Tunability of Pore Diameter and Particle Size of Amorphous

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Tunability of Pore Diameter and Particle Size of Amorphous Microporous Silica for Diffusive Controlled Release of Drug Compounds Caroline A. Aerts,† Els Verraedt,† Randy Mellaerts,† Anouschka Depla,† Patrick Augustijns,‡ Jan Van Humbeeck,§ Guy Van den Mooter,‡ and Johan A. Martens*,† Centre for Surface Chemistry and Catalysis, Katholieke UniVersiteit LeuVen, Kasteelpark Arenberg 23, B-3001 HeVerlee, Belgium, Laboratory for Pharmacotechnology and Biopharmacy, Katholieke UniVersiteit LeuVen, Herestraat 49, Bus 921, B-3000 LeuVen, Belgium, and Department of Metallurgy and Materials Engineering, Katholieke UniVersiteit LeuVen, Kasteelpark Arenberg 44, B-3001 HeVerlee, Belgium ReceiVed: May 8, 2007; In Final Form: June 25, 2007

Amorphous microporous silica (AMS) materials with variation in microporosity were prepared using an acidcatalyzed sol-gel procedure departing from tetraethylorthosilicate. The silicas were fined to specific particle sizes by crushing and sieving. AMS materials were loaded with 10 wt % ibuprofen either by uptake of molten ibuprofen or by adsorption of ibuprofen from a methylene chloride solution. DSC analysis of ibuprofenloaded AMS confirmed the molecular dispersion of ibuprofen on the silica material. In vitro ibuprofen release from AMS carrier was investigated in simulated intestinal fluid and in a dissolution medium simulating the gastrointestinal tract with simulated gastric fluid followed by simulated intestinal fluid. The release of ibuprofen molecules from the AMS silica carrier is governed by diffusion. The diffusivity of ibuprofen in the investigated series of AMS samples was in the range 10-14-10-11 m2 s-1. By adapting the porosity and particle size of AMS, the release could be evenly spread over periods from 3 to 100 h. This flexibility of AMS opens perspectives for designing tailor-made controlled release formulations.

1. Introduction Controlled release of a pharmaceutical compound during passage through the gastrointestinal tract may result in improved therapeutic effectiveness and enhanced patient’s compliance.1 Contemporary controlled release technology is especially organic polymer based and comprises reservoir and matrix systems. In reservoir systems, the drug is encapsulated within a polymeric film or coating.2 In matrix devices, the active agent is dispersed within the polymer matrix.2 Drug release can be pore diffusion controlled or osmotically driven. In formulations with biodegradable or soluble polymers, the controlling force is dissolution or erosion of the excipient.2 Silicon- and silica-based drug delivery systems have emerged as a promising alternative technology. Nanostructured porous silicon is derived from bulk silicon by anodization or stain etch processing, and drug release kinetics are controlled by altering the porosity.3 In another concept, drug molecules can be incorporatedduringsilicapolymerizationandsol-gelprocessing.4-12 Release of the drug molecules from such particles occurs by a combination of bio-erosion and pore diffusion. Ordered mesoporous silica materials can act as a porous reservoir from which the therapeutic compound is immediately released13 or from which drug molecules elude through diffusion.14-22 The drug release can be fine-tuned by chemical functionalization of the mesopore wall15,19-21 or by incorporating nanocaps for controlling the timing of the drug release.22 Crystalline microporous silicate materials and, in particular, zeolites were investigated as carrier materials for the delayed release of, e.g., pheromones, * Corresponding author. E-mail: [email protected]. † Centre for Surface Chemistry and Catalysis. ‡ Laboratory for Pharmacotechnology and Biopharmacy. § Department of Metallurgy and Materials Engineering.

anthelminthics, and ibuprofen.23-26 Silica offers other lessexplored possibilities. Silica can be polymerized as an amorphous microporous silica material (AMS) exhibiting molecular shape selectivity similar to that of zeolites.27-31 Under acidcatalyzed sol-gel conditions and at low water content (low r-value, referring in sol-gel literature to water:alkoxide molar ratio), the hydrolysis of tetraethylorthosilicate (TEOS), the silicon alkoxide source, is incomplete. The final gel contains residual ethoxy groups, which can be eliminated through calcination, whereupon a microporous material is obtained.27,32 We investigated the potential of AMS as a carrier for controlled drug delivery application using ibuprofen, an analgesic and antiinflammatory drug, as a model compound. We demonstrate that a drug compound such as ibuprofen can be loaded on amorphous microporous silica and released via configurational diffusion. 2. Experimental Section 2.1. Synthesis of Silica Carriers. Amorphous microporous silica materials were prepared according to Maier et al.27 by combining tetraethylorthosilicate (TEOS; Acros, 98%), technical ethanol, and HCl (37%, Vel). Four different AMS materials were synthesized (AMS1-AMS4). For the preparation of AMS1, the molar ratio of TEOS:ethanol:H+:water was 1:3:0.35:1.2. For AMS2, the r-value (water to TEOS ratio) was increased to 2. In the synthesis of AMS3 and AMS4, the molar ratios of TEOS: ethanol:H+:water were 1:3:1.01:3.5 and 1:3:1.74:6, respectively. The AMS synthesis procedure was as follows. The HCl solution was combined with water and added dropwise to the stirred solution of TEOS and ethanol. Stirring was continued for 24 h at room temperature. Subsequently, the sol was heated at 50 °C under quiescent conditions in a furnace for 3 days. A stiff transparent gel was obtained. The gel body was broken and the particles were heated to 65 °C with a heating rate of 0.1 °C

10.1021/jp0735076 CCC: $37.00 © 2007 American Chemical Society Published on Web 08/21/2007

AMS for Controlled Release of Drug Compounds

J. Phys. Chem. C, Vol. 111, No. 36, 2007 13405 TABLE 1: Particle Size Distributions of AMS2 Materials AMS2 material AMS280 AMS2200 AMS2250 AMS2380 AMS2800

µ

σ

A

80 203 244 378 805

64 67 109

18 21 19

the grains using a stereoscope. Material fined in a mortar, denoted AMS280, has a broad particle size distribution, with a mean diameter of 80 µm and a 75% confidence range from 30 to 225 µm (Figure 1a). Fractions obtained by sieving, denoted AMS2200, AMS2250, and AMS2380, displayed a normal distribution and could be fitted by a Gaussian distribution function:

( 21(x -σ µ) )

f(x) ) A exp -

Figure 1. Particle size distributions of AMS280 (a), AMS2200 (b), AMS2250 (c), AMS2380 (d), and AMS2800 (e). The distributions of AMS2200, AMS2250, and AMS2380 were fitted by Gaussian distribution curves (Table 1).

min-1. After 5 h at 65 °C the material was heated to the final temperature of 250 °C with a rate of 0.1 °C min-1. After 5 h at 250 °C the product was cooled to ambient temperature. The xerogel, consisting of coarse particles of millimeter size, was manually crushed using a mortar and pestle and subsequently sieved to the desired particle size. AMS material was fined to different extents. The particle sizes of the materials and the sample codes are given in Figure 1 and Table 1. The particle sizes of AMS280, AMS2200, AMS2250, and AMS2380 were measured using a Mastersizer Micro Plus apparatus (Malvern Instruments) based on the Fraunhofer laser diffraction theory. The particles were suspended in ethanol during analysis. The measurement range of the Mastersizer is between 50 nm and 555 µm. The particle size distribution of larger AMS2800 grains was obtained by measuring the size of

2

with µ being the mean particle diameter and σ the standard deviation of the particle size distribution. The particle size distribution of larger AMS grains with a mean diameter of 800 µm (AMS2800) did not fit with a Gaussian curve. 2.2. Ibuprofen Loading and in Vitro Release Experiments. Ibuprofen (Alpha Pharma) was loaded into AMS material using a melting method or a solvent method. Following the melting method, a physical mixture of AMS and ibuprofen powders was heated for 24 h in a stove at 100 °C, which is above the ibuprofen melting temperature. In the solvent method, AMS material was loaded with ibuprofen by adsorption from a methylene chloride solution. The drug was dissolved in methylene chloride (1 mg mL-1); after dissolution, dry AMS material was added. After slurrying the AMS material for 3 days in the ibuprofen solution, the solvent was evaporated under reduced pressure (200 mbar) at 25 °C using a rotavap device. The drug loaded material was subsequently dried for 24 h at 40 °C under reduced pressure. Drug loaded silica materials were dispersed in 1000 mL of dissolution medium at 37 °C under gentle agitation using a Hanson SR8-plus dissolution bath. At first, ibuprofen release was analyzed in simulated intestinal fluid, a phosphate buffer solution at pH 6.8. In other experiments the conditions of the human gastrointestinal tract were simulated. Ibuprofen release was performed in simulated gastric fluid (SGF, USP XXV, pH 1.2) for 2 h and, subsequently, in simulated intestinal fluid at pH 6.8 obtained by adding K2HPO4 (Merck) to the SGF solution. 2.3. Methods. Nitrogen adsorption isotherms at -196 °C were recorded on a Tristar instrument (Micromeritics). Before the measurements, samples were outgassed for 12 h at 250 °C. Specific surface area and pore volume were determined using BET and t-plot analysis, respectively. The low-pressure range (10-7 < P/P0 < 10-4) of the nitrogen adsorption isotherm was investigated on an ASAP 2020 instrument (Micromeritics). The isotherms were interpreted in terms of micropore diameters using the Horvath-Kawazoe method for slit-shaped pores.33 In situ Fourier transform infrared (FTIR) spectra of AMS powders, compressed to thin films of 1-6 mg cm-2, were recorded on a Nicolet 730 FTIR spectrophotometer under helium flow. The physical state of ibuprofen in the AMS materials was analyzed using differential scanning calorimetry (DSC; Q-1000, TA Instruments) in open aluminum sample pans. The samples were heated from -90 to 200 °C at 30 °C min-1. Data were treated mathematically using the Universal Analysis 2000 software program (TA Instruments).

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Figure 2. Nitrogen adsorption and desorption isotherms at -196 °C of AMS1, AMS2, AMS3, and AMS4.

TABLE 2: Pore Volumes, BET Surface Areas, and Main Pore Diameters of AMS Materials AMS material AMS1 AMS2 AMS3 AMS4

pore vol (mL g-1)

BET surf. area (m2 g-1)

main pore diam (nm)

0.13 0.27 0.37 0.48

247 537 731 886

0.36 0.38 0.39; 0.45 0.42; 0.47

The concentration of the drug substance in the dissolution medium was determined using an isocratic HPLC method with UV detection. The HPLC system consisted of a Lachrom L-7100 HPLC pump, an autosampler Model L-7200, a UV detector Model L-7420 set at 220 nm, and an Interface D-7000, all from Merck. UV signals were monitored and peaks were integrated using the D-7000 HSM software. All chromatographic separations were performed at room temperature. The analysis of ibuprofen was performed with a Merck Chromolith Performance RP-18e column. The mobile phase consisted of phosphate buffer (0.01 M, pH 5.5) and acetonitrile (Fisher Scientific) (60:40 v/v), filtered through a membrane filter (0.45 µm) and degassed by ultrasonication before use. The flow rate amounted to 1 mL min-1, and the injection volume was 10 µL. 3. Results and Discussion 3.1. Physicochemical Characterization of AMS. Amorphous microporous silica similar to the materials investigated here has been characterized by others using argon and nitrogen adsorption34 and using the diffusivity of small adsorbed molecules probed with pulsed field gradient NMR.35 Adsorption studies confirmed the microporous nature and revealed the micropore size distribution to be broader than in zeolites.34 The pulsed field gradient NMR study revealed the pore system to be essentially monodimensional.35 Nitrogen adsorption isotherms at -196 °C of the four AMS materials of the present study (millimeter-size particles) are shown in Figure 2. Adsorption and desorption branches of the isotherm coincide over the entire pressure range. All AMS samples exhibit a type I isotherm typical of microporous material. The AMS pore volume ranged from 0.13 to 0.48 mL g-1 (Table 2), which is high for a microporous material and in the range of the volumes typically found in zeolites. The micropore size of the AMS sample series was evaluated by analyzing the low-pressure region of the nitrogen adsorption isotherm using the Horvath-Kawazoe (H-K) method33 (Figure 3). AMS1 and AMS2 show a monomodal pore size distribution with a maximum around 0.36 and 0.38 nm, respectively. Compared to AMS1, the pore size distribution of AMS2 is a little more spread to larger diameters. AMS3 and AMS4 materials have pore size distributions with two maxima, viz. at 0.39 and 0.45 nm for AMS3 and 0.42 and 0.47 nm for AMS4. The micropore sizes in these two materials extend to 2 nm. AMS2 was prepared using more water than for AMS1, using

Figure 3. Micropore size distributions of AMS1 (a), AMS2 (b), AMS3 (c), and AMS4 (d), calculated using the Horvath-Kawazoe method for slit-shaped pores.33

r-values of 2 and 1.2, respectively. The higher water content in the AMS2 preparation leads to the formation of somewhat wider pores (Figure 3). An increase of both the HCl content and r-value in AMS3 and AMS4 materials results in a further pore widening. The nitrogen adsorption isotherms and micropore size distributions of Figures 2 and 3 were recorded on millimetersize particles of the different AMS materials. We verified that the grinding in a mortar of the four AMS materials did not alter the porosity. The validity of the original H-K model for estimating the micropore size has been questioned.36 The H-K method applied to nitrogen adsorption isotherms of zeolites appeared to be unable to discriminate between the pore size of ZSM-5 and Y zeolite, presenting a difference of more than 0.15 nm according to the crystallographic data.34 From the present characterization of the AMS materials using nitrogen adsorption and the H-K method (Figure 3, Table 2), the presence of a broad micropore size distribution and an evolution to wider pores in the series AMS1-AMS4 can be concluded. Given the limitations of the approach,34,36 the obtained absolute values of the micropore diameters probably are inaccurate. FTIR spectra of AMS280 evacuated at 200 and 400 °C are shown in Figure 4. The presence of vicinal hydroxyl groups on

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Figure 4. FTIR spectra of AMS2, evacuated at 200 and 400 °C.

the surface is manifested by the presence of a broad IR absorption in the range 3400-3700 cm-1 after evacuation at 200 °C (Figure 4). The presence of hydroxyl groups reveals the hydrophilic properties of this adsorbent material. Heating at 400 °C causes a decrease of the absorbance in the bathochromic part of the hydroxyl stretching vibration band due to partial dehydroxylation. The hydrophilicity was confirmed by the affinity of AMS for water. After hydration at room temperature in air of 75% humidity, the water uptake by AMS280 measured gravimetrically corresponds to 20 wt %. These amorphous microporous silica materials are hydrophilic in contrast to crystalline molecular sieves such as Silicalite-1, which hardly adsorbs water vapor at room temperature.37 3.2. Ibuprofen Loading of Amorphous Microporous Silica. The DSC thermogram of crystalline ibuprofen powder is presented in Figure 5a. Ibuprofen crystalline powder melts at 75 °C. When crystalline ibuprofen powder is heated to 100 °C, a temperature at which no chemical degradation occurs, and is subsequently cooled, the molten state is frozen and amorphous ibuprofen is obtained. A characteristic glass transition between -50 and -35 °C is observed in the second heating cycle (Figure 5b). The DSC thermogram of AMS280, loaded with 10 wt % ibuprofen using the melting method is shown in Figure 5c. The DSC curve of the ibuprofen loaded silica material reveals a broad endothermic transition in the temperature range 100125 °C owing to desorption of physically adsorbed water molecules. No melting peak or glass transition of ibuprofen was observed in the DSC curve of ibuprofen loaded AMS280, indicating the absence of bulk ibuprofen phases (Figure 5c). The DSC results indicate that ibuprofen is in a molecularly dispersed state. The external surface area of AMS particles is negligible (4 ( 0.5 m2 g-1) compared to the internal surface area and insufficient for adsorbing the ibuprofen molecules in a way avoiding interaction. It can be concluded that the majority of the ibuprofen molecules are located inside the micropores of the AMS materials. AMS2200, AMS2250, and AMS2380 were loaded with 10 wt % ibuprofen using the melting method. DSC analysis of ibuprofen loaded on AMS2200 and AMS2250 did not reveal any bulk ibuprofen phases. In the DSC analysis of ibuprofen on coarser AMS2, viz. AMS2380, a small peak ascribed to melting of crystalline ibuprofen was observed around 75 °C (Figure 5d), representing ca. 3.6 wt % of the total drug content. A larger particle size resulted in a more difficult uptake of ibuprofen in the pores. The large grains of the AMS2800 sample could not be loaded effectively with ibuprofen using the melting method. After heating to 100 °C the mixture of AMS2800 particles and ibuprofen powder turned into a sticky mass, owing to ibuprofen covering the surfaces of the grains. Using an alternative method involving the suspension of AMS2800 grains in a solution of ibuprofen in methylene chloride and evaporation of the solvent, an uptake of 3.6 wt % could be achieved. Upon loading

Figure 5. DSC analysis of crystalline ibuprofen (a), amorphous ibuprofen (b), ibuprofen-loaded AMS280 (c), and ibuprofen-loaded AMS2380 (d). The AMS materials were loaded with 10 wt % ibuprofen by the melting method.

ibuprofen into AMS2800 according to this method, DSC revealed that about 25% of the total ibuprofen drug content was present in the crystalline form. AMS3 and AMS4 materials presenting larger pore volumes (Table 2) and wider pore diameters (Figure 3) could be loaded with up to 20 wt % ibuprofen via the melting method. AMS3 and AMS4 irrespective of particle size were successfully loaded with ibuprofen using the melting procedure. The absence of DSC signals ascribed to crystalline or amorphous ibuprofen suggested that ibuprofen was molecularly dispersed in the micropores. AMS1 presenting the narrowest micropores in the series (Figure 3) could be loaded with a small quantity of ibuprofen only. The pore diameters appeared to be too small for the ibuprofen molecule. The smallest kinetic diameter of ibuprofen estimated from molecular models is ca. 0.43 nm. 3.3. In Vitro Release Experiments. The release of ibuprofen from AMS2200 in simulated intestinal fluid (SIF) is presented in Figure 6a. Ibuprofen release continues for up to 48 h. The cumulative ibuprofen release was 46% after 4 h and 75% after 8 h. After 48 h, all ibuprofen molecules were released from the silica excipient. Ibuprofen release from the coarser versions of

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Figure 7. Ibuprofen release from AMS2200 in a dissolution medium simulating the gastrointestinal tract. AMS2200 was loaded with 10 wt % ibuprofen by the melting method.

Figure 6. Ibuprofen release from AMS2200 in simulated intestinal fluid (pH 6.8) against time (a) and square root of time (b). AMS2200 was loaded with 10 wt % ibuprofen by the melting method.

TABLE 3: Ibuprofen Diffusivity (D) in AMS Materials AMS material AMS2

AMS3 AMS4

AMS280 AMS2200 AMS2250 AMS2380 AMS2800 AMS3800 AMS4800

D (m2 s-1) (1.4 ( 0.2) × 10-14 (3.7 ( 0.6) × 10-14 (4.1 ( 0.6) × 10-14 (5.9 ( 0.9) × 10-14 (5.6 ( 0.8) × 10-14 (3.4 ( 0.5) × 10-12 (1.1 ( 0.2) × 10-11

AMS2, viz. AMS2250 and AMS2380, was slightly slower compared to the release from AMS2200 particles. After 8 h, the drug release was 67% and 60%, respectively. The larger the particles, the smaller the surface-to-volume ratio, and the smaller the number of pore exits through which the ibuprofen molecules can diffuse out. For AMS2200 the data points of ibuprofen release versus time can be fitted with a curve that departs from the origin (Figure 6a). For AMS2380, an enhanced ibuprofen release was observed in the first minutes. This effect can be explained by the rapid dissolution of the small fraction of ibuprofen present under crystalline form on the outer surface of the AMS2380 particles as detected with DSC (Figure 5d). Provided the release of ibuprofen from AMS occurs via Fickian pore diffusion, the release is expected to fit linearly with the square root of time. This was indeed observed as illustrated in Figure 6b for AMS2200. Adopting the second law of Fick for spherical, isotropic, and isothermal grains, ibuprofen diffusivity in AMS2200, AMS2250, and AMS2380 was (3.7 ( 0.6) × 10-14, (4.1 ( 0.6) × 10-14, and (5.9 ( 0.9) × 10-14 m2 s-1, respectively (Table 3). Given the roughness of the assumptions in this estimation (isotropic particles, ideal spherical shape), this similarity of the diffusivities in the differently sized particles indicates an identical porosity. The diffusivity of ibuprofen in AMS2 is similar to that of the larger fluorescein dye molecules incorporated in mesoporous silica materials determined by Hellriegel et al., which amounts to (3.0 ( 0.5) × 10-14 m2 s-1.38 The diffusion coefficient of ibuprofen in AMS2 on the order of 10-14 m2 s-1 is in the range of values that are typical for configurational diffusion in molecular sieves.39 In a next step, ibuprofen release from AMS2200 was analyzed in a dissolution medium simulating the transition from acidic

Figure 8. Ibuprofen release from AMS2800 in a dissolution medium simulating the gastrointestinal tract. AMS2800 was loaded with 3.6 wt % ibuprofen by adsorption from a methylene chloride solution. The release is plotted against time (a) and square root of time (b).

to neutral environment in the human gastrointestinal tract (Figure 7). During the first 2 h, the release medium was simulated gastric fluid (SGF, pH 1.2). After 2 h, the pH was raised to 6.8 by adding K2HPO4, simulating human intestinal fluid (SIF). Cumulative ibuprofen release was 22% after 4 h and 51% after 8 h. The release of ibuprofen from the large AMS2800 grains loaded with 3.6 wt % ibuprofen was investigated in SGF followed by SIF (Figure 8). Ibuprofen release progresses slowly under acidic conditions. The pH change from 1.2 to 6.8 after 2 h causes a jump in ibuprofen release by ca. 25%. Note that the ibuprofen loading on this particular sample was problematic (vide supra). DSC analysis taught that ca. 25% of the ibuprofen was present in crystalline form. This percentage of residual ibuprofen that could not be taken up by the pores of the AMS grains apparently dissolves quickly at pH 6.8. The ibuprofen molecules that were effectively introduced into the pores were very slowly released. Cumulative ibuprofen release from AMS2800 grains was only 38% after 8 h, 70% after 45 h, and 88% after 98 h (Figure 8a). This demonstrates how ibuprofen release from AMS can be substantially slowed by increasing the particle size of the carrier material. Ibuprofen release from AMS2800 was linearly correlated to the square root of time

AMS for Controlled Release of Drug Compounds (Figure 8b), suggesting that the release is governed by pore diffusion. The ibuprofen diffusivity in AMS2800 was estimated at (5.6 ( 0.8) × 10-14 m2 s-1. This diffusivity is similar to the ones obtained with smaller AMS2 grains in SIF media (Table 3). The diffusivity of ibuprofen in AMS280 was determined in the combination of SGF and SIF release media and amounted to (1.4 ( 0.2) × 10-14 m2 s-1 (Table 3). Thus, the diffusivity in AMS2 varied little with particle size and ibuprofen loading. The average diffusivity in AMS2 materials over all performed measurements is (4.1 ( 0.6) × 10-14 m2 s-1. This magnitude of the diffusion coefficient shows that the diffusion of ibuprofen occurs in the configurational regime in molecularly sized pores, where diffusivities vary with orders of magnitude with subtle changes of pore diameters.39 Ibuprofen release from AMS3 and AMS4 with wider pores was much faster compared to AMS2. Ibuprofen diffusivity in AMS3800 and AMS4800 was (3.4 ( 0.5) × 10-12 and (1.1 ( 0.2) × 10-11 m2 s-1, respectively (Table 3). Diffusivity follows the order of micropore diameters (Table 2). Adaptation of the particle size of AMS3 and AMS4 carriers and, in this way, the diffusion path length is an additional tool for adjusting the release rate. 4. Conclusions AMS materials have unique properties for drug delivery applications. The porous silica matrix provides a high capacity for incorporation and subsequent controlled release of drug substances such as ibuprofen. Drug release from AMS is controlled by configurational diffusion in micropores. One of the key benefits of AMS drug delivery systems is the ability to control and fine-tune the kinetics of drug release by adjusting the porosity and the particle size of the matrix. This flexibility of AMS drug delivery technology offers the possibility to design future tailor-made drug formulations. By exploiting the tunability of AMS materials, the release time can be adjusted to 8-10 h, a time period during which in principle the oral drug can be absorbed in the gastrointestinal tract. Acknowledgment. C.A.A. and R.M. acknowledge the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT Vlaanderen) for a research fellowship. The work was supported by a K.U. Leuven interdisciplinary research project (IDO) and an industrial research fund (IOF). The authors gratefully acknowledge Jos Vervest from Micromeritics for analyzing the micropore size distribution of AMS on an ASAP 2020 instrument. References and Notes (1) Wise, D. L. Handbook of Pharmaceutical Controlled Release Technology; Marcel Dekker, Inc.: New York, 2000. (2) Bruck, S. D. Controlled Drug DeliVery; CRC Press, Inc.: Boca Raton, FL, 1983; pp 1-13. (3) Canham, L. T.; Sapsford, G. Pharmaceutical products and methods of fabrication therefore. WO0128529, April 26, 2001. (4) Kortesuo, P.; Ahola, M.; Karlsson, S.; Kangasniemi, I.; Kiesvaara, J.; Yli-Urpo, A. J. Biomed. Mater. Res. 1999, 44, 162.

J. Phys. Chem. C, Vol. 111, No. 36, 2007 13409 (5) Kortesuo, P.; Ahola, M.; Karlsson, S.; Kangasniemi, I.; Yli-Urpo, A.; Kiesvaara, J. Biomaterials 2000, 21, 193. (6) Ahola, M.; Kortesuo, P.; Kangasniemi, I.; Kiesvaara, J.; Yli-Urpo, A. Int. J. Pharm. 2000, 195, 219. (7) Kortesuo, P.; Ahola, M.; Kangas, M.; Kangasniemi, I.; Yli-Urpo, A.; Kiesvaara, J. Int. J. Pharm. 2000, 200, 223. (8) Ahola, M.; Sa¨ilynoja, E.; Raitavuo, M.; Vaahtio, M.; Salonen, J.; Yli-Urpo, A. Biomaterials 2001, 22, 2163. (9) Kortesuo, P.; Ahola, M.; Kangas, M.; Yli-Urpo, A.; Kiesvaara, J.; Marvola, M. Int. J. Pharm. 2001, 221, 107. (10) Kortesuo, P.; Ahola, M.; Kangas, M.; Leino, T.; Laakso, S.; Vuorilehto, L.; Yli-Urpo, A.; Kiesvaara, J.; Marvola, M. J. Controlled Release 2001, 76, 227. (11) Czuryszkiewicz, T.; Ahvenlammi, J.; Kortesuo, P.; Ahola, M.; Kleitz, F.; Jokinen, M.; Linde´n, M.; Rosenholm, J. B. J. Non-Cryst. Solids 2002, 306, 1. (12) Santos, E. M.; Radin, S.; Ducheyne, P. Biomaterials 1999, 20, 1695. (13) Mellaerts, R.; Aerts, C. A.; Van Humbeeck, J.; Augustijns, P.; Van den Mooter, G.; Martens, J. A. Chem. Commun. 2007, 1375. (14) Vallet-Regı´, M.; Ra´mila, A.; del Real, R. P.; Pe´rez-Pariente, J. Chem. Mater. 2001, 13, 308. (15) Mun˜oz, B.; Ra´mila, A.; Pe´rez-Pariente, J.; Dı´az, I.; Vallet-Regı´, M. Chem. Mater. 2003, 15, 500. (16) Horcajada, P.; Ra´mila, A.; Pe´rez-Pariente, J.; Vallet-Regı´, M. Microporous Mesoporous Mater. 2004, 68, 105. (17) Charnay, C.; Be´gu, S.; Tourne´-Pe´teilh, C.; Nicole, L.; Lerner, D. A.; Devoisselle, J. M. Eur. J. Pharm. Biopharm. 2004, 57, 533. (18) Doadrio, A. L.; Sousa, E. M. B.; Doadrio, J. C.; Pe´rez-Pariente, J.; Izquierdo-Barba, I.; Vallet-Regı´, M. J. Controlled Release 2004, 97, 125. (19) Zeng, W.; Qian, X.-F.; Zhang, Y.-B.; Yin, J.; Zhu, Z.-K. Mater. Res. Bull. 2005, 40, 766. (20) Izquierdo-Barba, I.; Martinez, A.; Doadrio, A. L.; Pe´rez-Pariente, J.; Vallet-Regı´, M. Eur. J. Pharm. Sci. 2005, 26, 365. (21) Horcajada, P.; Ra´mila, A.; Fe´rey, G.; Vallet-Regı´, M. Solid State Sci. 2006, 8, 1243. (22) Lai, C.-Y.; Trewyn, B. G.; Jeftinija, D. M.; Jeftinija, K.; Xu, S.; Jeftinija, S.; Lin, V. S.-Y. J. Am. Chem. Soc. 2003, 125, 4451. (23) Mun˜oz-Pallares, J.; Primo, E.; Primo, J.; Corma, A. In Proceedings of the 13th International Zeolite Conference; Galarneau, A., Di Renzo, F., Fajula, F., Vedrina, J., Eds.; Studies in Surface Science and Catalysis 135; Elsevier: Amsterdam, 2001; p 32-P-05. (24) Dyer, A.; Morgan, S.; Wells, P.; Williams, C. J. J. Helmintol. 2000, 74, 137. (25) Hayakawa, K.; Mouri, Y.; Maeda, T.; Satake, I.; Sato, M. Colloid Polym. Sci. 2000, 278, 553. (26) Horcajada, P.; Ma´rquez-Alvarez, C.; Ra´mila, A.; Pe´rez-Pariente, J.; Vallet-Regı´, M. Solid State Sci. 2006, 8, 1459. (27) Maier, W. F.; Tilgner, I.-C.; Wiedorn, M.; Ko, H.-C. AdV. Mater. 1993, 5, 726. (28) Maier, W. F.; Martens, J. A.; Klein, S.; Heilmann, J.; Parton, R.; Vercruysse, K.; Jacobs, P. A. Angew. Chem., Int. Ed. Engl. 1996, 35, 180. (29) Klein, S.; Martens, J. A.; Parton, R.; Vercruysse, K.; Jacobs, P. A.; Maier, W. F. Catal. Lett. 1996, 38, 209. (30) Hunnius, M.; Rufin´ska, A.; Maier, W. F. Microporous Mesoporous Mater. 1999, 29, 389. (31) Sto¨ckmann, M.; Konietzni, F.; Notheis, J. U.; Voss, J.; Keune, W.; Maier, W. F. Appl. Catal., A 2001, 208, 343. (32) Ro, J. C.; Chung, I. J. J. Non-Cryst. Solids 1991, 130, 8. (33) Horvath, G.; Kawazoe, K. J. Chem. Eng. Jpn. 1983, 16, 470. (34) Storck, S.; Bretinger, H.; Maier, W. F. Appl. Catal., A: Gen. 1998, 174, 137. (35) Krause, S.; Klein, J.; Ka¨rger, J.; Maier, W. F. AdV. Mater. 1996, 8, 912. (36) Rege, S. U.; Yang, R. T. AIChE J. 2004, 46, 734. (37) Rouquerol, F.; Rouquerol, J.; Sing, K. Adsorption by Powders & Porous Solids: Principles, Methodology and Applications; Academic Press: San Diego, 1999. (38) Hellriegel, C.; Kirstein, J.; Bra¨uchle, C. New J. Phys. 2005, 7, 1. (39) Weisz, P. B. Chem. Tech. 1973, 3, 498.