth of opportunities for engineering new functional materials and are regarded as promising carriers for drug delivery and other biomedical applications. Nevertheless, the study of drug delivery in MOFs is scarce. Only recently, a mesoporous MIL101 (MIL: Materials of Institut Lavoisier) has been tested for the delivery of ibuprofen (IBU), an analgesic and antiinflammatory drug.9 It was found that MIL-101 exhibited a remarkably high dosage capacity of IBU, up to 1.38 g/g MIL101. This finding is significant as only very small amount of material is then required for the administration of high dosage. The sorption and in vitro delivery of IBU were also examined in MIL-53, and the loading was about 0.22 g IBU/g MIL-53 and independent of metal type (Cr, Fe).10 Currently, the fundamental mechanisms of drug delivery in MOFs remain elusive. For instance, how would a drug interact with the host structure? Between metal oxide and organic linker, which plays a dominant role in drug adsorption and release? What is the different behavior for a drug in various MOFs? To * To whom correspondence should be addressed. Tel: +65-65165083. Fax: +65-67791936. E-mail: [email protected].

address these important questions for drug delivery, in this work we report a computational study on the energetics and dynamics of IBU in two host carriers, MIL-101 and UMCM-1. With evergrowing powerful computers, atomic and molecular computations are very helpful to provide underlying physics at the microscopic level, complement experiments, and assist in the rational design of novel nanomaterials for better drug delivery. In section II, the computational models used for IBU, MIL101, and UMCM-1 are described, including the interaction potentials between drug and MOFs. The methodology is briefly given in section III. More specifically, configurational-bias Monte Carlo (MC) and molecular dynamics (MD) simulations were employed to calculate the loading and mobility of IBU in MOFs at room temperature (298 K). The favorable conformations of IBU were identified using simulated annealing technique and followed by first-principles DFT calculations. In section IV, the loading capacity, lowest-energy conformation, binding energy, and displacement of IBU are reported. In addition, the highest-occupied molecular orbitals (HOMO) and band gap are presented to identify the possible bond formation between IBU and MOF cluster. Finally, the concluding remarks are summarized in section V. II. Models IBU was chosen as a model drug because it is a worldwide used pharmaceutical compound with analgesic and antipyretic features.11 It was first launched in late 1960s for the treatment of rheumatoid arthritis. Nowadays, it has become a core nonsteroidal anti-inflammatory drug and is commonly used for relief of arthritis, dysmenorrhea, acne, and fever. IBU exists with two enantiomers, in which (S)-IBU is active both in vitro and in vivo; consequently, (S)-IBU is considered in this study. MIL-101 is assembled by computationally designed supertetrahedra consisting of Cr trimers and 1,4-benzenedicarboxylic acid.12 Two types of exceptionally large mesoporous cages exist in MIL-101. The smaller one has 20 supertetrahedra, a free diameter of 29 Å accessible through pentagonal windows with 12 Å aperture; whereas the larger one has 28 supertetrahedra, a free diameter of 34 Å accessible through both hexagonal, and

10.1021/jp906429s CCC: $40.75  2009 American Chemical Society Published on Web 09/29/2009

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Figure 1. Atomic charges in the fragmental clusters of MIL-101 and UMCM-1 calculated from DFT. The cleaved bonds (indicated by circles) were terminated by methyl groups to maintain the original hybridization.

pentagonal windows with 14.7 × 16 Å aperture. Exposed Cr sites are formed in dehydrated samples by removing terminal waters in octahedral Cr trimers. UMCM-1 contains two organic linkers of different topologies, namely, terephthalic acid (H2BDC) and 1,3,5-tris(4-carboxyphenyl)benzene (H3BTB).13 The structure differs dramatically from those based on pure linkers. The metal clusters ZnO4 in UMCM-1 are connected with two BDC and four BTB linkers. The octahedral geometry of UMCM-1 leads to two types of pore, one is micropore with a dimension of 14 × 17 Å and the other is mesopore with a 1D hexagonal channel of 27 × 32 Å. Unlike MIL-101, no exposed metal sites exist in UMCM-1. To characterize MIL-101 and UMCM-1, the free volume and surface area were estimated from MC methods.14-16 A single helium was attempted to insert into the host structure and the integration of the energetic Boltzmann contribution gave the pore volume. The surface area was calculated by rolling over a probe along the adsorbent surface. The probe had a diameter of 3.68 Å corresponding to a nitrogen molecule. The interactions of IBU with MIL-101 and UMCM-1 in MC and MD simulations were modeled using Lennard-Jones (LJ) and Coulombic potentials. The LJ parameters were adopted from the Universal Force Field (UFF),17 as listed in the Supporting Information. A number of simulation studies have shown that UFF gives accurate predictions of adsorption and diffusion in MOFs.18-20 The Lorentz-Berthelot combining rules were used to calculate the cross LJ interaction parameters. For the Coulombic interaction, the atomic charges of IBU, MIL-101 and UMCM-1 were calculated from DFT. Because of the large size of host structures, the fragmental clusters as shown in Figure 1 were used for MIL-101 and UMCM-1. The cleaved bonds were terminated by methyl groups to maintain the original hybridization. It is widely recognized that quantum mechanically derived charges can vary greatly with the basis set when a small basis set is used but tend to converge beyond 6-31G(d).21 As a consequence, 6-31G(d) basis set was used in the DFT calculations for all atoms except the transitional metals, for which LANL2DZ basis set was used. LANL2DZ is a double-ζ basis set and contains effective pseudopotentials to represent the potentials of the nucleus and core electrons experienced by the valence electrons. This allows only the softer valence electron wave functions, which usually control the chemistry, to be explicitly treated and can significantly reduce computational cost. The DFT calculations used the Lee-Yang-Parr correlation functional (B3LYP) and were carried out using Gaussian 03.22 The concept of atomic charges is solely an approximation and no unique method is currently available to determine them on

a rigorous level. Commonly used methods in the literature include Mulliken population analysis,23 electrostatic potential (ESP) fit,24 restrained electrostatic potential (RESP) fit,25 and charges from electrostatic potentials using grid (CHELPG).26 Mulliken’s method is from the wave functions and usually overestimates the charges. In the ESP method, the electrostatic potentials are fitted at grids located with equal density on different layers around the molecule. The RESP method further sets the charges on the buried atoms to zero by using a penalty function in the fit. Similar to the ESP method, the electrostatic potentials are calculated in the CHELPG method at grids distributed on a cubic lattice. There is no specific rule on the selection of a particular method. In this work, the ESP method was used, because of easy implementation in calculations, to estimate the atomic charges of MIL-101 and UMCM-1. III. Methodology The maximum loadings of IBU in MIL-101 and UMCM-1 were estimated by grand canonical MC simulations using Materials Studio.32 The configurational-bias algorithm was used rather than the conventional Metropolis technique, which is prohibitively expensive in sampling the phase space of big molecules. In configurational-bias algorithm, a molecule is grown atom-by-atom biasing energetically favorable configurations while avoiding overlap with other atoms.27-29 The simulation box contained one unit cell for MIL-101 and two (1 × 1 × 2) unit cells for UMCM-1, and the periodic boundary conditions were exerted in all three dimensions. The LJ interactions were evaluated using a spherical cutoff of 15 Å and the Coulombic interactions were calculated using the Ewald summation with a precision of 10-5. The number of steps in the MC simulation was 107 steps for equilibration and subsequent 107 steps for production. Five types of trial moves were randomly attempted in the MC simulation, namely, translation, rotation, twist, regrowth, and exchange including creation and deletion with equal probability.30,31 To examine the mobility of IBU in MIL-101 and UMCM-1, MD simulations were conducted in canonical ensemble using Materials Studio.32 The frameworks of MIL-101 and UMCM-1 were considered to be flexible. It has been demonstrated that the dynamics of big molecules could be substantially influenced by the framework flexibility. For instance, diffusion in zeolites is usually accelerated in a flexible model due to the increased possible pathways for molecular jump.33 Nevertheless, the diffusion of benzene in IRMOF-1 was found to be considerably slower in a flexible framework compared to a rigid one and

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Figure 2. (a) Lowest-energy conformation of IBU in MIL-101 from simulated annealing. (b) Enlarged view for the location of IBU near the Cr3O metal-oxide in MIL-101. (c) Optimized conformation of IBU near the Cr3O metal-oxide in MIL-101. The distances are represented in angstroms. MIL-101: Cr, orange; C, gray; O, red; H, white. IBU: C, cyan; O, pink; H, purple.

attributed to the correlation motion of benzene with an organic linker.34 The temperature in MD simulations was maintained by a Nose´-Hoover thermostat and the velocity-verlet algorithm was used to integrate the equations of motion. The time step was 1 fs and the total simulation time was 250 ps. The total energy was monitored during the simulation to ensure proper energy convergence. Simulated annealing was used to identify the favorable conformations of IBU in MIL-101 and UMCM-1 by gradually decreasing temperature from 500 to 50 K. At a high temperature, the IBU molecule is capable of probing most configurational positions. With decreasing temperature, IBU molecule tends to reside in positions with lower energy. A handful of energy minima were found on the energy landscape due to the presence of multiple binding sites in the host structure. Thereafter, the lowest-energy conformation was selected and further optimized using DFT. The small cleaved clusters of MIL-101 and UMCM-1 were used in the optimization, which contained one metal oxide with the dangling bonds saturated by hydrogen atoms. The binding energies of IBU with clusters were estimated as the energy difference between adduct (IBU and cluster) and its constituents. IV. Results and Discussion The microscopic behavior of drug in a host matrix is largely governed by the intrinsic host structure. From our calculations, MIL-101 has a free volume 1.96 cm3/g and a surface area 3451 m2/g, close to the experimentally measured 1.74 cm3/g and 3780 m2/g.35 UMCM-1 has a free volume 2.28 cm3/g and a surface area 4764 m2/g. To our best knowledge, no experimental free volume is available in UMCM-1 for comparison; nevertheless, the calculated surface area is in accord with the experimental value 4730 m2/g.13 On the basis of these characteristics, UMCM-1 is apparently more porous than MIL-101. The maximum loading of IBU in MIL-101 is predicted to be 1.11 g IBU/g MIL-101 and agrees fairly well with the experimentally measured loading of 1.37.9 It is worthwhile to note that the dehydrated sample of MIL-101 was used in both experiment and simulation, whereas the loading of IBU measured experimentally was carried out from a solution with hexane as solvent. In our simulation, the solvent was not considered, which might contribute to the difference between predicted and experimental loading. In addition, the classical force field was used in our work and a better force field might improve the prediction. The loading in UMCM-1 is approximately 1.36 g IBU/g UMCM-1; however, no experimental result is available for comparison. Overall, MIL-101 and UMCM-1 exhibit four times greater of IBU loading than mesoporous silica MCM-41.1 A crucial factor

in drug delivery is desired loading. The substantially high loadings in MIL-101 and UMCM-1 suggest that they might be useful for drug delivery as a very small amount of carrier is needed for high dosage. From simulated annealing, the favorable conformations of IBU in host structure were identified. Part a of Figure 2 shows the lowest-energy conformation in a unit cell of MIL-101, which is enlarged in part b of Figure 2. Interestingly, the carboxylic group of IBU points toward the Cr atom of MIL-101 and the distance from the carboxylic O atom to the Cr atom is 2.261 Å. This remarkably supports the commonly recognized factor that metal oxides in MOFs are the preferential adsorption sites, which has been confirmed by numerous experimental and simulations studies for gas adsorption in various MOFs.36 The conformation in part b of Figure 2 was further optimized using DFT, and the binding energy was subsequently estimated between IBU and MIL-101 cluster. After DFT optimization, the distance between the carboxylic O atom of IBU and the Cr atom is 2.141 Å as shown in part c of Figure 2, slightly decreased from 2.261 Å obtained using simulated annealing. The Cr-O distance is very close to the experimentally determined 1.9-2.0 Å between Cr and terminal water.12 This suggests a coordination bond is formed between IBU and MIL101, which is consistent with the broadening NMR signals of IBU observed in experiment.9 Upon removal of terminal water, Cr site in MIL-101 possesses Lewis acidic character and forms a complex with IBU. The binding energy between IBU and MIL-101 is -73.17 kJ/mol, larger than -57 kJ/mol in MIL53(Cr)10 and close to those in natural zeolites.37 It is expected that the surrounding region of the metal oxide will get saturated as loading increases. Subsequently, adsorbed IBU will experience weaker interaction and reside a bit away from the metal oxide. Figure 3 shows the lowest-energy conformation in UMCM-1 from simulated annealing and DFT optimization. Compared with the distance between IBU and Cr atom in MIL-101, the location of IBU in UMCM-1 is far away from the metal oxide. The distance from carboxylic O atom to Zn atom is 7.027 Å, which increases to 7.267 Å after DFT optimization. The binding energy of IBU in UMCM-1 is -34.97 kJ/mol, only half of that in MIL101. As will be confirmed below, no chemical bond is formed between IBU and UMCM-1. Most likely, weak disperse and π-π interactions exist between the aromatic linker of IBU and UMCM-1. Figure 4 shows the highest-occupied molecular orbitals (HOMOs) to provide further information about the possible bond formation between IBU and host structure. The HOMOs are distinctly different in MIL-101 and UMCM-1. From the frontier

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Figure 3. (a) Lowest-energy conformation of IBU in UMCM-1 from simulated annealing. (b) Enlarged view for location of IBU near the metal oxide in UMCM-1. (c) Optimized conformation of IBU near the metal oxide in UMCM-1. The distances are represented in angstroms. Color codes: UCMC-1: Zn, green; C, gray; O, red; H, white; and Ibuprofen: C, cyan; O, pink; H, purple.

Figure 4. Highest-occupied molecular orbitals in IBU/MIL-101 and IBU/UMCM-1 complexes. A coordination bond is formed between the carboxylic group in IBU and the Cr3O metal oxide in MIL-101.

HOMOs, a coordination bond is observed to form between the carboxylic group in IBU and the Cr3O metal oxide in MIL101. The band gap, which quantifies the excitability to form a chemical bond, is only 0.064 eV in IBU/MIL-101. However, the band gap in IBU/UMCM-1 is prohibitively large as of 3.146 eV. This suggests it is difficult for IBU and UMCM-1 to form a bond as there are no frontier HOMOs between IBU and UMCM-1. Guest molecule confined in a nanoporous material behaves differently from that in bulk phase. Figure 5 shows the conformations of geometrically optimized IBU in vacuum, MIL101 and UMCM-1, respectively. The spatial arrangement of IBU in UMCM-1 is very similar to that in vacuum, demonstrating that IBU structure is not discernibly perturbed in UMCM-1. Similar behavior was observed for IBU in MIL-53.10 However, a rearrangement of the carboxyl group of IBU is observed in MIL-101 as a consequence of the bond formation between IBU and MIL-101 and the small pore volume available in MIL-101. The mobility of IBU in host structure was quantified by the mean-squared displacement (MSD) of a single IBU molecule in MIL-101 and UMCM-1. As shown in Figure 6, MSD in MIL101 is substantially smaller than in UMCM-1. This is attributed to the coordination bond formation between the electronegative carboxylic O of IBU and the Cr site of MIL-101, in addition to the small pore volume. These two factors strongly restrain the motion of IBU in MIL-101. A delayed release of IBU in MIL101 was indeed observed by experiment.9 However, a direct comparison is not possible because the drug release was experimentally conducted in a physiological body fluid. From Figure 6, it is expected that the release of IBU would be relatively faster in UMCM-1. With such information on the molecular behavior of drug molecule, one can understand drug release taking place in mesoporous materials from a microscopic level.

Figure 5. Optimized conformations of IBU in (a) vacuum (b) MIL101 (c) UMCM-1. Color code: C, cyan; O, pink; H, purple.

V. Conclusions We have studied the energetic and dynamic properties of IBU in mesoporous MIL-101 and UMCM-1 using molecular simulations and first-principles calculations. The loading of IBU in MIL-101 predicted matches well with experimental result and about four times greater than in MCM-41. The high loading suggests that only a very small amount of carrier is needed for drug dosage. Geometry optimization demonstrated that the lowest-energy conformation of IBU in MIL-101 is preferentially

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Figure 6. Mean-squared displacements of IBU in MIL-101 and UMCM-1. The inset is in the logarithmic scale.

located in proximal to the metal-oxide. This is similar to that observed for gas sorption in various MOFs, which has been verified both theoretically and experimentally. The binding energy between IBU and MIL-101 is two times as that in UMCM-1 due to the strong coordination between the carboxylic O atom of IBU and the exposed Cr atom of MIL-101. As a consequence, the spatial arrangement of IBU in MIL-101 is different from those in vacuum and UMCM-1; the mobility of IBU is smaller in MIL-101 than in UMCM-1. This work underscores that the molecular behavior of drug in porous materials plays a key role in drug loading and release. Thus, a clear molecular-level understanding is important for the development of novel drug delivery systems with better control of drug administration. Acknowledgment. The authors are grateful to the National University of Singapore for funding. Supporting Information Available: Table of LJ potential parameters for ibuprofen and MOFs adopted from UFF. This material is available free of charge via the Internet at http:// pubs.acs.org. References and Notes (1) Vallet-Regi, M.; Balas, F.; Arcos, D. Angew. Chem., Int. Ed. 2007, 46, 7548. (2) Wang, S. Microporous Mesoporous Mater. 2009, 117, 1. (3) Riehemann, K.; Schneider, W. S.; Luger, A. T.; Godin, B.; Ferrari, M.; Fuchs, H. Angew. Chem., Int. Ed. 2009, 48, 872. (4) Vallet-Regi, M.; Balas, F.; Colilla, M.; Manzano, M. Solid State Sci. 2007, 9, 768. (5) Munoz, B.; Ramila, A.; Perez-Pariente, J.; Diaz, I.; Vallet-Regi, M. Chem. Mater. 2003, 15, 500. (6) Doadrio, J. C.; Sousa, E. M. B.; Izquierdo-Barba, I.; Doadrio, A. L.; Perez-Pariente, J.; Vallet-Regi, M. J. Mater. Chem. 2006, 16, 462. (7) Horcajada, P.; Ramila, A.; Gerard, F.; Vallet-Regi, M. Solid State Sci. 2006, 8, 1243.

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