Correlation of Mesoporous Silica Structural and Morphological

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Correlation of Mesoporous Silica Structural and Morphological Features with Theoretical Three-Parameter Model for Drug Release Kinetics Raul - Augustin Mitran, Cristian Matei, and Daniela Berger J. Phys. Chem. C, Just Accepted Manuscript • DOI: 10.1021/acs.jpcc.6b09759 • Publication Date (Web): 02 Dec 2016 Downloaded from http://pubs.acs.org on December 3, 2016

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The Journal of Physical Chemistry

Correlation of Mesoporous Silica Structural and Morphological Features with Theoretical Three-Parameter Model for Drug Release Kinetics Raul - Augustin MITRAN†,‡, Cristian MATEI‡, Daniela BERGER‡,* † “Ilie Murgulescu” Institute of Physical Chemistry, Romanian Academy, 202 Splaiul Indepedentei, Bucharest, 060021, Romania ‡ University "Politehnica" of Bucharest, Faculty of Applied Chemistry and Material Science, 1-7 Polizu street, Bucharest, 011061, Romania ABSTRACT: Mesoporous silica materials are a promising class of nanocarriers for drug delivery systems. The drug release from these carriers depends on both the interactions between the silica mesopore surface and drug molecules and the diffusion of therapeutic agent molecules through the silica pores. In this work we have investigated the effects of mesopore functionalization with various organic groups, as well as the effects of pore size and geometry on the release of a model drug molecule, metoprolol. The mesoporous silica matrices and drug-loaded samples were characterized by small- and wide- angle X-ray diffraction, infrared spectroscopy, nitrogen adsorption-desorption isotherms and thermogravimetric analyses. The in vitro drug release profiles were analyzed in terms of the release rates of the burst and steady-state stages, as well as the fraction of metoprolol released during the burst stage using a theoretical three parameter model. The correlation between the pore size, arrangement and grafted organic groups and the drug release profiles are discussed. It was found that the three kinetics parameters describing the release profiles can be judiciously tailored through changing the textural properties of the carriers and the introduction of organic groups. INTRODUCTION Mesoporous silica nanoparticles (MSN) have been introduced as a carrier for drug delivery systems, 1-3 due to their excellent adsorption properties, high drug uptake values and biosafety.4-6 The interest towards MSN as drug carriers also stems from the numerous synthetic methods available to modify their properties and tailor the therapeutic agent release profiles. These methods include changing the mesopore surface properties through grafting organic moieties 7-10 or incorporation of hetero-atoms into the silica framework,11-14 tailoring the pore size and volume 15-17 or modifying the mesopore geometry and arrangement. 18-20 Unlike the design of mesoporous silica architecture, drug delivery profiles from MSN are still difficult to control and predict. This fact can be traced to the complexity of drug release from mesoporous carriers, which is influenced by the active agent diffusion and solvent counter-diffusion through mesochannels, the interactions between the drug molecules and the support surface groups, pH and counter-ions. 21-23 Therefore, exploring mesoporous carriers with various textural and surface properties is necessary for determining the drug release profiles and tailoring them towards specific applications. In this work we have investigated the influence of organic moieties with different acid and hydrophilic/hydrophobic properties, as well as the influence of mesoporous silica pore size and geometry on a model drug release kinetics. Specifically, MCM-41 supports functionalized with acidic (propyl sulfonic acid and propyl carboxylic acid) and basic (aminopropyl) hydrophilic groups or hydrophobic (mercaptopropyl, phenyl) organic groups have been investigated. Pore size has been varied between 2.3 and 6.6 nm for hexagonally ordered MCM-41 and SBA-15 carriers. A MCM-48 carrier with cubic interconnected pores has also been investigated. *

Corresponding author. E-mail address: [email protected]

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We have chosen metoprolol (MTP), a β1-receptor blocker widely used in the treatment of several cardiovascular diseases as a model drug. MTP is a water soluble, hydrophilic drug, with a molecular size estimated at 1.6 x 0.5 x 0.6 nm. (Fig. S1) This therapeutic agent contains a methoxy group, a phenoxy moiety, a hydroxyl and secondary alkyl amine functional groups, which could give rise to varied supramolecular interactions between the drug molecules and silica matrices (electrostatic interactions, hydrogen bonding, π-π stacking etc.). Furthermore, metoprolol delivery systems using mesoporous silica materials have been so far reported only for MCM-41 and SBA-15, 24 MCM-41 functionalized with a chiral complex 25 or SBA-15 functionalized with sulfonic acid groups. 26 The experimental metoprolol release profiles were fitted with a theoretical kinetics model, which consists of an equilibrium between drug adsorption and desorption on the mesopore surface, followed by diffusion in the release medium.27 The effects of the different MSN carriers on the MTP release profile was studied with the aim of establishing the relations between carrier properties and kinetics parameters governing the drug release kinetics. EXPERIMENTAL Materials and reagents MCM-41 (Sigma Aldrich), tetraethylorthosilicate (TEOS, Fluka), (3aminopropyl)triethoxysilane (APTES, Sigma-Aldrich), triethoxyphenylsilane (PhTES), 3cyanopropyltriethoxysilane (CPTES, Sigma-Aldrich), (3-mercaptopropyl)triethoxysilane (MPTES, Sigma-Aldrich), HCl 37% aqueous solution, H2SO4, poly (ethylene glycol)-block-poly (propylene glycol)-block-poly(ethylene glycol), EO20PO70EO20 (Pluronic® P123, average molecular weight 5800), cetyltrimethylammonium bromide (CTAB, Sigma-Aldrich), myristyltrimethylammonium bromide (C14TAB, Fluka) and solvents (Sigma-Aldrich) were used without further purification.. Metoprolol succinate (MTP) was provided by Polipharma Industries. Synthesis of pristine mesoporous silica SBA-15 mesoporous silica was obtained using a slight modification of our previously reported method.28 Pluronic P123 was dissolved into 1.9M HCl solution at 25°C. The solution was heated at 40°C and then TEOS was added. The sol was aged under magnetic stirring, at 800 rotations per minute for 24 h at the same temperature. The resulting suspension was transferred into a Teflon-line autoclave and aged statically at 100 °C for 24 h under autogenerated pressure. The solids were recovered by filtration and intensively washed. Finally, the surfactant was removed by calcination in static air at 550 °C for 5 hours, using a heating rate of 1 °C per minute. A molar ratio TEOS : P123 : HCl : H2O of 1.0 : 0.0163 : 6.25 : 184 was employed. MCM-48 was prepared following the procedure described in ref.29 Briefly, a sol containing a molar ratio Si: CTAB: NH3 :EtOH: H2O of 1: 0.41: 11: 53:344 was prepared and aged without stirring for 4 h at 30 °C. The precipitate was filtered off and washed. The white solids were dried at 60 °C overnight and calcined in air, at 550 °C for 5 h, using a 1 °C/min heating rate. The synthesis and characterization of MCM-41 silica obtained using the C14TAB surfactant (MCM-C14) was described elsewhere. 30 Briefly, C14TAB was dissolved into a solution of 25% NH3 in water under magnetic stirring. Next, TEOS was added at 25 °C and kept under stirring for 2 h. The reaction mixture was aged for 20 h at 25°C without stirring, followed by hydrothermal treatment at 150 °C for 24 h under 5 atm Ar pressure. The white solids were filtered off, washed and dried overnight at room temperature. MCM-C14 was obtained by calcination in air at 600 °C for 5 h, using a heating rate of 1 °C/min. A starting molar ratio of TEOS: C14TAB : NH3 : H2O = 1.0 : 0.137 : 3.3 : 158 was employed. ACS Paragon Plus Environment

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Post-synthesis functionalization of mesoporous carriers The grafting of organic groups onto the pristine mesoporous silica was carried out by dispersing 1 g mesoporous silica in 50 mL toluene, adding a suitable organosilane reagent and heating at reflux (110 °C) for 4 h. The resulting solids were recovered by centrifugation and washed with toluene, ethanol, water and 1M HCl solution. A molar ratio TEOS: organosilane of 1: 0.25 was employed for all syntheses. The resulting solids were dried overnight at room temperature. The following materials were obtained using the above mentioned synthesis protocol: “MPTES-MCM” (MPTES organosilane), “Ph-MCM” (PhTES organosilane), cyanopropyl-functionalized MCM-41 (CPTES organosilane), “APTES-SBA” and “APTES-MCM” (APTES organosilane). The synthesis and characterization of the aminopropyl-functionalized MCM-41 “APTES-MCM” was previously reported.23 The propylcarboxylic acid functionalized MCM-41 (“PCA-MCM”) was prepared according to a literature method,31 by treating 0.900 g cyanopropyl-functionalized MCM-41 sample with 60 mL 40% wt. aqueous H2SO4 solution at 70 °C for 24 h, filtered off and washed with water until neutral pH. Propylsulfonic acid functionalized silica (PSA-MCM) was obtained using a modified oxidation method of mercaptopropyl-MCM-41 silica (MPTES-MCM). 32, 33 1 g MPTES-MCM was dispersed under stirring at room temperature into 200 mL 0.5 M H2SO4 solution containing 10 % H2O2 for 24 h, followed by filtration. Metoprolol loading and in vitro release Drug-loading was performed through incipient wetness impregnation method, by adding an aqueous MTP solution (100 g⋅L-1) to the mesoporous carrier, followed by homogenization and vacuum drying. A 20% (wt.) MTP content was considered for all drug-loaded samples. The MTP-loaded samples are denoted “MTP@carrier”. The drug release profiles were obtained by UV-VIS spectroscopy, at 37 °C, in phosphate buffer solution (PBS) of pH=7.4 and under magnetic stirring (150 rpm). A quantity of drug-loaded samples containing 10 mg MTP was added to 90 mL PBS and samples were periodically withdrawn, centrifuged and analyzed by UV-VIS. The drug release experiments were performed in triplicate. 2.5 Characterization Small and wide-angle X-ray diffraction was carried out using Bruker D8 Discover and Rigaku MiniFlex II diffractometers, with Cu Kα radiation (λ=1.5406 Å). Nitrogen adsorption-desorption isotherms were recorded on a Quantachrome Autosorb iQ2 pore analyzer at 77 K. The specific surface area values were computed in the 0.1 - 0.3 relative pressure range using Brunauer–Emmett–Teller (BET) model, while average pore diameters were determined by the Barrett-Joyner-Halenda (BJH) theory from both the adsorption and desorption branches. The mesopore volume was computed at 0.80 p/p0 and it corresponds to pores smaller than 11 nm. Thermogravimetric analyses were carried out using a Mettler Toledo GA/SDTA851e equipment, under a 80 mL/min synthetic air flow. FT-IR spectra were acquired using a Bruker Tensor 27 spectrometer and KBr pellets. UV-Vis spectra were recorded on an Ocean Optics USB 4000 spectrometer.

RESULTS AND DISCUSSION Physico-chemical characterization



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A full structural and textural characterization on both mesoporous carriers and metoprolol loaded samples was carried out in order to identify the relevant properties affecting drug release kinetics. The ordered mesopore array, for either carriers or drug-loaded materials was evidenced using small-angle XRD (Fig. 1). The pristine silica carriers exhibit at least three well-defined Bragg reflections, which were indexed in the hexagonal P6m symmetry group in the case of MCM-41 and SBA-15 materials and in the cubic Ia3d symmetry group for MCM-48. 34 The introduction of organic moieties led to a decrease of the intensities of the Bragg reflections, which can be explained by an increase in electronic density inside the mesopores (Fig. 1 A, B and C). 35 Wide-angle XRD analysis of the drug-loaded hybrids (Fig. 1 D) shows no diffraction peaks, indicating that the drug molecules are only adsorbed inside the carrier channels, in amorphous state.

Fig. 1. Low-angle XRD analysis (A, B, C) of mesoporous carriers and drug-loaded samples and representative wide-angle XRD patterns (D) for the MTP-containing hybrids FT-IR spectroscopy has been carried out in order to confirm the presence of either grafted organic moieties, (Fig. 2 A) or of drug molecules in the drug-loaded samples (Fig. 2 B). The pristine mesoporous matrices present the characteristic IR vibrations: asymmetric and symmetric Si-O-Si stretching vibrations (~1090 cm-1 and at 800 cm-1, respectively), Si-OH stretching vibrations (960 cm-1) and the symmetric Si-O bending (465 cm-1).30 All samples also show the presence of physisorbed water (1640 cm-1) and of hydroxyl groups through the broad O-H stretching vibrations, centered at ~3425 cm1 . The presence of grafted organic groups is evidenced by the existence of C-H stretching vibrations ACS Paragon Plus Environment

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(2865-2980 cm-1) in the IR spectra of functionalized carriers (Fig. 2 A). IR bands characteristic for the various functional groups, such as carboxyl for PCA-MCM (1720 cm-1, C=O stretching vibration) or amine for APTES-SBA (broad band at 3300 cm-1, N-H stretching vibration) could also be identified (Fig. 2 A). Both the characteristic vibrations of the carriers and those associated with MTP molecules (2990-2855 cm-1 region for the C-H stretching and the 1555 – 1405 cm-1 “fingerprint” region for C-H bending and C=C stretching vibrations) could be identified in the FT-IR spectra of the drug-loaded samples, (Fig. 2 B) confirming the presence of the biologically active substance after the drug-loading procedure.

Fig. 2. FT-IR spectra of mesoporous carriers (A) and drug-loaded samples (B) Quantitative results concerning the amount of grafted organic groups for the functionalized silica matrices were obtained using TG analysis (see Supporting Information Fig. S2, Fig. S3). The molar ratios of silica to organic groups were computed from the total mass loss, by subtracting the contribution of physisorbed water in the 50-180 °C temperature range (Table 1). Nitrogen adsorption-desorption isotherms (Fig. 3) for both pristine and functionalized mesoporous carriers present hysteresis loop and are type IV, indicating that the samples are mesoporous. The grafting of organic molecules onto the silica pore walls results in a reduction of both adsorbed gas volume and average pore size (Fig. 3 A, C). A similar reduction of the average pore size and adsorbed gas volume can be noticed after drug loading, indicating that the biologically active substance is adsorbed into the matrix mesopores through interactions with the pore walls (Fig. 3 B, D). The specific surface area of the mesoporous carriers (Table 1) presents high values, between 850-1150 m2g-1 for all samples, with the exception of aminopropyl-functionalized supports. The lower specific surface area values of APTES-MCM might be explained by a partial blocking of the mesopores entrances, an effect already noted in the literature.9 Following the drug loading procedure, the porosity is greatly reduced, leading to the conclusion that the MTP molecules are adsorbed inside the support mesopores.



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Fig. 3. Nitrogen adsorption-desorption isotherms of MCM-41 (A) and SBA-15 (C) type mesoporous silica carriers and drug-loaded samples and their corresponding pore size distribution curves (B, D) Table 1. Textural parameters and silicon to organic moieties ratio for mesoporous carriers and drugloaded samples Sample MCM-41 APTES-MCM MPTES-MCM Ph-MCM PCA-MCM MCM-C14 MCM-48 SBA-15 APTES-SBA

Si/OM (mol) 8.9 12.5 12.6 8.6 2.7

*

SBET (m2g-1) 960 620 849 1140 850 775 971 870 285

Carriers dBJH ads dBJH des (nm) (nm) 2.8 2.8 2.2 2.8 2.3 2.3 2.3 2.3 2.3 2.3 2.4 2.4 2.1 2.1 9.6 6.6 7.4 5.8

Vmeso (cm3g-1) 0.81 0.30 0.48 0.56 0.45 0.61 0.59 1.16 0.51

SBET (m2g-1) 582 39 171 1.5 188 7 316 334 66


Drug-loaded samples dBJH ads dBJH des Vmeso (nm) (nm) (cm3g-1) 2.0 2.0 0.28 # -# 0.03 2.1 2.1 0.10 -# -# 0.00 2.0 2.0 0.10 -# -# 0.08 1.5 1.5 0.14 8.1 6.3 0.61 6.8 5.4 0.11

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*OM=organic moieties; #

the pores are completely filled with drug molecules

Metoprolol delivery kinetics The drug delivery profiles from all mesostructured carriers were obtained in phosphate buffer solution, pH 7.4, at 37°C and compared with MTP dissolution in the same medium. The cumulative drug release versus time plots (Fig. 4, 5) show that in all cases the MTP delivery from mesoporous carriers corresponds to the case III of drug release classification as reported by Ye et al.36 This case consists of a high initial burst stage (>30% drug released) followed by steady-state release. Case III release is desired for system combining both a strong initial dose and controlled release profile. Experimentally, a complete MTP recovery was noticed for all drug-loaded materials after 24 h. In all cases, the release from mesoporous matrices is significantly slower than the drug dissolution. The influence of grafted organic groups was studied by comparing the release profiles from various functionalized MCM-41 carriers with pristine MCM-41 sample and the drug dissolution (Fig. 4). The lowest burst release was found for the pristine MCM-41 and PSA-MCM or MPTES-MCM samples. Functionalization with hydrophobic phenyl groups led to comparable release profiles to the MTP@MCM-41 material. The aminopropyl functionalized carriers present the highest burst release, around 90% of the drug being recovered after 15 minutes. Interestingly, the cumulative burst release varies proportional to the pKa values of the organic or silanol groups. This fact could be explained by electrostatic interactions between the positively charged MTP molecules (at pH 7.4) and the silanols or organic groups, with stronger attractive interactions (lower surface group pKa values) yielding a lower MTP amount released during the burst regime.

Fig. 4. The MTP release profiles from functionalized MCM-41carriers in comparison with the drug dissolution. Symbols and lines denote experimental points and fitted data, respectively. A comparison of the drug release from pristine mesoporous silica (Fig. 5) highlights the influence of pore size and geometry on the drug release kinetics. The MTP delivery from hexagonallyordered MCM-41 and SBA-15 carriers is similar, with the burst release stage being completed after 1530 minutes. In contrast, the drug release from the MCM-48 support with interconnected open pores shows a more gradual transition between the burst and steady-state release stages (Fig. 5 C), denoting a different transport mechanism. The lowest amount of MTP released in the burst phase was noticed for the MCM-41 carrier with 2.8 nm pore size. Supports with either higher or lower average pore size presented an increase of the burst stage in comparison with MCM-41 (Fig. 5 D, E vs. B). The existence of an optimum pore size value could be rationalized based on the size of MTP molecule, having a ACS Paragon Plus Environment


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length of ~1.6 nm. Thus, the smaller pores of MCM-C14 might lead to steric hindrance effects, while the larger pores of SBA-15 promote MTP diffusion.

Fig. 5. Cumulative MTP release profiles from pristine silica carriers and APTES-SBA in comparison with drug dissolution. Symbols and lines denote experimental points and fitted data, respectively. The drug release data were fitted using a theoretical kinetics model developed by Zeng et al., 27 which considers both the pore diffusion / convection of molecules from the mesoporous matrix and drug - carrier supramolecular interactions. The transport of organic molecules through pore diffusion or convection can be approximated using a first-order kinetics equation, with the rate constant ks.37 Regarding drug-carrier interactions, the drug molecules which directly interact with the support are termed associated and they need to be dissociated from the carrier prior to release (Fig. 6). Both the association and dissociation processes are assumed to be reversible and to follow first-order kinetics.27 The experimentally obtained MTP release profiles have been described using eq. 1, which includes two exponential functions.

1

1

(eq. 1)

where m(t) and m(0) are the cumulative drug release at time t and the initial drug amount, respectively; ks represents the rate constant for the diffusion/ convection process; kon and koff are the rate constants for association and dissociation from the carrier, respectively and , !

" 4 $ /2 are the negative eigenvalues of the linear system used to obtain eq. 1. 27

The parameters of the theoretical model can be used to explain the release profiles. The rate constant for diffusion/convection, ks, is proportional to the release rate during the initial burst stage, while increasing the dissociation rate constant, koff, leads to faster release during the steady-state regime. 27 The magnitude of the initial burst release depends on the equilibrium between association and dissociation and it can be described by the free energy difference between free and bound states, '( ) * ∙ ln / (eq. 2), where kB is Boltzman’s constant and T represents the temperature. Higher ∆G values correspond to larger initial burst release amounts (Fig. 6).


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Fig. 6. Schematic representation of kinetics model and the correlation of kinetics parameters with the shape of the drug release profile The values of the rate constants for all drug-loaded samples were determined by fitting the experimental release data to eq. 1. The free energy difference between associated and dissociated MTP molecules were then calculated using eq. 2 (Table 2). A good fitting of the experimental results to the theoretical model was obtained in all cases (R2≥0.99). For comparison, the MTP dissolution was fitted with the same model, even though first-order kinetics were sufficient in this case. Quantitative information regarding the drug rate of diffusion during the burst stage can be found by analyzing the ks parameter (Table 1). The drug-loaded samples can be roughly classified into two groups, with slower burst release rates (ks ≈ 0.3 min-1) for MCM-41 / MCM-48 and with higher burst release rates (ks ≈ 0.6 min-1) for the MCM-41 carriers functionalized with organic groups. Thus, organic functionalization of MCM-41-type carriers can be a viable strategy to increase the drug diffusion rates. The same effect is less pronounced for SBA-15-type carriers, which show only a small increase in diffusivity after functionalization, likely due to their larger pore size. For samples employing pristine carriers, ks is also inversely correlated to the specific surface area (Table S1). ∆G parameter is proportional with the magnitude of the burst release stage. The positive ∆G values obtained for all samples indicate that the interactions between the drug and supports are not very strong, as dissociation is favored (koff>kon). Nonetheless, relatively lower values (∆G < 5.5⋅10-21 J) are obtained for MCM-41, MCM-48 and MCM-41 modified with propylsulfonic acid groups. At the other extreme, aminopropyl functionalized MCM-41 or SBA-15 exhibit the highest ∆G values and therefore the highest amount of MTP released during the burst stage. ∆G varies proportional to the pKa values of the surface groups, indicating that it is proportional to the strength of electrostatic interactions between drug molecules and carrier (Fig. 7). ∆G is also correlated with the average pore diameter for samples containing pristine silica (Table S1).



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Fig. 7. The correlation between ∆G and the pKa values of the organic substituents or silanol groups The carrier-drug interactions affect the value of the koff parameter, which is proportional to the release rate during the steady-state regime. Higher koff values and consequently faster delivery during steady-state were obtained for the pristine carriers. MCM-48 exhibits the highest values, at 0.0116 min1 . Grafting organic groups onto the silica matrix leads to a reduction of koff in comparison with the pristine mesoporous material. Moreover, the koff decrease is proportional to the acidic nature of the organic group, with more acidic groups having lower parameter values and thus slower release rate during steady-state. (Table 2) Table 2. Kinetics release parameters for the drug-loaded samples Sample ks(min-1) koff (103 min-1) kon (103min-1) 2.7187 25.24 0.39 MTP 0.3912 3.89 1.09 MTP@MCM-41 0.7736 3.79 0.41 MTP@APTES-MCM 0.7808 2.38 0.44 MTP@PCA-MCM 0.5686 3.80 1.03 MTP@Ph-MCM 0.6988 2.15 0.60 MTP@MPTES-MCM 0.5925 1.05 0.33 MTP@PSA-MCM 0.3619 11.61 3.98 MTP@MCM-48 0.6465 3.83 0.74 MTP@MCM-C14 0.4128 1.78 0.22 MTP@SBA-15 0.4425 1.54 0.17 MTP@APTES-SBA

∆G (10-21 J) 17.83 5.46 9.52 7.23 5.60 5.48 4.97 4.59 7.06 8.93 9.35

R2 1.0000 0.9903 0.9998 0.9949 0.9999 0.9970 0.9984 0.9902 0.9984 0.9964 0.9983

CONCLUSIONS We studied the influence of mesoporous silica functionalization with organic moieties, pore size and geometry on the drug release kinetics of a model therapeutic agent, metoprolol. The drug release kinetics was fitted using a three-parameter model and its parameters were correlated with the structural and textural properties of the silica carrier. All mesoporous supports preserved their mesostructure upon drug loading and could act as metoprolol reservoirs. The release profiles of all samples exhibit an initial burst release followed by a sustained steady-state release regime. The metoprolol release profile was described using a theoretical kinetics model through three parameters, the rate of burst release, the fraction of drug released during ACS Paragon Plus Environment

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this stage and the rate of the steady-state stage. We found that the three parameters describing the drug release can be independently tailored by changing the textural or surface properties of the mesoporous carriers. Thus the release rate during the burst stage can be lowered by using pristine MCM-41 carrier or increased by silica functionalization with any organic group, with the highest rate obtained for positively charged aminopropyl moieties. The burst release rate mainly depends on the carrier specific surface area and the presence of functional groups grafted inside the mesopores. The extent of metoprolol released during the burst stage is proportional to the average pore size of carrier, with lower values for MCM-41 or MCM-48. The pKa values of functional groups are directly proportional with the drug released amount during the burst stage, acidic groups leading to a reduction of this. Thus the carrier pore size and the electrostatic interactions between the positively charged metoprolol molecules and the organic groups grafted onto the mesoporous matrices influence the drug release amount during the burst stage. High release rate during the steady-state regime is correlated with the cubic mesopore array of MCM-48 matrix. Low release rate during the steady-state stage can be achieved by grafting organic groups onto MCM-41-type matrix. ASSOCIATED CONTENT Supporting Information. Thermogravimetric analyses, maximum experimental metoprolol release data, correlation between the textural features of mesoporous carriers and the kinetics model parameters etc. This material is available free of charge via the Internet at http://pubs.acs.org. ACKNOWLEDGEMENTS The authors are grateful for the financial support of the Romanian project PCCA no. 131/2012. REFERENCES (1) Vallet-Regi, M.; Rámila, A.; del Real, R.P.; Pérez-Pariente, J. A New Property of MCM-41: Drug Delivery System, Chem. Mater. 2001, 13, 308-311. (2) Vivero-Escoto, J.L.; Slowing, I.I.; Trewyn, B.G.; Lin, V.S.Y. Mesoporous Silica Nanoparticles for Intracellular Controlled Drug Delivery, Small 2010, 6, 1952-1967. (3) Aiello, R.; Cavallaro, G.; Giammona, G.; Pasqua, L.; Pierro, P.; Testa, F In Studies in Surface Science and Catalysis, Proceedings of the 2nd International FEZA (Federation of the European Zeolite Associations) Conference, Taormina, Italy, Sept 1-5, 2002; Aiello, G.G. R., Testa, F., Eds., Elsevier: Amsterdam, 2002. (4) Tang, F.; Li, L.; Chen, D. Mesoporous Silica Nanoparticles: Synthesis, Biocompatibility and Drug Delivery, Adv. Mater. 2012, 24, 1504-1534. (5) Li, Z.; Barnes, J.C.; Bosoy, A.; Stoddart, J.F.; Zink, J.I. Mesoporous Silica Nanoparticles in Biomedical Applications, Chem. Soc. Rev. 2012, 41, 2590-2605. (6) Colilla, M.; Gonzalez, B.; Vallet-Regi, M., Mesoporous Silica Nanoparticles for the Design of Smart Delivery Nanodevices, Biomater. Sci. 2013, 1, 114-134. (7) Feng, X.; Fryxell, G.E.; Wang, L.-Q.; Kim, A.Y.; Liu, J.; Kemner, K.M. Functionalized Monolayers on Ordered Mesoporous Supports, Science 1997, 276, 923-926. (8) Sevimli, F.; Yılmaz, A. Surface Functionalization of SBA-15 Particles for Amoxicillin Delivery, Microporous Mesoporous Mater. 2012, 158, 281-291.



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TOC Graphic


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Low-angle XRD analysis (A, B, C) of mesoporous carriers and drug-loaded samples and representative wideangle XRD patterns (D) for the MTP-containing hybrids Fig. 1 129x105mm (300 x 300 DPI)



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FT-IR spectra of mesoporous carriers (A) and drug-loaded samples (B) Fig. 2 69x30mm (300 x 300 DPI)


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Nitrogen adsorption-desorption isotherms of MCM-41- (A) and SBA-15- (B) type mesoporous silica carriers and drug-loaded samples and corresponding pore size distribution (B, D) Fig. 3 149x140mm (300 x 300 DPI)



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The MTP release profiles from functionalized MCM-41carriers in comparison with the drug dissolution. Symbols and lines denote experimental points and fitted data, respectively. Fig. 4 79x61mm (150 x 150 DPI)


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Cumulative MTP release profiles from pristine silica carriers and APTES-SBA in comparison with drug dissolution. Symbols and lines denote experimental points and fitted data, respectively. Fig. 5 79x61mm (150 x 150 DPI)



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Schematic representation of kinetics model and the correlation of kinetics parameters with the shape of the drug release profile Fig. 6 89x50mm (300 x 300 DPI)


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The correlation between ∆G and the pKa values of the organic substituents or silanol groups Fig. 7 59x44mm (300 x 300 DPI)


Correlation of Mesoporous Silica Structural and Morphological

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