Microporous and Mesoporous Materials 132 (2010) 258–267

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Microporous and Mesoporous Materials

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Controlled release of metoprolol tartrate from nanoporous silica matrices

Elena Ghedini a, Michela Signoretto a,*, Francesco Pinna a, Valentina Crocellà b, Luca Bertinetti b,Giuseppina Cerrato b

a Department of Chemistry University Cà Foscari, Consortium INSTM-RU of Venice, Calle Larga Santa Marta, 2137, 30123 Venice, Italyb Department of Chemistry IFM and NIS – Centre of Excellence, University of Torino, via P. Giuria, 7, 10125 Torino, Italy

a r t i c l e i n f o a b s t r a c t

Article history:Received 5 November 2009Received in revised form 2 March 2010Accepted 3 March 2010Available online 15 March 2010

Keywords:Nanoporous silicaTextural propertiesDrug delivery

1387-1811/$ - see front matter � 2010 Elsevier Inc. Adoi:10.1016/j.micromeso.2010.03.005

* Corresponding author. Tel.: +39 0412348650; faxE-mail address: miky@unive.it (M. Signoretto).

A series of nanoporous silica matrices (a silica gel matrix and two ordered mesoporous silica) have beeninvestigated as potential carriers for the controlled release of metoprolol tartrate a selective b1 receptorblocker used in the treatment of several diseases of the cardiovascular system. Particular attention wasdevoted to the optimisation of a reproducible and fast synthetic procedure. The textural properties, struc-ture and chemical nature of the porous surfaces were characterised by N2 physisorption, X-ray diffrac-tion, HR-TEM and FTIR analyses. The delivery profiles were collected in vitro in physiological solutionat pH 7.4.

It has been possible to observe a close correlation between the drug release kinetic and the texturalproperties of the carriers.

� 2010 Elsevier Inc. All rights reserved.

1. Introduction

The realisation of a new pharmaceutical form involves severalsteps, among which the selection of the excipients (stabilizingagents, lubricating, binding agents, sweetening, colouring, aroma-tizing, . . . ) that both improve and favour the acceptability of thefinal product by the patient. The choice of the carrier is of funda-mental importance as in most cases it affect the transfer modalityof the drug to the organism. With traditional formulations thedelivery of the active agent is total and immediate: it reaches amaximum value that could be out of the therapeutically range. Inthe last years many efforts have been devoted to the developmentof new formulations that can control both rate and period of drugdelivery. Using controlled drug delivery systems (DDS) designedfor long-term administration, the drug level in the blood is keptconstant for long time between the desired maximum and mini-mum value. Other important advantages of using controlled-deliv-ery systems can include: (i) the need for fewer administrations, (ii)optimal use of the drug at issue, and (iii) increased patientcompliance.

An inert, biocompatible and stable matrix has to be adopted inthe design of an ideal DDS. The traditional carriers currently em-ployed are either natural or synthetic polymers (such as microcap-sules, cells, lipoproteins, liposomes, . . .), but an increasing numberof studies is actually addressed to the development of alternativesupports, such as silica-based materials that have attracted a lot

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of interest [1–8]. Silica matrices show high biocompatibility–bio-degrability [1,9] (these materials are biodegradable to monosilicicacid (in the long run) in the intestine) and resistance to microbialattack; these systems exhibit higher mechanical strength,enhanced thermal stability, and negligible swelling in organicsolvents if compared to most organic polymers. Moreover, phys-ico-chemical and textural properties of silica can be modulatedad hoc by the choice of a tailored synthetic approach. Among thedifferent techniques adopted for silica preparation, the sol–gel pro-cess is particularly attractive, as it permits to control the physico-chemical features (textural properties, hydrophilic–hydrophobiccharacter) of the material simply through the proper choice ofthe synthesis parameters (such as composition of precursors mix-ture, catalysts, pH range, ageing). The relatively mild processingconditions allow the incorporation of the bioactive molecule intothe matrix in a one-step process [10,11]. In the case of silica-baseddelivery systems, the kinetic release of the drug is ruled by severalfactors and an important key-role is played by both physico-chem-ical nature of silica surface and the interaction between the carrierand the active molecule. These interactions can be of different nat-ure: chemical interaction (hydrogen or electrostatic bond) and/orsteric interaction related with the texture of the carrier. This lastinteraction is very marked in the case of ordered nanoporous silica,like MCM-41, SBA-15 and so on.

Recently we have studied several silica systems as carrier forsustaining the drug release of ibuprofen. We have investigatedthe behaviour of methyl-modified silica matrix prepared by asol–gel approach or ordered silica matrices pure and modified withaminopropyl groups [12–14].

Fig. 1. Molecular model of metoprolol tartrate.

E. Ghedini et al. / Microporous and Mesoporous Materials 132 (2010) 258–267 259

In the present work we have focused the attention on both syn-thesis and characterisation of silica carriers for the controlled re-lease of metoprolol tartrate (MPT) (see Fig. 1). Several points ofnovelty are presented in this paper, as reported in the following:

(i) For the first time, MPT has been used as drug model todevelop a DDS by using silica as carrier. Metoprolol is fre-quently employed to alleviate several diseases of the cardio-vascular system and its administration by means of aprolonged DDS is desirable, as confirmed by the controlledrelease formulations of metropolol present on the market.

(ii) Two innovative and reliable techniques have been optimisedfor the synthesis of the investigated drug-silica systems: aone-pot sol–gel approach and an incipient wetness impreg-nation method. The drug is usually adsorbed on the (silica)carrier by post-synthesis wet impregnation.

(iii) A thorough comparison between a silica gel and two meso-porous carriers is here reported.

Aim of our work has been the investigation of the effect of bothtextural and physico-chemical properties of the carriers on thedrug delivery behaviour. The target has been pursued through adepth analysis and comparison of three different silica matrices.

2. Experimental

2.1. Materials

Tetraethoxysilane (TEOS) (Aldrich, 98%), NaOH (Fluka, 97%),EtOH (Fluka, 99%), Tris Buffer Saline (Fluka), HCl (Fluka, 37%),Cetyltrimethyammonium bromide (CTA-Br) (Fluka, 99.5%), Pluron-ic 123 (Aldrich), Metoprolol Tartrate (MPT, 99%). All reagents havebeen used as received.

2.2. Synthesis

In order to ensure the drug stability after adsorption, all theMPT/Silica composites were prepared by using mild synthesis con-ditions (room temperature, gentle stirring. . .) as described in detailin the following sections.

2.3. Silica gel

Drug/silica composites were synthesised by a one-step sol–gelprocess. In a typical procedure, the silica precursor (TEOS) wascombined with ultra pure water (acidified with the addition of afew drops of HCl 0.01 M) in the opportune molar ratio (1TEOS:5H2O) and the mixture was homogenised by sonication. A water(milliQ water) solution of metoprolol tartrate (40 g/L) was addedto the obtained sol under continuous stirring in order to favourthe homogeneous dispersion of the drug in the final material. Eachindividual sample (silica + MPT) was obtained by dispensing 1 mLof the sol into a polyethylene cylindrical vial (diameter: 1.2 cm,thickness: 1 cm) the monolithic and homogeneous tablets wereleft to age in a closed environment at room temperature for oneday, in order to ensure the complete reticulation of the gel andto reach a constant weight. Each tablets (diameter: 1.0 cm; thick-ness: 0.5 cm) contains 80 mg of MPT (real amount). The MPT realcontent was verified by means of TG analyses (TG analyses wereperformed in the 25–600 �C interval using a NETZSCH STA 409instrument in flowing air with temperature ramp set at 10 �C/min).

2.4. Mesoporous samples

MCM-41 and SBA-15 matrices were synthesised as reported in aprevious work [15].

The drug was embedded on the as-synthesised carriers byincipient wetness impregnation. In a typical synthesis, an oppor-tune amount of metoprolol tartrate is dissolved in ethanol. Thenthe drug-containing solution is added to the silica support contain-ing the same pore volume as the volume of solution that wasadded. Capillary action draws the solution into the pores. Thedrug/silica composite was then dried at 50 �C for 12 h to drive offthe volatile components within the solution. The silica/drug sam-ples (MCM-41 + MPT or SBA-15 + MPT) were conformed (pressure2.5 Ton for 5 min) as 0.3 g capsules (diameter 1.0 cm; thickness:0.5 cm, MCM-41 + MPTp and SBA-15 + MPTp).

All the capsules contain 80 mg of MPT.This method was used to adsorb MPT also in a commercial silica

(Akzo, 329 m2/g) used as reference frame.

2.5. Delivery release (in vitro study)

In vitro study of metoprolol release from the substrates wasperformed as follows.

In a typical experiment, a capsule was soaked in the opportunevolume (10 mL) of a saline solution (Tris Buffer Saline Solution) atpH 7.4 and maintained at 37 �C. Samples of 1 mL were removed atpredetermined times and replaced by the same volume of the freshmedium. The drug concentration in the liquid phase was evaluatedby UV spectrometry at 274 nm (Perkin–Elmer k40 instrument).Calibration curve of metoprolol was determined by taking absor-bance vs. metoprolol concentration between 0 and 2000 ppm asreference parameters. The effective concentration in solution wascalculated on the basis of the following equation [16]:

Ceff ¼ Capp þmV

Xt�1

1

Capp

260 E. Ghedini et al. / Microporous and Mesoporous Materials 132 (2010) 258–267

where Ceff is the corrected concentration at time t, Capp is the appar-ent concentration at time t, v is the volume of sample taken and V isthe total volume of the dissolution medium.

In order to check the reliability of the collected data, a test wascarried out in the previously reported conditions by taking a singlesample from the dissolution medium at the end of the releaseexperiment. We have obtained the same drug concentration valueof that calculated on the basis of the formula for a drug release teststudied with multiple sampling.

In order to check the reproducibility, each release test has beencarried out three times by collecting, each time, the data analysissimultaneously from two identical tablets.

2.6. Characterisation

Specific surface area and pore size distribution were obtainedfrom N2 adsorption–desorption isotherms at �196 �C (MICROMER-ITICS ASAP 2000 Analyser). Surface area was calculated by the BETequation [17], whereas the mesopore size distribution was deter-mined by the BJH method [18], applied to the N2 adsorption iso-therm branch. Before the N2 adsorption gas experiment all thesamples were outgassed at RT for 12 h.

X-ray diffraction patterns of the samples were obtained on aPhilips PW 1820/00 instrument with Cu Ka radiation at 40 kVand 30 mA.

FTIR spectra were obtained on a BRUKER 113v spectropho-tometer (2 cm�1 resolution, MCT detector). All silica-based sam-ples were inspected in the form of self-supporting pellets (�10mg cm�2). All samples were activated in controlled atmosphereat beam temperature (BT, namely�50 �C) in quartz cells connectedto a gas vacuum line, equipped with mechanical and turbomolecular pumps [residual pressure p < 10�5 Torr (760 Torr =101325 Pa)]. Samples have been treated (i.e., evacuated) only atBT from 1 up to 60 min in order to get rid of all physisorbedspecies.

HR-TEM images were obtained with a JEOL 3010-UHR instru-ment (acceleration potential: 300 kV; LAB6 filament) equippedwith an Oxford INCA X-ray energy dispersive spectrometer (X-

Fig. 2. Absorbance FTIR spectra in the 4000–1500 cm�1 range for the plain silica gel (pur1350 cm�1 spectral region.

EDS) with a Pentafet Si(Li) detector. Samples were ‘‘dry” dispersedon lacey carbon Cu grids.

3. Results and discussion

3.1. Silica gel

The silica gel samples were prepared by a one-step sol–gelapproach: the drug was introduced on the liquid sol with the re-quested amount of water and, after condensation/drying, transpar-ent, monolithic and homogeneous tablets have been obtained. Thisoptimised process turns out to be an efficient way to obtain, in arelatively short time, a silica/drug composite available for deliverystudies. Each capsule contains 80 mg of metoprolol tartrate; thisamount has been selected on the basis of the content of MPT onthe pharmaceutical formulations actually available (80–100 mg)in commerce. Higher concentration of the bioactive molecule couldbe incorporated in the gel after the proper optimisation of the syn-thetic procedure (the maximum concentration that can be reachedis strictly correlated with its solubility in water).

Firstly, the silica gel system has been characterised by means ofFTIR spectroscopy in order to obtain information about (i) surfaceterminations (i.e., intrinsic and/or added functionalities) and (ii)the nature of the interaction between the silica surface and theMPT embedded drug.

The comparison between the FTIR spectra obtained after 1 h ofevacuation at RT of pure silica gel and of composite silica gel/MPTsamples is reported in Fig. 2. The temperature of the thermal dehy-drating treatment has been kept almost close to the physiologicaltemperature (i.e., �37 �C), in order to avoid any decomposition/alteration of the drug itself. It is possible to observe that, in low-medium dehydration conditions, the typical OH pattern of thesilica matrix is strongly affected by the presence of the bioactivemolecule. In fact, the characteristic band ascribable to ‘‘free”Si–OH species (mOH � 3745 cm�1) is totally absent in the case of sil-ica + MPT sample. On the other hand, the envelope located in the3500–2400 cm�1 spectral region, mainly due to OH species inter-acting by H-bonding, represents now the main component [19], to-

e) and containing metoprolol tartrate (+MPT); inset: magnified section of the 1750–

E. Ghedini et al. / Microporous and Mesoporous Materials 132 (2010) 258–267 261

gether with a huge envelope (located at lower m, 3000–2800 cm�1)and due to the mCH stretching vibration of all CH-containing surfacespecies. The Si–O–Si modes characteristic of the silica matrix (lo-cated in the 2100–1600 cm�1 region) are still present, indicatingthat the original structure has been partly retained despite theintroduction of the drug molecule. Moreover, it is worth notingthat the presence of additional bands on the profile of the silica/drug composite are due to the presence of MPT. The bands locatedat high wavenumbers (envelopes at �3450 cm�1 and �2800–3000 cm�1) can be ascribed to the stretching vibrations of eitherNH and/or CH species. On the other hand, other spectral compo-nents are evident in the 1750–1350 cm�1 range, most likely dueto (i) the mC=O stretching vibration of carboxylic acid (�1700cm�1), (ii) the vibration of C@C bond of the aromatic ring(� 1600 cm�1), (iii) the mOCO stretching (asymmetric and symmet-ric) modes of all carboxylate species (�1580 and �1400 cm�1,respectively), and (iv) the asymmetric dCH3 deformation (�1460cm�1) [20,21]. Moreover, the other two components located at�1570 and �1515 cm�1 are ascribable, on the basis of their spec-tral behaviour and of the literature [21], to the (asymmetric andsymmetric) bending modes of all NH-containing species. All thesefeatures further confirm the presence of the bioactive molecule assuch on the matrix interacting with the silica surface by hydrogenbond.

The adsorption/desorption isotherms and the pore distributionsof the silica gel and of the silica gel + MPT systems are reported inFig. 3, and the main data are summarised in Table 1: it is evidentthat the textural features of the silica gel are strongly influencedby the MPT presence. Both silica samples exhibit an irreversibletype IV isotherm; in the case of the pure silica gel the capillary con-

Fig. 3. N2 adsorption/desorption isotherm and BJH pore size

Table 1Textural data for the silica supports and for the drug loaded samples.

Sample BET Surface area (m2/g) Pore diameter (nm

Silica gel 400 3.0Silica gel + MPT 305 6.5MCM-41 1157 2.5MCM-41p 785 2.5MCM-41 + MPT 857 2.2MCM-41 + MPTp 360 2.2SBA-15 995 7.0SBA-15p 409 6.0SBA-15 + MPT 457 5.8SBA-15 + MPTp 300 3.6–5.3a

densation in mesopores is located at low relative pressure (�0.4) inagreement with the presence of small mesopores (3 nm), as con-firmed by the BJH pore size distribution. On the other hand, the iso-therm of the silica + MPT system displays a considerable inflectionoccurring at high relative pressure in the 0.6 < p/p0 < 0.9 range: thissuggests the presence of large mesopores (�7 nm), as it can be ob-served in the BJH distribution curve. This result highlights thestrong influence of the MPT drug on the silica gel reticulation pro-cess and in the silica gel network.

The drug delivery behaviour was investigated as reported inSection 2. The drug release after 1, 10 and 30 days after the synthe-sis of the silica + MPT capsule has been studied in order to evaluatethe effect of the ageing on the delivery behaviour. The desorptionprofile after 10 and 30 days (not reported for the sake of brevity)coincides perfectly with that obtained after 1 day; this is, conse-quently, the time necessary to complete the reticulation of thegel. This interesting result indicates the rapid availability of the sil-ica + MPT sample and its stability during the time. Fig. 4 shows thedelivery profile relative to a 1 day-aged capsule. It is possible to ob-serve that the release rate is very fast and almost all the drugembedded on the silica carrier is delivered in the first 24 h. The re-lease profile is very similar to that obtained for the commercial sil-ica employed as reference material: still, there is a slightimprovement in the case of the silica + MPT carrier and the deliv-ery continues until the 24 h.

As previously reported [13], the drug delivery from the silicaxerogel matrices is essentially ruled by a diffusion process. Themain factors determining the diffusion and consequently the re-lease rate are the morphology/structure of the carrier and theinteraction between the silica surface and the bioactive molecule.

distribution of silica gel and of silica gel + MPT samples.

) Total pore volume (mL/g) Micropore Volume (mL/g)

0.70 0.200.52 0.000.90 0.100.60 0.080.62 0.050.28 0.051.07 0.350.80 0.000.64 0.200.39 0.00

Fig. 4. Metoprolol (%) release from under investigation as a function of theimmersion time in physiological solution (n = 3, mean ± sd).

Fig. 5. N2 adsorption/desorption isotherm (a) and BJH pore size distribution (b) ofMCM-41, MCM-41p, MCM-41 + MPT and MCM-41 + MPTp; (p = pressed samples).

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In the present case, MPT interacts with surface silanol groupsonly by weak hydrogen bonds that are not able to strongly retainthe drug; moreover, the texture of the sample is absolutely un-adapted for a real control of the drug delivery process. In fact,the amorphous structure of the gel and its pore dimensions, verylarge if compared with the molecular size of MPT (�1.4 nm), favourthe rapid diffusion of the drug from the matrix into the physiolog-ical solution.

In order to better evaluate the effect of the texture and of themorphology of the silica supports on the delivery behaviour, theperformances in DDS of two ordered mesoporous silica have beeninvestigated.

3.2. Mesoporous carriers

Two ordered materials have been selected: MCM-41 and SBA-15.

These silica-based systems possess well known physico-chemi-cal properties and have been widely studied for their potentialapplications in several fields, involving selective adsorption–desorption processes: separation, chemical sensors, shape selectivecatalysis and, more recently, drug delivery [22–24]. Both matricesare characterised by a 2-D hexagonal organisation of pores that arecentred around 3 nm for MCM-41, and around 7 nm for SBA-15.The introduction of the active molecule in these carriers requireda post synthetic approach that has been developed in order toachieve a final procedure which could be reproducible, efficientand relatively fast to realize.

As reported in the experimental section, MPT was introduced inthe calcined silica by ‘‘incipient wetness impregnation”, startingfrom a solution containing the selected amount of drug. This meth-od permits an accurate control of the actual load of drug embeddedon the silica carrier and is, in our opinion, a reliable method to ob-tain embedded drug/silica systems. After drug loading, the com-posites were formed as tablets of comparable dimensions andweight, as reported in Section 2.

Samples texture was evaluated by N2 physisorption, X-ray dif-fraction and HR-TEM analyses. For the sake of clarity, we startreporting the results obtained in the case of the MCM-41 matrix.

Adsorption/desorption isotherms and pore size distributions ofMCM-41-based materials are reported in Fig. 5; the relevant tex-tural data are collected in Table 1.

In the case of the plain MCM-41 system, N2 physisorption mea-surement follows a type IV isotherm, without hysteresis loop be-tween the adsorption and the desorption branches, in goodagreement with literature data [25] relative to materials with sim-ilar pore size (�3 nm). The isotherm exhibits:

(i) an important adsorption at low relative pressure probablyassociated with the monolayer coverage of the pore wallsby nitrogen;

(ii) a second well-defined step uptake at approximately p/p0 =0.2–0.3, ascribable to the filling of the mesopores due to cap-illary condensation, followed by a plateau at p/p0 > 0.35.

The sharpness of the second step reflects a narrow and uniformdistribution of the pore size; this result will be further confirmedby transmission electron microscopy measurements. In the caseof the MCM-41 + MPT sample, the amount of adsorbed nitrogendecreases with a concomitant slight shift of the capillary condensa-tion to smaller values of p/p0. In fact, it is possible to observe thatthe BET surface area, very high for MCM-41 sample (1157 m2/g),exhibits a contraction of �25% after the addition of MTP, withthe parallel decreasing of the pore diameter (2.6 nm for plainMCM-41, 2.3 nm in the case of MCM-41 + MPT). Both effects canbe plausibly attributed to the presence of the drug into the mesop-ores. Despite changes of both surface area and pore size, the shapeof the isotherm is retained after the drug introduction, indicatingthat the mesoporous texture of the support has been preserved.MCM-41p and MCM-41 + MPTp (p = pressed sample) are charac-terised by an isotherm similar to that of the plain (unpressed)MCM-41 and MCM-41 + MPT systems: however, a significant de-crease in both volume and surface area is evident. This indicatesthat a partial collapse of pores structure occurs after the pressing

Fig. 6. X-ray diffraction patterns of MCM-41, MCM-41 + MPT, MCM-41p and ofMCM-41 + MPTp.

E. Ghedini et al. / Microporous and Mesoporous Materials 132 (2010) 258–267 263

action for both systems and this phenomenon is very pronounced,especially in the presence of the drug (MCM-41 + MPT sample).

In order to gain more information about the structure of thesamples and to better investigate the effect of the forming process(pressure application) on the original mesoporous structure andmorphology of the silica support, X-ray diffraction and HR-TEMhave resorted to: the diffraction patterns of MCM-41 and MCM-41 + MPT and of the corresponding pressed samples are reportedin Fig. 6. The diffraction profile of the pure silica system is charac-terised, in the low angle region, by an intense and well resolvedpeak associable with the reflection of the (1 0 0) plane, indicative

Fig. 7. HR-TEM images of the MCM-41 samples. (a) plain MCM-

of an ordered structure. In the 2h region between 3� and 6� otherpeaks are evident: they are typical of an hexagonal symmetry(p6 mm) of the pores. The pressed material (MCM-41 + MPTp)exhibits only a well-defined but less intense reflection, generatedby the (1 0 0) plane. This result confirms that the ordered structureof the MCM-41 is partially preserved despite the strong mechanicalaction.

As far as the morphology of the various MCM-41 samples isconcerned, the following can be noted:

– as for the plain MCM-41 system, the HR-TEM image reported insection (a) of Fig. 7 exhibits the typical shape of this silica-basedmaterial, made up of ordered particles of at least 200 nm size.Traces of an ordered ‘‘fringes” system can be easily observed,most likely due to the ordered pores characterising the material.When the MCM-41 powder is pressed, no evident difference inmorphology is observed: the image reported in section (b) ofFig. 7 confirms this assumption;

– in the presence of MTP, little differences with respect to thepure siliceous material are evident: in fact, as it can be seenin sections (c) and (d) of Fig. 7, the typical MCM-41 morphologyis still observable, even if aggregates have formed and the poresnetwork could be somehow seems less ordered.

Therefore, it is possible to conclude that the loading of MPT onMCM-41 samples by incipient wetness impregnation allows to ob-tain a final material that retains almost all the original morpholog-ical properties of the support. Moreover, on the basis of thetextural data (in particular, surface area and pore volume), it ispossible to state that partly of the drug is located in the poreschannel.

41; (b) MCM-4p; (c) MCM-41 + MTP; (d) MCM-41 + MTPp.

Fig. 8. Absorbance FTIR spectra in the 4000–1500 cm�1 range for MCM-41 and SBA-15 systems.

Fig. 9. Metoprolol tartrate molecule and pore channel of MCM-41.

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FTIR results confirm (see Fig. 8) the retention of the originalstructure of the silica network despite the introduction of the drug(as stated by the presence of the typical mSi–O–Si modes in the 2100–1600 cm�1 spectral region). Moreover, the band due to free OHgroups is partially consumed upon drug introduction: see the mOH

band located at �3745 cm�1, and due to the stretching mode ofsurface OH groups free from any interaction. This spectral compo-nent decreases a lot in intensity when MPT is introduced in the sil-ica system, indicating that the drug interacts with the silica surfaceat the expenses of these species, leading to the formation of spec-tral components ascribable to OH interacting by weak hydrogenbond: see the large envelope located at m < 3500 cm�1.

As for all the other IR components, apart those typical of the sil-ica network, they can be all ascribed to the presence of the drug it-self: these features have been discussed in the ‘‘Silica gel” sectionand can be here further confirmed. In particular, it is possible toobserve that the only significant difference between the two sys-tems (MCM-41 + MPT and SBA + MPT) concerns the presence ofthe band at 1700 cm�1. This band is present to a high extent onlyin the case of the MCM-41 system, because the carboxylate speciesderiving from MTP-drug are likely to be present in both associated(in the form of carboxylic acid) and dissociated (in the form of car-boxylate ions) forms. In the case of the other two systems (SBA-15and sol–gel silica) the same species are likely to be present only inthe dissociated form, leading to almost no IR spectroscopic evi-dence relative to the mC=O stretching vibration of carboxylic acid(�1700 cm�1).

Fig. 4 shows the desorption profile of MPT from MCM-41. Firstof all, it is possible to note that, at the end of the delivery experi-ment, both shape and dimensions of the tablet result un-changed.This confirms that the release process is due to the drug diffusionout of the tablet and not to the dissolution of the silica matrix. Thesame result was found for the other silica matrices. MPT desorbsfrom MCM-41 with a fast release rate in the first 5 h (35% of thedrug released), followed by a gradual and continuous delivery thatproceed till 48 h. This behaviour is very similar to that required foran ideal drug delivery systems [14] as represented in the figure bythe dashed line.

It can be recalled that both ordered texture (in particular, porechannel dimensions, see Fig. 9) and structure of the carrier maystrongly influence the drug diffusion from the carrier to the solu-tion. In fact, in the case of MCM-41 system, that possesses pore size(2.5 nm) comparable to that of MPT (1.4 nm), the diffusion processis controlled to a very high extent.

Unfortunately, in our experimental conditions we haveachieved only a partial release (�75 wt%) of the drug initially

embedded in the silica matrix. This results could be related withseveral factors, among which the overvaluation of the drug effec-tively introduced in the matrix but, more plausibly, it could be alsoassociated with the texture of the sample. In fact, part of the drugcould remain trapped inside the pores of the silica matrix, as a con-sequence of the pores occlusion after the compaction process.

In order to obtain a drug delivery profile similar to that of MCM-41 systems, but exhibiting higher percentage of final drug released,we have evaluated as potential carrier a mesoporous silica withlarger pore dimensions, i.e., a SBA-15 system.

By using the same procedure described for the MCM-41 mate-rial, 80 mg of MPT have been introduced in a SBA-15 system; thismaterial has been characterised in order to gain information aboutits physico-chemical properties and texture.

Surface area and porosity data obtained by physisorption anal-yses are reported in Table 1, whereas the N2 adsorption–desorptionisotherms and pore size distribution are shown in Fig. 10.

Upon nitrogen adsorption, SBA-15 exhibits an irreversible typeIV isotherm with a clear type-H2 hysteresis loop that is typical ofmaterials possessing cylindrical mesopores. The isotherm displaysa sharp inflection occurring at relative pressure in the 0.6 < p/p0 < 0.9 range, corresponding to the capillary condensation phe-nomenon which strongly suggests the presence of pores of med-ium size (�7 nm). The sharpness of this step indicates a uniformand narrow pore size, as it can be observed in the BJH distributioncurve. The introduction of MPT brings about a considerable de-crease of both surface area and pore volume, as confirmed by datareported in Table 1. The detrimental effect is more important thanin the case of the MCM-41 silica support: this fact is probably re-lated with the presence of micropores on the SBA-15 walls that to-tally disappear after the drug adsorption. In fact, as reported inTable 1, the consistent micropores volume fraction of the plainSBA-15 sample disappears almost completely in the SBA-15 + MPT system. Moreover, a decrease of the medium pore diam-eter can be observed, most likely attributed to the presence of thedrug inside the mesopores. The compaction of the samples carriesout a significant effect on the texture of both SBA-15 and SBA-15 + MPT: a considerable change in the shape of the hysteresisloop, indicating a less ordered and uniform pore organisation, isevident in particular in the case of the drug loaded system. Thisis also confirmed by the BJH curve: in fact, for this sample, the dis-tribution is broad and bi-modal.

X-ray diffraction profiles, in the low 2h region, for SBA-15 andSBA-15 + MPT and for the pressed systems are reported inFig. 11. The low angle XRD pattern of SBA-15 is characterised bythe presence of a prominent peak located at 2h � 0.8� and of an-other weak peak at 2h � 1.8�: they can be ascribed to the (1 0 0)

Fig. 10. N2 adsorption/desorption isotherm (a) and BJH pore size distribution (b) ofSBA-15, SBA-15p, SBA-15 + MPT and SBA-15 + MPTp; (p = pressed samples).

Fig. 11. X-ray diffraction patterns of SBA-15, SBA-15 + MPT, SBA-15p and of SBA-15 + MPTp.

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and (1 1 0) diffractions, respectively, associated with the 2-Dp6 mm hexagonal symmetry. After MPT introduction and compac-tion, the XRD profile of the material still exhibits the presence ofthe characteristic low angle reflections, due to the periodic orderedstructure of the hexagonal supports. However, there are some sig-

nificant differences between the diffraction profiles of SBA-15 + MPTp sample and that of the parent supports: in fact, the rel-ative intensity of X-ray reflections remarkably decreases, and thisfeature is accompanied by both a slight broadening and a shift tolower values of 2h of the peaks.

Therefore, it is possible to state that the ordered structure of thesilica support has been retained to a certain degree, but both N2

physisorption data and XRD analyses suggest that a degradationof the periodic mesostructure of silica supports might have oc-curred upon incorporation of MPT in the SBA-15: it is to note thatthis degradation is decidedly more pronounced than in the MCM-41 system.

The surface properties and the nature of the interaction of thedrug with the silica surface were investigated also in this case byFTIR spectroscopy; the absorption profiles are reported in Fig. 8.The spectral profiles of both pure and modified SBA-15 samplesin the 4000–1500 cm�1 region are very similar (see Fig. 8) to thatexhibited by the corresponding pure and modified MCM-41 sam-ples, so that it can be concluded that MPT interacts with the silicamatrix by hydrogen bond.

Fig. 4 illustrates the release of MPT from SBA-15 as a functiontime. The collected data indicate a significant difference in the re-lease profiles if we compare the behaviour of the SBA system withthat of the MCM-41.

The delivery rate increases considerably when SBA-15 is used ascarrier, as �65% of the loaded drug is released in the first 5 h ofimmersion in physiological solution; moreover, the total amountof drug released (85%) is larger than in the case the other mesopor-ous system. Despite this last positive result, the delivery behaviourexhibited by the SBA-15 + MPT tablet is not proper for a controlleddrug delivery system. As MPT interacts with the silica surface onlyby hydrogen bond, we can plausibly consider that this result can beassociated whit the texture of the carrier, in particular with its poredimensions (6 nm), which are larger if compared with the drugmolecular dimensions.

To shed some light on this aspect, HR-TEM analyses of the dif-ferent SBA-15 samples have been carried out and the relevant re-sults are reported in Fig. 12.

Plain SBA-15 samples present a highly ordered morphology: seesection (a) of Fig. 12, in which large particles (dimensions > 200 nmsize) exhibiting highly ordered traces of the hexagonal pores net-work constituting the silica matrix. When plain SBA-15 is com-pacted into tablets, the pressing process brings about somemodifications, namely tending to disrupt the particles contourseven if the ordered pores structure is still retained (see section(b) in Fig. 12). The presence of MTP in the SBA-15 material resultsin a similar modifying effect, maybe more effective on the obstruc-tion of the pores: see for instance section (c) in Fig. 12, in whichonly the pores are only partly still observable. On the other hand,a much more drastic effect can be ascribed to the compaction ofthe drug-added material: in fact, if we inspect section (d) ofFig. 12 it is evident that the silica system has been totally upset.No traces of the pores are now observable and the ordered struc-ture of the particles has been totally lost: the contours are smoothand roundish and the crystallites exhibit an ‘‘amorphous” habit.

HR-TEM analyses, in total agreement with X-ray diffraction andphysisorption measurements, confirm that for SBA-15 based sys-tems, in particular when loaded with MPT, the effect of the formingprocess under pressure is absolutely detrimental for its orderedstructure and the low quality of the delivery observed for this sys-tem can be related to this feature: in fact, its release profile is verysimilar to that of the amorphous silica gel carrier. This is a furtherproof of the strict correlation between the texture of the samplesand their performance in the drug delivery test. It is possible toconclude that MCM-41 is the best candidate as carrier for the de-sign of new drug delivery systems, as it exhibits a gradual and con-

Fig. 12. HR-TEM images of the SBA-15 samples. (a) plain SBA-15; (b) SBA-15p; (c) SBA-15 + MTP; (d) SBA-15 + MTPp.

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tinuous release profile. This result is related with several factors, inparticular with the textural properties of this matrix and its goodpreservation despite the pressure application during the formingprocess. This last aspect is very important and must be taken ingreat account in the selection of a drug delivery carrier. In fact,an in-depth study about the chemical and mechanical stability ofthe support is fundamental in order to modulate ad hoc the syn-thetic approach and the forming process of the final DDS.

In any case, MCM-41 exhibits a disadvantage: only part of thedrug originally loaded can be released in the present delivery con-ditions. In order to overcame this problem, the modification of thenature of the silica surface (i.e., hydrophylicity/hydrophobicity)could be considered and then further investigations are needed.

4. Conclusions

In this work we have synthesised and studied micro- and mes-oporous silica as possible carriers to sustain the release of meto-prolol tartrate, a drug used in the treatment of several diseasesof the cardiovascular system.

A reliable and reproducible synthetic procedure has been opti-mized for the preparation of stable silica/drug systems. We haveobserved a close correlation between the drug release and the tex-tural properties of the matrices.

Among the investigated silica systems, the best performancewas achieved by the MCM-41 material, which exhibits pore dimen-sions comparable to that of the drug (size selectivity). In this case,the drug release is very similar to that auspicated for an ideal DDSformulated for a long-term administration and it could well agreewith the MPT therapeutical demand, even if a still unsolved draw-back is represented by part of the drug that is not released by thesilica matrix.

Acknowledgements

The authors want to thank Prof. Giuseppe Cruciani (Universityof Ferrara) for supplying XRD data and Dr. Andrea Chiminazzofor the excellent technical assistance.

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