Role of Hydrolysis Degree in the Drug−Matrix Interactions of

20022

J. Phys. Chem. C 2010, 114, 20022–20027

Role of Hydrolysis Degree in the Drug-Matrix Interactions of Nanosized Sol-Gel Titania Reservoirs for Epilepsy Treatment T. Lo´pez,*,†,‡,§ K. Espinoza,† A. Kozina,† A. Galano,| and R. Alexander-Katz⊥ Laboratorio de Nanotecnologı´a para Medicina, Instituto Nacional de Neurologı´a y Neurocirugı´a “MVS”, 14269 Me´xico D.F., Me´xico, Departamento de Atencio´n a la Salud, UniVersidad Auto´noma Metropolitana Xochimilco, 04960 Me´xico D.F., Me´xico, Department of Chemical and Bimolecular Engineering, Tulane UniVersity, 70118 New Orleans, United States, Departamento de Quı´mica, UniVersidad Auto´noma Metropolitana Iztapalapa, 09340 Me´xico D.F., Me´xico, and Departamento de Fı´sica, UniVersidad Auto´noma Metropolitana Iztapalapa, 09340 Me´xico D.F., Me´xico ReceiVed: June 10, 2010; ReVised Manuscript ReceiVed: August 5, 2010

Nanostructured titania reservoirs were synthesized by the sol-gel method. An antiepileptic drug phenytoin was encapsulated for the targeted drug delivery. NMR studies confirmed that the drug does not undergo substantial modifications during the sol-gel process. The water/alkoxide ratio rw was varied from 2 to 24 to evaluate the role of hydrolysis degree on the drug-matrix interactions. The interactions were found to be of hydrogen-type between amine and carbonyl groups of phenytoin and hydroxyl groups of titania. Tridental complex was found to be the most favorable out of three complexes proposed. To form this complex for each phenytoin molecule, two hydroxyl groups of titania are needed. It was found that when the water/alkoxide ratio rw ) 16 the hydroxylation degree is the highest, which allows us to bind the largest amount of the drug. I. Introduction Phenytoin sodium (5,5-diphenylhydantoin sodium salt) is an antiepileptic drug commonly used to suppress the abnormal brain activity during a seizure. However, the efficiency of phenytoin is significantly reduced by the presence of the hematoencephalic barrier, which represents an obstacle for a large number of drugs. Recently it was shown that mesoporous nanostructured titania reservoirs synthesized by the sol-gel method and implanted into the temporal lobe of the brain are quite promising for the epilepsy treatment.1 The main advantage of these drug delivery systems is a targeted and prolonged release of anticonvulsants at a constant rate.2,3 They also prove to be biocompatible and avoid side effects connected to the dosage fluctuation.4-6 The reservoirs have such properties that the drug is gradually released from them during sufficiently long time, sustaining a certain constant level of concentration. The drug release profile is significantly affected by the drug-matrix interactions. Together with material morphology (surface area, porosity, pore size distribution, particle size, and aggregation), which will be discussed elsewhere, interactions can be controlled to obtain more reproducible and predictable release kinetics.7-13 In the particular case of the drug incorporated into the sol-gel titania, there are two principal question that one should study: (i) does the synthesis process affect the structure-activity relation and the stability of the drug and (ii) what functional groups of the matrix and the drug participate in the interaction? There are different types of interactions that can be found in the modern drug delivery systems: electrostatic (Coulombic),14,15 hydrophobic,16,17 or hydrogen-type. * Corresponding author. E-mail: [email protected]. Tel.: +525556063822, ext 5034. † Instituto Nacional de Neurologı´a y Neurocirugı´a “MVS”. ‡ Universidad Auto´noma Metropolitana Xochimilco. § Tulane University. | Departamento de Quı´mica, Universidad Auto´noma Metropolitana Iztapalapa. ⊥ Departamento de Fı´sica, Universidad Auto´noma Metropolitana Iztapalapa.

Sol-gel titania, if it is not calcinated, has a surface covered with hydroxyl groups with the average density of 5 OH/nm2.18 These terminal hydroxyls can interact with a heteroatom of the drug molecule serving as adsorption sites favoring the drug distribution inside the matrix. Naturally, the number of OH groups capable of binding the drug would define the amount of the drug that can be carried by the matrix, whereas the strength of the interaction would define the drug diffusion out of the reservoir. The two parameters together will influence the release profile. Thus, the surface coverage by OH groups determines the adsorption behavior and the surface reactivity.19 The degree of hydrolysis, and as a result the surface OH coverage, can be controlled by adjusting the parameters of the sol-gel synthesis. One of the main parameters to control is the water/alkoxide ratio rw.19,20 For example, it is generally expected that the concentration of OH groups in the network structure increases with increasing rw.21 However, there is always a certain amount of OR groups regardless of the amount of water present. Only at the dilution as high as rw ) 1000 do no organic impurities seem to be present.18 However, until now no systematic studies were done to clarify this question and moreover for the systems carrying a drug. In the present work we encapsulated phenytoin in the titania matrix using the sol-gel approach. To clarify the role of hydroxyl groups in the drug bonding, we varied the water/ alkoxide ratio rw from 2 to 24 with all the other parameters fixed. We used 13C solid state NMR analysis to confirm the presence of phenytoin without structural changes. On the basis of the NMR peak shifts we suggest the most probable phenytoin-titania complexes. The complexes were optimized using theoretical calculations and were confirmed by the experimental data from IR spectroscopy. We systematically studied how the hydrolysis degree affects the relative amount of OH groups in titania. The results obtained with IR spectroscopy were confirmed by the TGA/DSC analysis.

10.1021/jp105356q  2010 American Chemical Society Published on Web 11/09/2010

Sol-Gel Titania Reservoirs for Epilepsy Treatment II. Materials and Methods A. Synthesis of Phenytoin-Titania Reservoirs. The solgel method was used to synthesize titania reservoirs. Titanium(IV) tetrabutoxide (Ti(OC4H9)4, 98%, Sigma Aldrich) was contineously added (0.1 ml/min) to the mixture of deionized Millipore filtered water, filtered ethanol (96%, Metrochem), and sodium phenytoin (99%, Sigma Aldrich) at 25 °C under constant stirring. The molar ethanol/alkoxide ratio was kept constant and equal to 8. The ratio sodium phenytoin/alkoxide was fixed to 7.5 mg per 1 g of alkoxide (1.175 mol %). The molar ratio water/alkoxide rw was varied from 2 to 24. The resulting homogeneous sol was then left to gelate for 24 h under the constant stirring and after that was dried naturally at room temperature. Obtained white powder was then dried at 40 °C in a vacuum for 24 h. B. Characterization of Phenytoin-Titania Reservoirs. Infrared (IR) spectra were recorded on a Shimadzu IRAffinity-1 Fourier transform infrared spectrophotometer 10 times for each sample and then averaged. The error bars were calculated by taking into account the largest deviation from the average. NMR studies were performed with the Bruker Instrument model Advance II-300 using a 4 mm CP-MAS probe (31P-15N) at 5 kHz. Thermogravimetric analysis was performed with Pyris 1 TGA, Perkin-Elmer Instruments thermogravimetric analyzer under a nitrogen atmosphere in the range of temperatures 30-800 °C at the heat rate of 20 °C/min. Differential scanning calorimetry analysis was done with a DSC 2920, TA Instruments calorimeter in the temperature range 0-400 °C at the heat rate of 10 °C/min. C. Theoretical Modeling. Theoretical calculations have been carried out with the Gaussian 0322 package of programs within the density functional theory (DFT) formalism. Geometry optimizations were performed without any symmetry constraint using Becke’s three-parameter hybrid functional23 with the LYP correlation functional,24,25 which includes both local and nonlocal terms (B3LYP) and LanL2DZ basis set. When LanL2DZ Dunning/Huzinaga valence double-ζ D95 V26 is applied, the basis set is used for elements in the first row of the periodic table, and the Los Alamos effective core potential27-29 (ECP) is used for for Na-Bi. Frequency calculations were carried out for all the studied systems at the same level of theory, and the minimum character of the modeled structure was identified by the number of imaginary frequencies (NIMAG ) 0). Thermodynamic corrections at 298.15 K were included in the calculation of the relative energies. The energy release associated with the formation of the phenytoin-titania complexes in terms of Gibbs free energies were calculated by taking into account the solvent cage effects. For that, the reference state was changed from 1 atm to 1 M and the solvent cage effects were included according to the corrections proposed by Okuno30 by taking into account the free volume theory.31 These corrections are in good agreement with those independently obtained by Ardura et al.32 and have been successfully used by other authors.33-39 In addition, the infrared (IR) spectra of phenytoin-titania complexes were computed. All the IR spectra were obtained without using any scaling factor. III. Results and Discussion A. Phenytoin-Titania Interactions. To establish the structure and the conformation of the drug inside the titania matrix as well as the possible effects of the synthesis on phenytoin, NMR, IR spectroscopy and computations were used. To detect phenytoin structural changes, the analysis was obtained for pure

J. Phys. Chem. C, Vol. 114, No. 47, 2010 20023

Figure 1. Solid state 13C NMR spectrum of pure phenytoin. The peak letters indicate corresponding phenytoin atoms in the phenytoin structure given on the right.

Figure 2. Solid state 13C NMR spectrum of the phenytoin-titania complex. The peak letters indicate corresponding phenytoin atoms given in Figure 1.

phenytoin and the drug inside the matrix. The solid state 13C NMR study has two principal functions: to determine if phenytoin is attached to the matrix with or without any changes in the structure and to establish what part of the molecule couples to the titania functional groups (hydroxyl groups). To answer these questions, the 13C NMR spectra of pure phenytoin and the complex were analyzed by focusing on the shifts of the principal signals. Figure 1 shows the solid state 13C NMR spectrum of pure phenytoin. There are six signals exhibited in the phenytoin spectrum. The band at 71.50 ppm (a-peak) is assigned to the sp3 quaternary carbon of the hydantoin ring. The signal is shifted to the low field because of the deshielding effect of the two aromatic rings attached to this carbon. There are three signals found in the region between 125.48 and 141.19 ppm corresponding to different carbons of the aromatic system (b, c, d, and e peaks). Finally, there are two signals of the carbonyl groups at 174.59 and 192.38 ppm, which correspond to the carbons of the amide and urea groups, respectively (f and g peaks). The 13 C NMR spectrum of the phenytoin-titania complex is shown in Figure 2. The spectrum in Figure 2 exhibits the peak of the quaternary carbon of the hydantoin at 76.95 ppm, which confirms the presence of the hydantoin ring inside the matrix (Figure 1). In the region of aromatic carbon there is one broad band corresponding to the integration of the 12 aromatic carbons of the drug. It was not possible to observe the peaks of the carbonyl groups for the following reasons: low concentration of the drug inside the matrix or/and the increase of the relaxation times because of the chemical environment of these carbons. Also, one can see other peaks in the aliphatic region of the spectrum

20024

J. Phys. Chem. C, Vol. 114, No. 47, 2010

Lo´pez et al.

Figure 3. Optimized geometries of phenytoin-titania complexes: C-I and C-II are monodentate complexes, and C-III is the tridentate complex. The corresponding corrected Gibbs free energies of formation of each complex are given below.

at 63.13, 34.65, 18.83, and 12.50 ppm. These peaks correspond to the nonhydrolyzed butyl radicals attached to the titania matrix. The comparison of both spectra indicates that the same signals are present. This means that phenytoin is attached to titania without any structural change. The slight shift of the signals in Figure 2 as compared with pure phenytoin implies that the structure of the phenytoin molecule in the matrix is more rigid than “free” phenytoin. The largest shift difference was found to take place for the two carbons of the hydantoin ring (a and e peaks in Figure 2). Thus, the hydantoin ring in the phenytoin molecule is the system that interacts with OH groups of the titania matrix. These conclusions allow us to propose more accurate possible complexes between the hydantoin ring and titania hydroxyl groups. Three different complexes (C-I, C-II, C-III) were obtained with optimized geometries. On the basis of the charge density of phenytoin, first, the geometries of two different complexes (C-I, C-II) were optimized. The optimized geometries of these complexes are shown in Figure 3. The distance of the hydroxyl bond O-H in the complex was found to be 1.648 Å, which was 0.13 Å longer as compared with the pure titania reference. This bond elongation is due to a weak hydrogen interaction between titania and the phenytoin molecule. The computed differences in the Gibbs free energy (shown in Figure 3) connected with the formation of the complexes together with the bond elongation indicate that C-II is more favorable than C-I. The last complex proposed (tridentate C-III, in Figure 3) has three simultaneous weak hydrogen-type interactions: two hydroxyl groups of titania interact with two oxygen atoms (of carbonyl groups) of phenytoin and there is an oxygen bridge from titania to a proton of the amine group of phenytoin. The calculated Gibbs energies show that C-III is more favorable in comparison to C-I and C-II. Since hydroxyl groups of titania participate in the complex formation, phenytoin adsorption on titania seems to depend much on the hydroxylation degree of titania. The computed Infrared (IR) spectra of complexes C-II and C-III (low energy conformer) are shown in Figure 4a. Due to the nature of the interactions shown in Figure 3, we will focus our attention on the difference in the signals of C-II and C-III complexes corresponding to the vibrations that should be strongly influenced by the complexes formation: the N-H and the CdO stretching vibrations. There are two regions of the most interest in the spectra: 3200-3600 and 1700-1780

Figure 4. Infrared spectra of pure phenytoin, pure titania, and the phenytoin-titania complexes: (a) computed (for C-II and C-III); (b) experimental with rw ) 8 as given in the legend.

cm-1. Region 3200-3600 cm-1 shows an intense signal at 3400 cm-1 of C-II and two signals at 3250 and 3400 cm-1 of C-III corresponding to the stretching vibrations of the N-H bond of the phenytoin molecule in the complex. The double signal of C-III is due to the fact that one proton of the urea N-H is bound to the oxygen atom of titania. In the other region (1700-1780 cm-1) the spectrum of C-II shows two signals around 1740 and 1760 cm-1, which do not appear in the spectrum of C-III. This is due to the phenytoin-titania interactions that occur when the phenytoin amine group binds to the hydroxyl group of titania keeping free vibrational movement of the carbonyls. In complex C-III, not only the amine group but also the carbonyl groups interact with the hydroxyl proton of titania. This interaction decreases the freedom of the CdO bond, resulting in the reduction of the signals in that region. Thus, the spectral differences of the two complexes are useful to define the type of complex in our experimental systems. To determine what is the most probable structure of the complex, we compared the N-H and CdO regions of the theoretical spectra with the experiment shown in Figure 4b. In Figure 4b four IR spectra are shown: pure phenytoin, pure titania, a phenytoin-titania complex synthesized by sol-gel and a physical mixture of pure titania and phenytoin. The physical mixture was prepared in such a way that the relative amount of the drug in it was equivalent to the estimated amount of phenytoin in the sol-gel titania. This was done to compare bound phenytoin and “free” phenytoin at the same relative concentration to exclude the possibility of the change of the band intensities because of the concentration difference. This allowed us to attribute the signal change to the formation of the complexes. The spectrum of pure titania shown by the black solid line in Figure 4b (the lowest one labeled by TiO2) has two main bands. The strong and broad band centered at 3373 cm-1 is

Sol-Gel Titania Reservoirs for Epilepsy Treatment

Figure 5. Infrared spectra of phenytoin-titania complex (gray) and physically mixed phenytoin and titania (light gray) normalized to the carbonyl band at 1774 cm-1.

assigned to the stretching vibrations of hydroxyl groups involved in a variety of hydrogen bonds. The shoulder at the higher wavenumber region (at around 3450 cm-1) is indicative that there is a small fraction of feebly interacting hydroxyls. The band at 1630 cm-1 corresponds to the bending deformation mode of molecular water. These bands are also present in the phenytoin-titania complex and their solid mixture. The IR spectrum of pure phenytoin (dash-dotted upper line labeled Ph in Figure 4b) showed a great variety of bands. At high energy the vibration bands related to the amino groups are observed: at 3620 cm-1 for NH(CO2)2, at 3292 cm-1 for N-H, and at 3062 cm-1 for NsCOsN. The signal at 3292 cm-1 is also present in sol-gel titania-phenytoin complex and its physical mixture (the two spectra in the middle) slightly shifted to lower energy (3273 cm-1). The bands at 1768 and 1692 cm-1 are the fingerprints of phenytoin corresponding to ν(CdO) modes. The same modes are present in the titaniaphenytoin complex and the physical mixture, indicating the presence of the drug within the matrix. The signal at 1600 cm-1 corresponds to the stretching vibrations of the CdC bond of the aromatic rings with the contribution of the bending water deformation. Its intensity is significantly lower for the encapsulated phenytoin, suggesting a certain conformational constrain of the rings in the complex. The band at 1446 cm-1 is assigned to skeletal C-C modes of the aromatic rings and to ν(C-N) modes of the imidazol ring, and the one at 1382 cm-1 to δ(N-H) modes in the imidazol. To compare experimental signals of physical mixture and phenytoin-titania complex (dark gray and light gray solid lines in Figure 4b), two regions of interest could be considered. In the first region (3200-3600 cm-1) it was not possible to detect the difference in the N-H signals, since these signals overlap with the wide band corresponding to the O-H vibrations in the real titania-phenytoin complex. The other region (1700-1780 cm-1) was not masked by the matrix signals and was used for comparison as suggested in the theoretical calculations. Figure 5 shows a closer look at the carbonyl bands in this region. As one can see from Figure 5, in the experimental spectrum of the sol-gel complex the signals of the carbonyl groups are significantly reduced as compared with the signals of pure phenytoin and the physical mixture. This is in good agreement with the picture suggested in the calculations for the spectrum of C-III. However, the carbonyl group signals do not disappear completely, as suggested in an “ideal” theoretical system. This implies that the complex C-II is also present in the reservoirs even though probably in a lower amount as compared with C-III. Also, the presence of the drug occluded in the pores but

J. Phys. Chem. C, Vol. 114, No. 47, 2010 20025

Figure 6. IR spectra of titania reservoirs with phenytoin for different water/alkoxide ratios rw. Dashed vertical lines indicate the region of area integration with the wavenumber limits.

Figure 7. Calculated areas under the O-H peak of the IR spectra as a function of rw for phenytoin loaded titania.

not bound to the matrix may contribute to the signal. Thus, the results above indicate the presence of C-III in the system even though it is hard to conclude in what proportion to C-II and “free” phenytoin it is formed. B. Titania Hydroxylation Degree. The results above suggest that to bind one phenytoin molecule, the titania matrix should have at least two active sites (OH groups). This implies that the hydroxylation degree of titania affects the amount of phenytoin that can be bound. Thus, the amount of water used during the sol-gel process should influence the amount of the bound phenytoin by changing the degree of hydroxylation of the matrix. The hydroxylation degree of the matrix with phenytoin was studied with respect of water/alkoxide ratio rw. Figure 6 shows IR spectra of titania reservoirs loaded with phenytoin in the region of characteristic frequencies of OH groups for different water/alkoxide ratios rw. The wide band at around 3350 cm-1 corresponds to the stretching vibrations of hydroxyl groups of the titania matrix. The band intensity and the width are correlated with the number of hydroxyl groups. Thus, the area under the band may be used to estimate the degree of hydroxylation of the material. The areas under each spectrum curve were calculated in the region between 3080 and 3700 cm-1 and are shown in Figure 7. As one can see from Figure 7, the dependence of the degree of hydroxylation (area) of titania reservoirs on water content rw is nonlinear: it gradually increases to rw ) 16 and then decreases. It seems to have the highest amount of hydroxyls for rw ) 16, which is the most favorable to bind larger amounts of the drug. It is well-known that the water/alkoxide ratio has a large influence on the process of hydrolysis and further condensation

20026

J. Phys. Chem. C, Vol. 114, No. 47, 2010

Figure 8. TGA and DSC curves of phenytoin-titania complex with water/alkoxide ratio rw ) 16: solid line, TGA; dashed line, DSC. The temperature of phenytoin decomposition (360 °C) is marked by the arrow.

in the sol-gel synthesis.19 Thus, it is expected that the increase of amount of water during the synthesis increases the hydroxylation of the particles. The first stage of the sol-gel process (hydrolysis) is highly dependent on the ratio rw. In the case of low water content, not all the alkoxide molecules are hydrolyzed when the polymerization process already starts.38 This results in linear polymer chains with a larger amount of OR (where R is a radical) groups. As we increase the amount of water in the reaction, the hydrolysis is more complete and the number of hydroxyls on the surface increases. However, when one reaches sufficiently high water/alkoxide ratios rw ) 24, the formed structures are more compact, since hydrolysis and condensation are promoted, which results in more branched structures with smaller number of terminal surface hydroxyls. This is reflected in a slight decrease of the area in Figure 7. Thus, just by varying one parameter of the synthesis such as the water/alkoxide ratio one can control the load of the drug in the matrix. C. Thermogravimetric (TGA) and Differential Scanning Calorimetry (DSC) Analyses. Figure 8 shows a typical TGA and DSC curves for the phenytoin-titania complex for water/ alkoxide ratio rw ) 16. The curves in Figure 8 are similar to the ones previously reported for titania systems.37,38,40,41,42 There are three main weight loss regions in the TGA curve (Figure 8). The first weight loss in the region 30-235 °C is due to the loss of the volatile species physically adsorbed in the matrix (water, ethanol). In DSC this process is reflected by the endothermic peak at around 120 °C. The second region between 235 and 420 °C is attributed to the gradual removal of chemically bonded water and organic components such as unhydrolyzed alkoxide ligands (alkyls) bonded in the titanium. The second endothermic peak in the DSC curve at 290 °C corresponds to this desorption process. This is the region of our interest, since it provides information about the relative amount of hydroxyls on the matrix surface. Also, at about 360 °C, phenytoin decomposition starts, which is reflected in the upturn in the DSC curve. For technical reasons it was not possible to obtain the complete exothermic peak at around 400 °C; however, the upturn and the data in ref 43 are a good indication of it. The peak is attributed to phenytoin degradation and the phase transition from amorphous to anatase titania. The further weight loss at the temperatures above 440 °C is due to the removal of the organic residues (carbon dioxide, amorphous carbon, etc.).41 We calculated the weight loss in the region 235-420 °C of the TGA curve for the phenytoin-titania complexes with different water/alkoxide ratios rw to estimate the relative amount of hydroxyls on the titania surface. Even though there is a

Lo´pez et al.

Figure 9. Calculated weight loss in the region 235-420 °C of the TGA curve as a function of rw for phenytoin loaded titania.

contribution of organic components to the weight loss in this region, their amount in the matrix should be correlated with the ratio rw. For this reason their contribution should not change the general tendency. The results are summarized in Figure 9. Figure 9 shows that the loss of weight increases almost linearly with increase of rw up to rw ) 16 and then decreases at rw ) 24. This reflects the dependency of the amount of terminal hydroxyls, alkyls, and bound phenytoin on the water/alkoxide ratio. Unfortunately, it was not possible to distinguish between hydroxyl and alkyl groups in this method. However, we can assume that the amount of unhydrolyzed alkyls should decrease and the amount of the bound phenytoin increase with an increase of rw. Thus, we can conclude that the weight loss tendency reflects well the correlation between the amount of hydroxyls in titania. The general tendency in the dependency in Figure 9 is very similar to that shown in Figure 7 with the maximum of hydroxylation for rw ) 16. This coincidence allows us to conclude that the estimation of the relative hydroxylation degree is quite reliable, since it was confirmed by both techniques. IV. Conclusions The NMR studies confirmed that the drug does not undergo substantial modifications during the sol-gel process. The hydantoin ring is the main part of the phenytoin molecule that participates in the hydrogen-type interactions with hydroxyl groups of the titania matrix. The tridental complex C-III is the most favorable to form as confirmed by theoretical calculations and IR spectroscopy. The amount of hydroxyl groups on the titania surface is crucial for the phenytoin load in titania reservoirs. IR and TGA/DSC analyses showed that with increase of rw, the hydroxylation degree increases up to rw ) 16 and then decreases. Thus, rw ) 16 seems to be the most favorable to bind the largest amount of the drug because of the highest hydroxylation degree. Acknowledgment. We highly appreciate the financial support of the Mexican National Council of Science and Technology (CONACYT) within the project FONCICyT 96095, the National Institute of Neurology and Neurosurgery (INNN), and the Autonomous Metropolitan University (UAM). We gratefully acknowledge the support of Atilano Gutie´rrez in the NMR studies. References and Notes (1) Lopez, T.; Quintana, P.; Ortiz-Islas, E.; Vinogradova, E.; Manjarrez, J.; Aguilar, D. H.; Castillo-Ocampo, P.; Magana, C.; Azamar, J. A. J. Mat. Char. 2007, 58, 823.

Sol-Gel Titania Reservoirs for Epilepsy Treatment (2) Fidalgo, A.; Lopez, T.; Ilharco, L. J. Sol-Gel Sci. Technol. 2009, 49, 320. (3) Heredia-Cervera, B. E.; Gonzalez-Azcorra, S. A.; RodriguezGattorno, G.; Lopez, T.; Ortiz-Islas, E.; Oskam, G. Sci. AdV. Mater. 2009, 1, 63. (4) Lopez, T.; Alexander-Katz, R.; Castillo, P.; Gonzalez, M.; Manjarrez, J.; Gonzalez, R. D.; Ilharco, L.; Fidalgo, A.; Rieumont, J. J. Mater. Sci. 2009, 44, 5459. (5) Lopez, T.; Martinez-Gonzalez, C. L.; Manjarrez, J.; Plascencia, N.; Balankin, A. S. Appl. Mech. Mater. 2009, 15, 127. (6) Lopez, T.; Manjarrez, J.; Rembao, D.; Vinogradova, E.; Moreno, A.; Gonza´lez, R. D. Mater. Lett. 2006, 60, 2903. (7) Kortesuo, P.; Ahola, M.; Kangas, M.; Yli-Urpo, A.; Kiesvaara, J.; Marvola, M. Int. J. Pharm. 2001, 221, 107. (8) Radin, S.; Ducheyne, P.; Kamplain, T.; Tan, B. H. J. Biomed. Mater. 2001, 57, 313. (9) Aughenbaugh, W.; Radin, S.; Ducheyne, P. J. Biomed. Mater. 2001, 57, 321. (10) Fidalgo, A.; Ilharco, L. M. Chem.sEur. J. 2004, 10, 392. (11) Meixner, D. L.; Dyer, P. N. J. Sol-Gel Sci. Technol. 1999, 14, 223. (12) Viitala, R. M.; Jokinen, M.; Maunu, S. L.; Jalonen, H.; Rosenholm, J. B. J. Non-Cryst. Solids 2005, 351, 3225. (13) Viitala, R. M.; Jokinen, M.; Tuusa, S.; Rosenholm, J. B.; Jalonen, H. J. Non-Cryst. Solids 2005, 36, 147. (14) Song, S.-W.; Hidajat, K.; Kawi, S. Langmuir 2005, 21, 9568. (15) Vallet-Regi, M.; Ramila, A.; del Real, R.; Perez-Pariente, J. Chem. Mater. 2001, 13, 308. (16) Mun˜oz, B.; Ramila, A.; Perez-Pariente, J.; Diaz, I.; Vallet-Regi, M. Chem. Mater. 2003, 15, 500. (17) Lee, J.; Cho, E. C.; Cho, K. J. Con. Rel. 2004, 94, 323. (18) Mueller, R.; Kammler, H. K.; Wegner, K.; Pratsinis, S. E. Langmuir 2003, 19, 160. (19) Brinker, C. J.; Scherer, G. W. Sol-gel science: the Physics and chemistry of sol-gel processing; Academic Press: London, U.K., 1990; pp 108-112. (20) Yoldas, B. E. J. Non-Cryst. Solids 1984, 63, 145. (21) Yoldas, B. E. J. Mater. Sci. 1986, 21, 1087. (22) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;

J. Phys. Chem. C, Vol. 114, No. 47, 2010 20027 Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision D.01; Gaussian, Inc.: Wallingford, CT, 2004. (23) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (24) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785. (25) Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989, 157, 200. (26) Dunning, T. H., Jr.; Hay, P. J., Ed; Schaefer, H. F. Modern Theoretical Chemistry; Plenum: New York, NY, 1976; Vol. 3. (27) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270. (28) Wadt, W. R.; Hay, P. J. J. Chem. Phys. 1985, 82, 284. (29) Wadt, W. R.; Hay, P. J. J. Chem. Phys. 1985, 82, 299. (30) Okuno, Y. Chem.sEur. J. 1997, 3, 212. (31) Benson, S. W. The Foundations of Chemical Kinetics; Krieger: Malabar, FL, 1982. (32) Ardura, D.; Lopez, R.; Sordo, T. L. J. Phys. Chem. B 2005, 109, 23618. (33) Alvarez-Idaboy, J. R.; Reyes, L.; Cruz, J. Org. Lett. 2006, 8, 1763. (34) Galano, A. J. Phys. Chem. A 2007, 111, 1677. Addition/Correction. J. Phys. Chem. A 2007, 111, 4726. (35) Galano, A.; Cruz-Torres, A. Org. Biomol. Chem. 2008, 6, 732. (36) Galano, A. J. Phys. Chem. C 2008, 112, 8922. (37) Song, K. C.; Pratsinis, S. E. J. Colloid Interface Sci. 2000, 231, 289. (38) Pouxviel, J. C.; Boilet, J. P.; Beloeil, J. C.; Lallemand, J. Y. J. Non-Cryst. Solids 1987, 89, 345. (39) Soler-Illia, G. J. A. A.; Louis, A.; Sanchez, C. Chem. Mater. 2002, 14, 750. (40) Nomura, M.; Meester, B.; Schoonman, J.; Kapteijn, F.; Moulijn, J. A. Chem. Mater. 2003, 15, 1283. (41) Zhang, M.; Wang, J.; Fu, H. J. Mater. Process. Technol. 2008, 199, 274. (42) Mun˜oz, E.; Boldu´, J. L.; Andrade, E.; Novaro, O.; Bokhimi, X. J. Am. Ceram. Soc. 2001, 84, 392. (43) Montoya, I. A.; Viveros, T.; Domı´ngez, J. M.; Canales, L. A.; Schifter, I. Catal. Lett. 1992, 15, 207.

JP105356Q