Indomethacin Embedded into MIL-101 Frameworks: A Solid-State

Article pubs.acs.org/JPCC

Indomethacin Embedded into MIL-101 Frameworks: A Solid-State NMR Study Tomaž Č endak,† Emanuela Ž unkovič,† Tina Ukmar Godec,† Matjaž Mazaj,† Nataša Zabukovec Logar,†,‡ and Gregor Mali*,†,§ †

National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia CO-NOT Centre of Excellence, Hajdrihova 19, 1000 Ljubljana, Slovenia § EN-FIST Centre of Excellence, Dunajska 156, 1000 Ljubljana, Slovenia ‡

S Supporting Information *

ABSTRACT: Interactions of drug molecules embedded within the pores of drug-delivery matrices significantly influence the drug-release rate and profile. In this Article, we used solid-state NMR experiments to inspect the interactions of indomethacin drug and tetrahydrofuran solvent molecules within mesoporous MIL-101 metal−organic framework materials. MIL-101 matrices were prepared using two types of linkers, terephthalic acid for MIL101(Cr) and MIL-101(Fe), and amino-terephthalic acid for MIL-101(Al)-NH2 and MIL-101(Fe)-NH2. Loading MIL-101 matrices with indomethacin proved to be very efficient; the obtained delivery systems accommodated from 0.9 to 1.1 g of indomethacin per 1 g of MIL-101 material. NMR measurements showed that regardless of the type of the framework metal centers or the type of the organic linker indomethacin did not attach to the metal−organic framework. Interactions between indomethacin molecules themselves were also not detected. On the contrary, the smaller tetrahydrofuran solvent molecules did attach to the framework metallic trimeric units with hydrogen bonds. The bonds and the geometry of the porous system prevented the tetrahydrofuran molecules to be expelled from the MIL-101 matrix during drying. Information on interactions and proximities among neighboring nuclei was obtained by 1H homonuclear correlation and 1H−13C heteronuclear correlation NMR measurements. Distance-dependent influence of paramagnetic chromium and iron centers was also exploited.

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of mixtures of gases,10 catalysis,11,12 chemical sensing,13−15 and diverse medical applications.16−20 Biomedical applications21,22 include MOFs as contrast agents for magnetic resonance imaging23−25 or computed tomography26 and delivery matrices for bioactive gases27−30 or miscellaneous drugs.31−37 Not all types of MOFs are biocompatible, and some present a health risk due to possible leaching of toxic metal ions and other hazardous components. Such problems can be eluded with selection of suitable nontoxic MOFs (iron(III) carboxylate MOFs for example) or so-called bio-MOFs built from rigid biomolecules and biocompatible metal cations.38,39 In spite of the intense research in the field of drug-delivery systems, there are still numerous unanswered questions regarding the details of the interactions between the drug molecules and the carriers. Studies devoted to such interactions are not abundant, even though recent experimental and computational studies of ordered mesoporous silicates have shown that the interactions between the drug molecules and the mesoporous matrix crucially determine the release of drugs

INTRODUCTION Several therapeutic (drug) molecules suffer from low stability or poor solubility in biological conditions and/or inadequate ability to penetrate the target cells. Therapy with such drugs generally requires the administration of large doses and may thus lead to serious side effects, especially if the drug is distributed throughout the body in a nonspecific way. To circumvent the problems, over the last few decades a lot of effort has been dedicated to the development of various drug carriers. Encapsulation of drug molecules into such carriers should improve the solubility and penetration of the drug, and should enable better control over the drug-release rate and targeting within the body. In addition to polymers,1 liposomes,2 and mesoporous silicates,3,4 porous metal−organic framework (MOF) materials recently emerged as promising drug carriers.5,6 MOFs are crystalline materials built of metallic centers connected with organic molecules. The diversity of coordination geometries of metallic centers and variety of organic ligands give rise to numerous possibilities for tailoring pore dimensions and physicochemical properties of MOFs. Tunable pore size coupled with high surface area and accessible metal sites enables MOFs to be used for a variety of applications ranging from gas7,8 and heat storage9 to separation © 2014 American Chemical Society

Received: June 21, 2013 Revised: March 5, 2014 Published: March 5, 2014 6140

dx.doi.org/10.1021/jp412566p | J. Phys. Chem. C 2014, 118, 6140−6150

The Journal of Physical Chemistry C

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Figure 1. Structure of MIL-101 viewed along (101) direction (a), the same structure represented by supertetrahedra (b), and two types of cages in MIL-101 (c); straight lines connect centers of supertetrahedra.

from the mesopores.40 The lack of investigations is partly due to difficulties of the inspection of these interactions at the atomic level; the encapsulated drug molecules do not exhibit structural long-range order and thus cannot be studied by wellestablished diffraction-based techniques. Nevertheless, information about the drug molecules embedded within the pores of porous materials can often be obtained by nuclear magnetic resonance spectroscopy which is not limited to the systems that exhibit long-range order. For example, Babonneau et al. published several NMR-based studies of drug molecules and drug carrier interactions including studies of encapsulation of liposomes, benzoic acid, lauric acid, ibuprofen, glycine, etc. in various silica materials.41−46 Devautour-Vinot et al. recently presented a very informative multitechnique (dielectric relaxation, NMR and FTIR spectroscopies, DFT calculations) study of the encapsulation of caffeine molecules in −H, −NH2, −Br, and −2OH functionalized UiO-66(Zr) MOFs.32 They observed that functional groups, regardless of their polarity, do not act as adsorption centers and that caffeine molecules are primarily attracted by organic linkers. With dielectric relaxation spectroscopy they revealed significant changes in ligand dynamics upon caffeine adsorption and proposed that −NH2 functionalization leads to easier transition of caffeine molecules from tetrahedral to octahedral cages of UiO-66 while bulky −Br groups reduce the rate of such transition. In our group we have already conducted a detailed investigation of the model drug-delivery system based on the mesoporous silicate matrix SBA-15 and indomethacin.47 In the present Article we advanced the aforementioned study with the investigation of the encapsulation of indomethacin (IMC) into a porous MIL-101(X) with a goal to compare the drug-delivery system based on the mesoporous silicate with the drug-delivery system based on the porous MOF. MIL-101(Cr), originally Cr3F(H2O)2O[(O2C)-C6H4-(CO2)]3·nH2O (n ∼ 25), is built of inorganic trimers that consist of three chromium atoms in an octahedral environment arranged in the corners of the supertetrahedra. The six edges of the supertetrahedron are six 1,4-BDC anions (Figure 1a,b). The microporous supertetrahedra are connected one to another through common vertices and form a porous framework with two types of cages, one delimited by 20 and another by 28 supertetrahedra (Figure 1c). The cages have internal free diameters of ∼2.9 nm and ∼3.4 nm, and accessible pore volumes of ∼12.7 nm3 and ∼20.6 nm3.48 Aluminum49 and iron50 analogues of the original chromium MIL-101 can be prepared as well. MIL-101 has already been tested as a drug carrier; ibuprofen (IBU) was

successfully encapsulated into the chromium MIL-10134 while azidothymidine triphosphate (AZT-TP) and cidofovir (CDV) were incorporated into the iron analogue with the aminofunctionalized linkers.6 In the case of smaller IBU molecules, the loading efficiency was extremely high (∼1.4 g IBU per 1 g MIL-101(Cr)), whereas in cases of AZT-TP and CDV the loading efficiencies were moderate (∼0.4 g drug per 1 g of MIL-101(Fe)-NH2). The main analytical tool for the inspection of the encapsulation of IMC molecules into MIL-101 porous matrices was solid-state NMR spectroscopy. The MIL-101/IMC system is too complex to be analyzed by DFT calculations. Indeed, the unit cell of the porous matrix MIL-101 is much larger than, for example, the unit cell of UiO-66, indomethacin is a larger molecule than caffeine, and the number of molecules embedded within a single cavity of MIL-101 is much larger than the number of caffeine molecules within a single cavity of UiO-66. In this Article we address the questions, whether or not the drug−drug and drug-matrix interactions can be identified, and whether the selection of the metal center and the functionalization of the framework with amino groups influence the incorporation of the drug and the drug−matrix interactions. For this purpose MIL-101(Cr), MIL-101(Al)-NH2, MIL101(Fe), and MIL-101(Fe)-NH2 were prepared, and IMC was incorporated into them. Three out of the four above listed MIL-101 drug carriers contain paramagnetic metal centers. Strong hyperfine and through-space dipolar interactions between the unpaired electrons of the paramagnetic centers and the NMR-active nuclei, which accelerate nuclear spin relaxation, shift NMR signals, and make some of them “invisible”, render the NMR study of the IMC incorporation very demanding.

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EXPERIMENTAL SECTION Preparation of Materials. MIL-101(Al)-NH2 was crystallized from solution with molar ratio of reactants 1 AlCl3· 6H2O:1.46 2-amino-benzene-1,4-dicarboxylic acid (BDCNH2):183 N,N-dimethylformamide (DMF) after 72 h of treatment at 403 K in a round-bottom flask. The material was activated overnight in methanol at room temperature.49 MIL-101(Fe) and MIL-101(Fe)-NH2 were obtained by 24 h solvothermal reaction at 383 K of mixtures with molar ratios 1.8 FeCl3·6H2O:1 benzene-1,4-dicarboxylic (BDC):137 DMF and 2 FeCl 3 ·6 H 2 O:1 BDC-NH 2 :157 DMF, respectively. 50 Activation of MIL-101(Fe) was performed in DMF at 333 K, followed by drying at 333 K and treatment in acetone at 323 K. Activation of MIL-101(Fe)-NH2 was simpler; the material was cleaned in DMF at room temperature. MIL-101(Cr) was 6141



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decoupled using the PMLG-556 scheme with pulse length of 6.2 μs. Polarization was transferred to carbons using the Lee− Goldburg scheme57 with contact time of 100 μs. During acquisition, heteronuclear XiX decoupling was used. 1H−13C heteronuclear correlation spectrum of MIL-101(Al)-NH2/IMC was obtained at 16 kHz rotation frequency with relaxation delay of 3.5 s. Polarization transfer was accomplished with RAMP cross-polarization with contact time of 6 ms. The measurement was performed with 17 increments in indirect dimension with 4112 scans per increment and XiX decoupling during acquisition.

synthesized solvothermally at 493 K for 8 h from mixture with molar ratio of reagents 1 Cr(NO3)3·9H2O:1 BDC:256 H2O:0.3 HF48 and activated by the method proposed by Hong et al.51 Drug Loading Procedure. This procedure began with the preparation of solutions of IMC in tetrahydrofuran (THF); 100 mg of IMC was dissolved in 1 g of THF. Into this solution 100 mg of activated MIL-101 was added. Prior to emerging into the solution, MIL-101 matrices were dried in vacuum at 403 K. After 2 h of stirring the MIL-101/IMC/THF solution, the solid impregnated material was filtered out of the solution and dried first at room temperature for 24 h in a ventilation dryer and second at 323 K for 24 h in a vacuum dryer. Immediately after drying, the samples were placed in an exicator under inert Ar atmosphere to avoid exposure to moisture and were kept in such conditions until immediately before the measurements. The obtained samples were denoted with MIL-101(X)/IMC, with X = Al, Cr, or Fe. Elemental Analysis. The distribution and quantity of chlorine, aluminum, chromium, and iron within the MIL-101 matrices loaded with IMC were observed by energy dispersive X-ray analysis mapping (EDX) with an INCA Energy system (Oxford Instruments) attached to the Zeiss Supra 3VP fieldemission microscope. Mapping analyses were performed on the surfaces of the samples with an approximate area of 900 μm2 and exposure time of 1600 s. For each sample several surfaces were examined. Solid-State Nuclear Magnetic Resonance. 1H and 13C NMR spectra were recorded on 600 MHz Varian system equipped with 1.6 mm NB Triple Resonance HXY FastMAS probe and 3.2 mm Varian NB Double Resonance HX MAS probe. Larmor frequencies were 599.662 MHz for 1H nuclei and 150.799 MHz for 13C nuclei. Chemical shifts were reported relative to the signals of 1H and 13C nuclei in tetramethylsilane. 1 H echo MAS spectra were recorded at 20 kHz sample rotation frequency with 5 s of relaxation delay. 1H−13C CPMAS spectra were recorded at 16 kHz sample rotation frequency with 3 s of relaxation delay for aluminum MIL-101 and 1 s of relaxation delay for chromium and iron analogues. Polarization transfer was achieved with RAMP52 cross-polarization (ramp on the proton channel) with contact times of 5 and 1 ms for aluminum and chromium/iron MIL-101, respectively. High-power XiX53 heteronuclear proton decoupling was applied during acquisition. Two-dimenisonal 1H double-quantum homonuclear-correlation BABA54 spectrum of β-IMC was recorded at 25 kHz sample rotation frequency and 7 s of relaxation delay with a single BABA cycle for double-quantum excitation and recoupling. Spectral width in indirect dimension was 25 kHz. Spectrum was recorded in 150 steps in indirect dimension with 32 scans at each increment. BABA spectrum of MIL-101(Al)NH2/IMC was recorded at 20 kHz sample rotation frequency with relaxation delay of 4 s and indirect-dimension spectral width of 20 kHz. Single BABA cycle was used for doublequantum excitation and recoupling. There were 35 increments in indirect dimension with 64 scans at each increment. 1H 2D spin-diffusion measurement in MIL-101(Al)-NH2/IMC was carried out at 20 kHz sample rotation frequency with 40 increments in indirect dimension and 144 scans per increment. Four RFDR55 cycles were employed during the mixing period. Heteronuclear 1H−13C correlation spectrum of β-IMC was recorded at 10 kHz rotation frequency with relaxation delay of 5 s. Number of increments in indirect direction was 25 with 580 scans at each increment. During t1 evolution, protons were

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RESULTS AND DISCUSSION Out of four different MIL-101 matrices that we had prepared, MIL-101(Al)-NH2 was the only one without paramagnetic metal centers and was therefore the most convenient for the detailed spectroscopic analysis. Nitrogen sorption measurements showed that specific surface area and pore volume both reduced by an order of magnitude upon incorporation of IMC into the aluminum MIL-101 (Supporting Information, Figure S1). Elemental analysis proved that loading of MIL-101(Al)NH2 with IMC was very efficient; the material accumulated approximately 1.8 molecules of IMC per one building unit of MIL-101(Al)-NH2 (corresponding roughly to 0.95 ± 0.15 g of IMC per 1 g of MIL-101(Al)-NH2). With the assumption that the molecules are spatially uniformly distributed among cages, the above loading efficiency suggests that MIL-101(Al)-NH2/ IMC contains about 17 IMC molecules per smaller cage and about 28 IMC molecules per bigger cage, and that these molecules occupy roughly 7 and 12 nm3 in a smaller and a bigger cage, respectively. The occupied volumes were obtained by estimating the volume of a single IMC molecule to 0.42 nm3, based on the crystal structure of γ-IMC. The volume occupied by IMC molecules is smaller than the available pore volume in MIL-101(Cr) (12.7 nm3 and 20.6 nm3), but slightly larger than the volume expected for MIL-101(Al)-NH2. Namely, for the available pore volume for MIL-101(Al)-NH2, the literature reports about a factor of 2 smaller values than for MIL-101(Cr) (e.g., 500 cm3 STP/g for MIL-101(Al)-NH2 compared to 1100 cm3 STP/g for MIL-101(Cr)).49 On the contrary, our computations using the Connolly approach estimate that amino functionalization of the MIL-101 framework should decrease the available pore volume by less than 10%, hence suggesting that loading efficiencies could be as high or even higher as the one observed for our MIL-101(Al)-NH2/ IMC. Inside the cavities of MIL-101(Al)-NH2, adsorbed IMC molecules cannot form an ordered crystalline particle, and one can imagine that the molecules experience quite different environments, some being closer to the framework, other being deeper inside the cavities. It is also possible that the arrangement of the molecules varies from cavity to cavity. Obtaining the microscopic insight into such a complex drug delivery system therefore presents a significant challenge. We begin the spectroscopic investigation of the system by comparing the 1H−13C CPMAS spectra of MIL-101(Al)-NH2/ IMC to the spectra of bulk β-IMC, empty MIL-101(Al)-NH2, and IMC incorporated into the pores of the mesoporous silicate SBA-15 (Figure 2). Some peaks in the above-mentioned spectra are labeled; the peak labels correspond to the labels of particular carbon atoms that are presented in Scheme 1. β-IMC is a crystalline solvate of IMC and THF, and its 1 H−13C CPMAS NMR spectrum is presented in Figure 2 6142



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H−13C CPMAS NMR spectrum of SBA-15/IMC is interesting because it belongs to nanometer-sized IMC particles within the mesopores and because it is not obstructed by the contributions of the mesoporous matrix (the silicate framework of SBA-15 contains no carbon atoms). Compared to those of crystalline βIMC, signals in the CPMAS spectrum of SBA-15/IMC are substantially broadened, but the majority of them is not shifted. The signals of the solvent THF molecules are not detected. The 1H−13C CPMAS NMR spectrum of MIL-101(Al)-NH2/ IMC comprises contributions of the embedded IMC molecules and of the organic part of the framework. In some parts of the spectrum, especially in the region between 110 and 140 ppm, signals of the drug molecules and of the framework BDC-NH2 linkers overlap severely while in some other parts the signals of the IMC molecules and of the framework linkers are clearly separated. An example of such separated signals are the two signals resonating at 151 ppm (L1) and 156 ppm (I4). The L1 signal can be assigned to the linker carbon atoms that have amino groups attached to them, while the I4 signal belongs to the IMC aromatic carbon atoms that have −O−CH3 groups attached to them. In the direct-excitation 13C MAS NMR spectrum (Supporting Information, Figure S8) the areas under these two peaks were used to determine the number of IMC molecules per one BDC-NH2 linker. The obtained number, 0.55 ± 0.05, leads to the loading efficiency of 0.85 ± 0.10 g of IMC per 1g of MIL-101(Al)-NH2 which concur with the value obtained by the elemental analysis. It should be noted here that the analysis of CPMAS NMR spectra is not convenient for the quantitative determination of the amount of IMC within MIL101(Al)-NH2. Because of different cross-polarization dynamics for the IMC molecules and the BDC-NH2 linker, the ratio of areas under the two signals in the CPMAS spectrum varies substantially with the duration of the CP period and does not lead to a proper loading efficiency (Supporting Information, Figure S9). Detailed inspection of the 1H−13C CPMAS NMR spectrum of MIL-101(Al)-NH2/IMC (Figure 2b) leads to two interesting observations. First, unlike the spectrum of SBA-15/IMC the spectrum of MIL-101(Al)-NH2/IMC clearly confirms the presence of THF within the pores. According to the directexcitation 13C MAS NMR spectrum (Supporting Information, Figure S8), in the pores of MIL-101(Al)-NH2/IMC there are 1.4 ± 0.2 THF molecules per two molecules of IMC. This is slightly larger than the fraction of THF molecules in the bulk crystalline β-IMC (one THF molecule per two molecules of IMC). The reason for the difference between the two drugdelivery systems might be in the geometry of the mesopores. SBA-15 has long cylindrical channels with the diameter of 9 nm from which small THF molecules, upon careful drying procedure, can escape relatively easily. Differently from that, MIL-101(Al)-NH2 possesses spherical cavities interconnected by small windows with the diameter of 1.2 nm, through which migration of molecules is more difficult. The solvent issue will be discussed in more detail later in this section. The second interesting observation related to the 1H−13C CPMAS NMR spectrum of MIL-101(Al)-NH2/IMC is that, upon loading of the drug carrier with IMC, the carboxylic carbon peak at 173 ppm (L2, L3) narrows substantially. This suggests that the metal−organic framework undergoes structural ordering when it is filled with IMC molecules, and perhaps explains why experimentally determined pore volume before the drug loading procedure is smaller than the volume that is eventually occupied by the drug molecules. The

Figure 2. (a) 1H−13C CPMAS NMR spectra of bulk crystalline βIMC, SBA-15/IMC, loaded and empty MIL-101(Al)-NH2. Peak labels correspond to selected carbon atoms within IMC molecule (I1−I6), THF molecule (T1, T2), and BDC-NH2 linker (L1−L3). Vertical dotted lines enable easier comparison of signal positions. (b) Comparison of the 1H−13C CPMAS NMR spectrum of MIL101(Al)-NH2/IMC with the sum of the spectra of SBA-15/IMC and MIL-101(Al)-NH2. Arrows indicate details where the differences are the most pronounced.

because the solvate crystallizes from identical solution as the one used for the impregnation of MIL-101(Al)-NH2. The spectrum exhibits very narrow lines and, supported by previous studies of γ-IMC,58 allows for partial peak assignment. Contributions in the spectrum corresponding to the −CH3 carbon nuclei (labeled as I1), −CH2 carbon nuclei (I2), −O− CH3 carbon nuclei (I3), amide carbon nuclei (I4), and also some other contributions are clearly split into two equally strong signals, showing that β-IMC contains two inequivalent IMC molecules in its asymmetric crystallographic unit. The spectrum also exhibits two signals that arise from THF molecules and resonate at 25 (T1) and 68 (T2) ppm. The analysis of the 13C MAS NMR spectrum of β-IMC (Supporting Information, Figure S7) shows that this solvate comprises exactly one molecule of THF per two molecules of IMC. The 6143



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Scheme 1. Schematic Representation of IMC Molecule (a), THF Molecule (b), and BDC-NH2 Linker (c)a

a

With labels of selected carbon atoms (I for indomethacin, T for THF, and L for linker) and approximate dimensions of the molecules.

Figure 4. 1H BABA 2D NMR spectrum of β-IMC.

Figure 3. (a) 1H MAS NMR spectra of bulk crystalline β-IMC, SBA15/IMC, loaded and empty MIL-101(Al)-NH2. (b) Comparison of the 1H MAS NMR spectrum of MIL-101(Al)-NH2/IMC with the sum of the spectra of SBA-15/IMC and MIL-101(Al)-NH2. Arrows indicate details where the differences are the most pronounced.

Figure 5. 1H−13C PMLG-LG-HETCOR 2D NMR spectrum of βIMC.

procedure, when immersed into the solution of IMC in THF, however, the framework could slightly rearrange, order, and open up pores, and thus enable extensive loading with IMC. 1 H MAS NMR spectra (Figure 3) provide less information, because the resolution of these spectra is rather low and various signals are not well separated. Still, the spectra confirm the

activated, empty MIL-101(Al)-NH2 might exhibit defects and/ or distortions that in some parts of the material obstruct the passage of nitrogen molecules and thus effectively lower the extent of nitrogen adsorption. During the drug loading 6144



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Figure 6. 1H BABA 2D NMR spectrum of MIL-101(Al)-NH2/IMC.

Figure 8. 1H−13C HETCOR 2D NMR spectrum of MIL-101(Al)NH2/IMC.

implausible to assume that all IMC molecules adsorbed inside MIL-101(Al)-NH2 are deprotonated as it would be hard to compensate for all the excess electric charge. Perhaps the hydrogen-bonding proton peak becomes hardly observable simply because hydrogen bonds among IMC molecules within the pores become very rare. More probably, though, the peak lowers considerably due to broadening caused either by a variety of the proton’s chemical surroundings or small differences in the lengths and angles of hydrogen bonds. Such, even small, variations could severely impact the proton spectrum while leaving carbon spectrum more or less intact. When comparing 1H MAS NMR spectra of the bulk crystalline β-IMC and of the MIL-101(Al)-NH2/IMC, another interesting difference can be observed at the low-frequency part of the spectra. The signal belonging to the −CH3 protons of IMC (I1), which in β-IMC resonates at 0.3 ppm, shifts to −0.5 ppm in the spectrum of MIL-101(Al)-NH2/IMC, thus indicating that the conformation of the IMC molecules, at least the orientation of the more exposed −CH3 groups, changes when the molecules get embedded into the mesopores. In order to obtain more information about the location and about interactions of IMC and THF molecules within the cavities of MIL-101(Al)-NH2, two-dimensional homonuclear and heteronuclear correlation NMR experiments were carried out. In Figures 4 and 5 we first present 1H double-quantum homonuclear-correlation (BABA) and 1H−13C heteronuclear correlation (HETCOR) spectra recorded in β-IMC. The spectra provide some information about the hydrogen-bonding scheme of molecules within the crystalline β-IMC and confirm the assignment of the selected signals in the carbon and proton NMR spectra to individual carbon and hydrogen atoms. The 1 H BABA 2D NMR spectrum shows that the hydrogenbonding protons “see” equivalent protons in close proximity (the 12.4 ppm peak on the diagonal) and the protons resonating at 1.9 ppm, but they do not see protons resonating at 1.2 and 3.1 ppm. The HETCOR 2D NMR spectrum confirms that the protons resonating at 1.9 ppm are the protons of the −O−CH3 group (I3) and that the protons resonating at 1.2 and 3.1 ppm are the protons on the T1 and T2 carbon atoms of the THF molecules. The HETCOR spectrum also

Figure 7. 1H spin-diffusion 2D NMR spectrum of MIL-101(Al)-NH2/ IMC.

presence of THF molecules in the MIL-101(Al)-NH2/IMC. The 1H MAS NMR spectrum of β-IMC exhibits a well resolved signal at 12.4 ppm that can be assigned to protons involved in hydrogen bonds. As it will be shown later, the protons in the hydrogen bonds within β-IMC come from the carboxylic groups. In the spectrum of MIL-101(Al)-NH2/IMC the signal belonging to the hydrogen-bonding protons can hardly be detected anymore. In the study of incorporation of ibuprofen (IBU) into MIL-101(Cr) Horcajada et al. observed the disappearance of hydrogen-bonding protons peak and attributed it to the deprotonation of the carboxylic group which occurred upon the insertion of IBU molecules into the chromium matrix.34 As ibuprofen was embedded in the chromium matrix in the form of an anion, the researchers assumed that IBU molecules could interact with either framework benzene ring protons or metal centers or terminal water molecules of the chromium trimeric units and concluded that the broadening of IBU signals is consistent with the distribution of all described interactions. It would be somewhat 6145



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Figure 9. 1H−13C CPMAS (a) and 1H MAS (b) spectra of MIL-101(X) matrices loaded with IMC.

THF molecule, is offered by the 1H−13C HETCOR spectrum presented in Figure 8. The spectrum shows that the only carbon atom that gives rise to a (weak) cross peak with the hydrogen-bonding proton is the carboxylic atom of the framework linker (L2/L3). The same carbon atom also yields a cross peak with the protons on the T2 atoms of THF. Since only the L2 and/or L3 carbon atoms are close to hydrogen bonds and since neither L1 nor I6 see this bond, we can conclude that THF molecules are most probably bonded to the framework trimeric units and not to the framework amino groups or to the carboxylic groups of the IMC molecules. The IMC molecules do not seem to interact with the framework. In addition to the MIL-101(Al)-NH2/IMC drug-delivery system we also prepared similar systems based on MIL101(Cr), MIL-101(Fe), and MIL-101(Fe)-NH2 matrices. Unfortunately, we were not able to synthesize the aluminum analogue without the amino groups and the chromium analogue with the amino groups. MIL-101(Cr) exhibited somewhat larger surface area and pore volume than MIL101(Al)-NH2 and thus upon loading with IMC stored more IMC, 2.0 ± 0.3 molecules of IMC per building unit of MIL101(Cr). Similar quantities of IMC were detected also in MIL101(Fe), 1.6 ± 0.3 molecules of IMC, and MIL-101(Fe)-NH2, 2.2 ± 0.3 molecules of IMC per building unit of the matrix. Comparison of 1H−13C CPMAS and 1H MAS NMR spectra of MIL-101(Al)-NH2/IMC with the spectra of other matrices loaded with IMC is presented in Figure 9. NMR spectroscopy of iron- and chromium-based materials is very difficult since these materials include paramagnetic metal centers. Strong coupling of unpaired electrons at paramagnetic metal centers with magnetic moments of the studied nuclei causes the shortening of relaxation times and, possibly, the hyperfine and pseudocontact shifts. Due to short relaxation times, the transfer of polarization from protons to carbon nuclei is less effective in paramagnetic frameworks and CPMAS technique produces spectra of lower quality compared to nonparamagnetic aluminum MIL-101 (Figure 9a). The closer the observed

shows that the carboxylic I6 carbon atoms are coupled to the hydrogen-bonding protons and to protons of the −CH2 group of IMC (I2). All this implies that the two IMC molecules within the asymmetric unit of β-IMC form a bidentate hydrogen bond between the carboxylic groups of the two molecules (in a similar way as IMC molecules within γ-IMC), and that THF molecules do not interact appreciably with the IMC molecules (i.e., although being a hydrogen bond acceptor the THF molecule within β-IMC is not involved in the hydrogen bond). 1 H double-quantum homonuclear correlation NMR spectrum of MIL-101(Al)-NH2/IMC (Figure 6) exhibits no signal of the hydrogen-bonding protons. The strongest interactions are detected among the protons of the THF molecules (the diagonal and off diagonal peaks at 1.2 and 3.1 ppm in the single-quantum dimension). The protons of the IMC −CH3 groups (I1) interact with the I3 protons, which further couple to the aromatic protons. It seems that THF protons again do not interact strongly with the IMC molecules. The double-quantum homonuclear-correlation BABA spectroscopy detects only relatively strong dipolar interactions. To detect also somewhat weaker interactions a more robust 1H spin-diffusion NMR measurement was carried out. The most intense cross peaks in the recorded 2D spectrum (Figure 7) coincide with the ones already described in case of the 1H BABA spectrum. However, in the spin-diffusion spectrum additionally a weak cross peak between a hydrogen-bonding proton and a proton resonating at about 3 ppm is detected. This indicates that hydrogen atoms on the T2 carbon atoms of the THF molecules are coupled to hydrogen-bonding protons in the neighborhood, which implies that THF molecules could be involved in hydrogen bonds. Since THF molecules act as hydrogen-bond acceptors they need a hydrogen-bond donor to form a hydrogen bond. In MIL-101(Al)-NH2/IMC, hydrogenbond donors can be carboxylic groups of IMC molecules, hydroxy groups and water molecules of the framework trimeric units, and amino groups of the framework linkers. A clue, which of the possible donors is involved in the hydrogen bond with a 6146



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Figure 10. 1H MAS spectra of empty MIL-101(Cr) (black) and loaded MIL-101(Cr)/IMC (red). Enlarged segments show the centerband next to second and forth spinning sidebands. Labels THF and IMC point to the non-negligible contributions of THF and IMC in the spectrum of MIL101(Cr)/IMC.

spectrum of the former material is, disregarding a poorer signal-to-noise ratio, almost identical to the spectrum of SBA15/IMC. In the spectrum we can detect neither framework contributions nor contributions from THF molecules. The signals of I5 and I6 IMC carbon atoms that do not have hydrogen atoms directly attached to them are also substantially reduced because of the impeded CP. As all MIL-101 matrices were loaded the same way, by impregnating the porous material with the solution of IMC in THF, we can expect that THF molecules are present in the pores of MIL-101(Fe) in a similar way as in the pores of MIL-101(Al)-NH2 and MIL-101(Cr). Since we can no longer detect contributions of THF in the 1 H−13C CPMAS NMR spectrum, we can conclude that THF molecules are again very close to Fe centers; i.e., they are again attached to the framework trimeric units. The situation is very similar in the case of MIL-101(Fe)-NH2/IMC. The effect of paramagnetic metal centers is visible also in the proton spectra of paramagnetic drug-delivery systems, and it manifests itself in the appearance of many spinning sidebands (Figure 9b). Proton spectra are obtained by direct excitation techniques (single pulse or echo sequence) so the short relaxation times do not cause severe signal loss as in the case of CPMAS technique. Protons are also less influenced by strong contact hyperfine interactions so it is rather safe to assume that

nuclei are to the paramagnetic centers the harder it is to detect them; consequently, we assume that the peaks visible in the 1 H−13C CPMAS NMR spectra of paramagnetic MIL-101 frameworks comprise predominantly contributions of carbon nuclei that are the farthest away and therefore the least susceptible to the effect of paramagnetic metal centers. Among the 1H−13C CPMAS NMR spectra of paramagnetic MIL-101 frameworks loaded with IMC, the spectrum of MIL101(Cr)/IMC is the most similar to the spectrum of MIL101(Al)-NH2/IMC. Nevertheless, one can clearly see that the signals of carbon atoms that are proximal to chromium centers are all lowered. The most prominent changes in the signal intensities are observed for contributions of L2, L3, and L1 atoms. Influence of chromium centers on signals of other aromatic carbon atoms of the framework linker could not be evaluated, because the signals overlap with the signals of aromatic carbon atoms of IMC. It is interesting to note that the signals of the THF carbon atoms nearly vanish. It seems that, as proposed above, THF molecules are indeed very close to chromium in the trimeric units, so that the transfer of polarization from protons to carbon nuclei in THF is strongly hindered. The influence of paramagnetic metal centers is even stronger in MIL-101(Fe)/IMC and MIL-101(Fe)-NH2/IMC. The 6147



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spectra. This material is available free of charge via the Internet at http://pubs.acs.org.

we can detect the contributions of all framework protons and protons of the embedded molecules. Taking a closer look at the 1 H MAS NMR spectra of MIL-101(Cr) and MIL-101(Cr)/ IMC (Figure 10), we can notice substantial differences between the centerband regions of the pure aluminum and chromium MIL-101 proton NMR spectra. Namely, the spectrum of pure MIL-101(Cr) shows noticeable contributions in the 10−15 ppm range which are not visible in the spectrum of the aluminum analogue. As there are no hydrogen-bonding protons in pure MIL-101(Cr) we assign these contributions to framework protons that experience the strongest Fermi or pseudocontact shifts. The simplest hypothesis would be that these shifted peaks belong to the protons that are most influenced by, i.e., closest to, the chromium metal centers (water and bridging OH group protons of the chromium trimers). Further, a look at the spinning sidebands tells us that the higher the rank of the sideband, the more the sideband of the loaded MIL-101(Cr)/IMC matches the sideband of the empty MIL-101(Cr). This directly implies that the contributions of the framework protons exhibit the broadest spinningsideband powder pattern, which is understandable as these protons are the most strongly influenced by the paramagnetic chromium centers. The only nonframework contribution to the high-rank sidebands has isotropic shift between 1 and 4 ppm and can most probably be attributed to THF protons (in the fourth spinning sideband in Figure 10 the contribution of THF protons is visible between 134 and 138 ppm). These protons exhibit a broad pattern of spinning sidebands because the THF molecules are attached to the chromium trimeric units. The contributions of protons of IMC are limited to the centerband, and few low-rank sidebands, proving again that IMC molecules are not very close to the framework metal centers and are not attached to the framework.

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Corresponding Author

*E-mail: [email protected]. Phone: +38614760412. Fax: +38614760300. Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Slovenian Research Agency research projects P1-0021 and J1-5447.

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REFERENCES

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CONCLUSIONS Aluminum, chromium, and iron MIL-101 frameworks loaded with indomethacin molecules are very complex systems that can accommodate up to 25 drug molecules into each of their smaller pores and up to 45 drug molecules into each of their larger pores. In spite of the complexity of such systems, modern solid-state NMR methods, exploiting the extremely high sensitivity of atomic nuclei to their local environment, are able to provide an insight into the arrangement of molecules within the pores. The results of our NMR measurements show that, regardless of the nature of the metal center and the presence or absence of the amino groups on the organic linker, indomethacin molecules within MIL-101 matrices do not attach to the framework, neither to metallic trimeric units nor to BDC/BDC-NH2 linkers. On the contrary, the solvent tetrahydrofuran molecules do attach to the metallic trimers by hydrogen bonds. These hydrogen bonds and the specific geometry of the porous system, composed of spherical cavities interconnected by narrow passages, obstruct the removal of the solvent from MIL-101 matrices. This is why mesoporous matrices with wide channels, like SBA-15, are probably more appropriate for drug delivery.

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AUTHOR INFORMATION

ASSOCIATED CONTENT

S Supporting Information *

Nitrogen sorption isotherms, XRD powder patterns, results of elemental analysis, and direct-excitation 13C MAS NMR 6148



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Indomethacin Embedded into MIL-101 Frameworks: A Solid-State

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