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Aspirin Loading and Release from MCM-41 Functionalized withAminopropyl Groups via Co-condensation or PostsynthesisModication Methods

Ashish Datt, Izz El-Maazawi, and Sarah C. Larsen*

Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, United States

*S Supporting Information

ABSTRACT: A comprehensive study of aspirin loading and release fromMCM-41 and amine functionalized MCM-41 was conducted. Two differentfunctionalization methods, co-condensation and postsynthesis modication,were utilized and compared. All of the MCM-41 samples were thoroughlycharacterized before and after aspirin loading by powder X-ray diffraction,

nitrogen adsorption isotherms, and thermogravimetric analysis to determinethe structure and physicochemical properties such as surface area, porevolume, and functional group loading. Molecular level details about theaspirinMCM-41 interactions were revealed through FTIR and 13C solid-state NMR experiments. For the aminopropyl-functionalized MCM-41, thecarboxylic acid group of aspirin associates with the amine group of thefunctionalized MCM-41. In all of the samples, an interaction between theaspirin phenyl group and the mesoporous silica host was hypothesized basedon shifts in the phenyl group 13C NMR resonances. Molecular dynamicssimulations supported the NMR observations in that the phenyl group of the aspirin was determined to be oriented parallel tothe pore wall. The release data indicated that both the distribution and loading of the amine functional groups in MCM-41inuenced the release properties of aspirin.

INTRODUCTIONA major issue in pharmaceutics is the incorporation of active drug

molecules into inorganic materials for controlled releaseapplications. Mesoporous silica materials are inorganic materials,which are synthesized in the presence of surfactants that act astemplates for the polycondensation of silica species.13 Themesoporous silica material, MCM-41 (Mobil Crystalline Ma-terial), is shown in Figure1. Mesoporous silica materials have

pore diameters ranging from 2 to 15 nm. The pore sizes can bevaried during synthesis by varying time, temperature, and thechoice of the surfactant. High surface areas and large pore sizesmake mesoporoussilica an ideal material for hosting moleculesofdifferent sizes, shapes, and functionalities. Many examples ofdrug molecules loaded into mesoporous silica materials havebeen reported in the literature.429 Ibuprofen has been

extensively studied as a model drug adsorbed on the mesoporoussilica materials, such as MCM-41, SBA-15, and hexagonalmesoporous silica (HMS) materials.15,18,21,22,3033 Thesemesoporous silica materials (MCM-41, SBA-15, and HMS)differ in their pore diameters, thickness of the walls, and thespecic synthetic conditions. Anticancer drugs have been studiedfor controlled release using mesoporous silica hosts.26,34,35

Mesoporous silica is an attractive host due to properties, suchas high surface areas, tunable pore sizes with narrowdistributions, well-dened surface properties, low toxicity, andvery good biocompatibility.16,18 Pore diameters, pore volumes,particle morphology, and surface modications are criticaltextural properties of mesoporous silica that control the drugloading and release properties. Modication with organicfunctional groups is an important method of varying the drugloading and release properties of mesoporous silica materials.The drug moleculeorganic group interaction and the locationand number of organic groups on the surface are importantfactors in drug loading and release. Vallet-Regi and co-workersconcluded that adsorption of drug molecules on mesoporoussilicawas related to surface electrochemistry, whereas release ofdrug molecules was inuenced by the surface area and diffusionthrough the pores.36

Received: June 28, 2012Revised: July 27, 2012Published: August 2, 2012

Figure 1. Representative structures of MCM-41 (left) and aspirin(right).

Article

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2012 American Chemical Society 18358 dx.doi.org/10.1021/jp3063959|J. Phys. Chem. C2012, 116, 1835818366
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In general, mesoporous silica materials can be functionalizedusing two different methods: co-condensation and postsynthesisgrafting, as illustrated in Figure 2.2 In the co-condensation

method, an organosilane with the desired functional group isadded during the synthesis so that the organic functionality isincorporated into mesoporous silica directly duringthe synthesis.In postsynthesis grafting, calcined mesoporous silica is treatedwith the organosilane that reacts with surface silanol groups. Thedistribution of functional groups varies depending on the methodof modication. In the case of co-condensation, the functionalgroups are more evenly distributed throughout the mesoporoussilica while in postsynthesis grafting, the functional groups areless regularly distributed. In postsynthesis methods, reaction ofthe organosilane at the opening of the mesopores can lead to areduction in the diffusion of molecules into or out of themesoporous silica.2 The amount of loaded functional group canalso be controlled by varying the amount of organosilane usedduring modication. The functional group loading can affect thesurface area and the surface charge of the mesoporous materials.Amine functionalized mesoporous silica materials have beenprepared by several groups for evaluation as drug deliveryhosts.5,913,3638 Studies have addressed adsorption or releaseand factors such as the loading level of the amine group, thespecic amine functionality, and the nature of the mesoporoussilica host.

In the study reported here, aspirin (Figure1) was chosen as amodel drug due to its small molecular size, good pharmacologicalactivity, and short biological half-life.39,40 In addition, it has acarboxyl group that can interact with surface silanol groups oramino groups on the pore walls and may be useful for thecontrolled drug release. The loading and release of aspirin fromMCM-41 modied with aminopropyltriethoxysilane (APTES)functional groups was investigated in order to develop afundamental understanding of the interactions of aspirin withthe mesoporous silica host and how these impact loading andrelease properties. Two modication methods, co-condensationand postsynthesis grafting, were evaluated and compared interms of the effect on the loading and release of the model drug,aspirin. The MCM-41 materials were extensively characterizedby powder X-ray diffraction (pXRD), thermogravimetric analysis(TGA), and nitrogen adsorption for surface area and porevolume measurements. The aspirin loaded materials were

characterized spectroscopically using FTIR and solid-stateNMR before and after aspirin loading. Molecular dynamics(MD) calculations were conducted to provide additional insightinto the experimental results.

EXPERIMENTAL PROCEDURES

Materials. 3-Aminopropyltriethoxysilane (APTES, Sigma-

Aldrich), tetraethoxysilane (TEOS, Sigma-Aldrich), hexadecyl-trimethylammonium bromide (CTAB, Sigma-Aldrich), andacetylsalicylic acid (aspirin, Alfa Aesar) were used as received.

Synthesis of MCM-41.The MCM-41 was prepared usingcetyltrimethylammonium bromide (CTAB) as the surfactant,water as the solution, and sodium hydroxide as a catalyst.37

Tetraethyl orthosilicate (TEOS) was added as a silica source.The mixture contained a molar ratio of 1 CTAB:7.564TEOS:2.551 NaOH:4652 H2O. The solution was then agedfor 2 h until a white product formed. The product was lteredand washed with deionized water and ethanol. It was then driedin an oven at 373 K for at least 12 h. The dried product washeated with air to 600 C for 6 h.

Co-condensation of APTES with MCM-41. The aminefunctionalization reaction was similar to the synthesis of MCM-41 except that in addition to the silicon source, the amine source(4 and 8 mmol for CC-1 and CC-2, respectively) was addedsimultaneously. The contents were ltered, washed, and dried inan oven overnight. The template removal was done through anextraction process to prevent the removal of the amine groups. Ina typical extraction process, 1 g of the material was mixed withethanol and hydrochloric acid and stirred for 24 h at roomtemperature. The resulting material was ltered, washed, anddried.41 These samples will be referred to as MCM-CC-1 andMCM-CC-2 for the lower and higher APTES loaded samples,respectively.

Postsynthesis Grafting of the APTES on MCM-41. The

postsynthesis grafting procedure involved re

uxing 1 g ofcalcined MCM-41 and APTES (4 or 8 mmol) in toluene at120 C for 6 h The resulting sample was ltered, washed with 1:1mixture of dichloromethane and diethyl ether, and dried in anoven at 100C. These samples will be referred to as MCM-PS-1and MCM-PS-2 for the lower and higher APTES loaded samples,respectively.

Characterization.The textural properties of the MCM-41materials were characterized using a variety of techniques. TheMCM-41 structure was veried using powder X-ray diffraction(pXRD) (Siemens D5000 X-ray diffractometer with Cu Kandanickel lter). A broad-range pattern (2=1to55witha0.04stepsize, 1 s/step) was collected. Surface areas and pore volumes ofthe MCM-41 materials were measured using nitrogen adsorption

and a Nova 1200 nitrogen adsorption instrument (Quantach-rome). Approximately 100 mg of MCM-41 was dried overnightat 120 C in vacuum. A 7-point BET isotherm and a 50-pointadsorption/desorption isotherm were measured and used forcalculation of the surface area and total pore volume. The totalpore volume (Vtot) was calculated bymeasuring the amount ofadsorbed nitrogen at 0.97 P/P0.42 The pore diameter ofmesoporous silica was calculated using the literature reportedrelation

=

+

W cd

V

V1d

p

p

1/2

(1)

Figure 2.Schematic diagram illustrating the functionalization of MCM-

41 by (A) co-condensation and (B) postsynthesis grafting.

The Journal of Physical Chemistry C Article

dx.doi.org/10.1021/jp3063959|J. Phys. Chem. C2012, 116, 183581836618359

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whereWdis the pore size,Vpis the primary mesopore volume, is the pore wall density (ca. 2.2 cm3/g for siliceous materials), disthe XRD (100) interplanar spacing, and c is the constantdependent on the pore geometryand is usually equal to 1.155 forhexagonally ordered pores.43 Thermogravimetric analysis(TGA) was conducted using a TA Instruments Q5000 with aheating rate of 5 C/min under a nitrogen atmosphere. TheAPTES loading was calculated from the weight loss measured byTGA assuming that all of the ethoxy groups were hydrolyzedand/or bonded to the silica surface.

FT-IR spectra were recorded using the Nicolet FT-IRspectrometer, and the samples were pressed into disks by mixingthem in the ratio of 1:5 with KBr. The spectra were recorded inthe range of 4004000 cm1. Nuclear magnetic resonance(NMR) experiments were conducted on a 500 MHz BrukerAvance III spectrometer with 3.2 mm zirconia rotors. 13C1Hcross-polarization magic angle spinning (CP MAS) experimentswere conducted on the MCM-41 and aspirin-loaded MCM-41using a 3.2 mm rotor and a MAS spinning speed of 10 kHz. 13Csingle pulse (SP) MAS experiments were conducted with protondecoupling. Adamantane was the chemical shift referencematerial.

Aspirin Loading and Release.The mesoporous silica wasloaded with the aspirin by mixing the aspirin in ether until itdissolved and then adding the MCM-41 with magnetic stirringfor1224hat25 C. The solution wasltered and dried at 25 Covernight. For release proles, 100 mg of the loaded MCM-41was placed in a phosphate buffer solution with pH = 7.4 at 37.4C. The contents were stirred at 100 rpm, and 2 mL aliquotswere removed at regular intervals of time. The aliquots werecentrifuged in order to ensure no solid was in suspension, andtransparent supernatants were analyzed for aspirin with UVvisspectroscopy (Varian Cary 100 Scan) at = 296 nm. The amountof released aspirin was calculated using the equation

= +

C C

v

V Ct t

t

t,corr0

1

(2)

where Ct,corris the corrected concentration at time t(corrected toaccount for changes in volume),Ctis the apparent concentrationat timet,vis the volumeofthe sample taken, and Vis the totalvolume of the solution.31 Experiments were conducted induplicate, and the values were averaged.

Theoretical Procedure. Molecular dynamics (MD) simu-lations were conducted in order to better understand the locationof aspirin in the mesoporous silica pores. A twofold approach wastaken in the MD simulations. First, the cubic box of silica wasused to perform a MD simulated annealing process to 10 000 Kin order to obtain liquid silica, and then the system was quenchedto 298 K to obtain amorphous silica. Second, the MD simulationwas conducted in the presence of aspirin and amorphous silica.For the rst step, the CHIK potential parameters were usedbecause this force eld has been shown to behave well at hightemperatures.44 For the second step, i.e., for the amorphous silicaand loaded aspirin simulations, the potential parametersdeveloped by Lee and co-workers were used so that thehydrogen bonding and the interactions of the phenyl ring withthe silica surface could be included.45

All of the simulations were performed using GROMACSmolecular dynamic package.46,47 Amorphous silica at roomtemperature (298 K) and pressure (1 bar) was obtained fromsilica melt (at higher temperature). The interactionbetween theparticles was calculated using the CHIK potential.44 In order to

obtain the silica melt, initially a cubic box containing 32 000 O(oxygen) and 16 000 Si (silicon) atoms was suitably placed in asimple cubic box. Each simulation box was equilibrated for atleast 500 ps at 10 000 K inisothermalisobaric (NPT)ensemble.The system was coupledtoParrinelloRahman pressure bath tomaintain 1 bar pressure.48 The temperature of the system wasregulated using a V-rescale algorithm as implemented inGROMACS.46,47 Proper periodic boundary conditions wereapplied in order to simulate the system in the three dimensions.The leapfrog algorithm was used to integrate the equation ofmotion with 1 fs time step. Cutoffs for short-range interactionsand the real space part of the Coulomb interactions were set to1.1 nm. The long-range electrostatic interactions were treatedusing particle mess ewald (PME) summation technique.49,50

Simulations were also carried out at a temperature of 3600 K inorder to validate the method. This was conrmed by comparingthe simulated bulk density and pair distribution functions (OO,SiSi, and SiO) with available results in the literature at 3600K.44

A box of silica melt (at 10 000 K) was quenched to 298 K andallowed to equilibrate for 50 ps in order to obtain the amorphoussilica. The dimensions of the amorphous silica box, thusobtained, were approximately 8.98 nm 8.98 nm 8.98 nm.A cylindrical silica nanopore of diameter 3.2 nm was obtained byremoving the atoms in the xy plane along the z axis. The totalelectroneutrality of the whole system was ensured (assumingcharges for Sias +2e,O as1e, H as+0.5e) byadding H atoms todangling oxygen atoms near the pore. The distance betweenoxygen and hydrogen atoms was kept at around 1 .51,52 Theunsaturated oxygen atom to add hydrogen to was chosenrandomly. Aspirin parameters were taken from general AMBERforce eld (GAFF).53 In order to convert the AMBER typeparameters to use in Gromacs package, we used the scriptdeveloped by Sorin et al. The initial conguration of the systemof aspirin and mesoporous silica was generated with aspirin beingin the center of the nanopore of the silica.51,52 The Lennard-

Jones (LJ) parameter for Si, O, and H were taken from Lee et al.45The cross LJ parameters for silica and as well as the drugmolecule were calculated using LorentzBerthelot combinationrules. Proper periodic boundary conditions were applied to thewhole system and NVT ensemble for 400 ps. The Si, O, and Hatoms of the silica nanopore were frozen during the course of theNVT simulation.

RESULTS

Synthesis and Characterization of MCM-41 Function-alized with APTES by Co-condensation and Postsyn-thesis Grafting.MCM-41 was synthesized, characterized, andfunctionalized with APTES using co-condensation and postsyn-thesis grafting methods. Figure 3 shows the representative pXRDpatterns for MCM-41 and for MCM-41 functionalized withAPTES by co-condensation and postsynthesis grafting beforeand after aspirin loading.

The pXRD patterns exhibit strong reection peaks at (100),(110), and (200) (2 2.2, 4.0, and 4.6, respectively), indicatinga hexagonally ordered mesoporous structure. The diffractionpatterns for the amine functionalized and aspirin loadedmaterials generally exhibit maxima of decreased intensity,indicating that the long-range ordering of the mesoporousstructure decreased signicantly after drug loading and with theincorporation of organic groups, but the mesoporous structurewas retained after the loading of the drug molecules. This isattributed to the pore lling by organic groups, as a result of



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which higher order diffraction peaks (110 amd 200) are observedwith weaker intensities in functionalized and drug loadedsamples. In the diffraction patterns, the intensity of the parentpeak of MCM-41 (2 2.2) has also decreased in thefunctionalized and drug loaded samples. The decreased intensitycan again be attributed to the pore lling but can also be partiallyattributed to other factors such as incomplete hydrolysis of thesiloxane bridges during synthesis of the mesoporous silica. Itshould be noted that the higher order peaks decrease more forsamples prepared by postsynthesis modication relative to thoseprepared by co-condensation. This is due to the fact that theAPTES functional groups were added during the synthesis in theco-condensation method, so the structure is not affected as muchas during postsynthesis modication. The pore diameters (Wd)calculated from the XRD patterns and eq1are provided in Table

1. As expected, the pore diameter decreases after functionaliza-tion, relatively more for the postsynthesis modied samplesrelative to the co-condensed samples. The pore diameters alsodecrease after aspirin loading.

The surface areas, pore volume, and pore size distributionswere analyzed using the nitrogen adsorptiondesorptionmeasurements for all MCM-41, APTES functionalized, andaspirin loaded MCM-41 samples. A representative isotherm forMCM-41 with and without aspirin is shown in Figure 4. Thesurface areas and pore volumes are provided in Table 1.

Isotherms for all of the samples are provided as SupportingInformation. All of the samples exhibit capillary condensationprocess from P/P0 from 0.1 to 0.3. The isotherms exhibit a typeIV isotherm which is characteristic of the mesoporous materials

having cylindrical mesopores.42

The surface area and pore

volume decrease both with amine and aspirin loading. Thedecrease in pore volume, pore diameter, and surface area allindicate that the aspirin is adsorbed into the pores of MCM-41.

TGA was conducted on all of the samples. A representativeTGA of MCM-PS-1 is shown in Figure 5. The thermogram of

pure aspirin seen in inset shows two distinct weight losses around140 and 260C which may be attributed to the onset of melting

followed by the decomposition of the drug. The rst weight loss

Figure 3. Powder X-ray diffraction patterns of (a) MCM-41, (b) MCM-41-Asp, (c) MCM-CC-1, (d) MCM-CC-1-Asp, (e) MCM-CC-2, (f)MCM-CC-2-Asp, (g) MCM-PS-1, (h) MCM-PS-1-Asp, (i) MCM-PS-2, and (j) MCM-PS-2-Asp.

Table 1. Physicochemical Properties of the MCM-41 before and after Aspirin Loading

sampleSA before (after),a

m2/gVporebefore (after),

a

cm3/g Wd,a nm

APTES loading,b

mmol/gaspirin loading,b mmol/g

(mg/g)aspirin remaining after release,c

mg/g

MCM-41 1120 (810) 0.91 (0.67) 3.50 (3.33) 0.55 (100) 10

MCM-CC-1 803 (661) 0.68 (0.53) 3.34 (3.17) 0.45 0.67 (120) 44

MCM-CC-2 744 (520) 0.41 (0.28) 2.96 (2.66) 0.54 0.94 (170) 116

MCM-PS-1 757 (618) 0.48 (0.35) 3.08 (2.84) 0.54 0.67 (120) 59

MCM-PS-2 729 (518) 0.46 (0.31) 3.05 (2.75) 0.60 0.72 (130) 71

aBefore aspirin loading (after aspirin loading). bCalculated from the TGA data assuming that the all of the ethoxy groups reaction were lost due tobondng to the silica surface and/or were hydrolyzed. cMeasured by UV/vis.

Figure 4. Nitrogen adsorptiondesorption isotherm for (a) parentMCM-41 material and (b) MCM-41 with aspirin.

Figure 5.TGA of MCM-PS-1 with aspirin.



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in the pure aspirin can be attributed to the elimination of aceticand salicyclic acids on heating the compound followed by thesecond weight loss which accounts for the decomposition of thesolid residue. Similar trends could be seen in the drug loadedsamples in the different host systems with an extended range oftemperature for the decomposition of the drug. In case of APTESfunctionalized samples, two weight changes are seen correspond-ing to the loss of physisorbed water followed by thedecomposition of the functional group around 250 C onward.The TGA data were used to determine the amine group andaspirin loading for the MCM-41 samples from the measuredweight loss. The complete results are listed in Table 1. TheAPTES loadings range from 0.45 to 0.60 mmol/g, and the aspirinloadings range from 0.55 to 0.94 mmol/g. The highest APTESloading was observed for MCM-PS-2, and the highest aspirinloading was observed for MCM-CC-2.

NMR and FTIR Characterization of the MCM-41 andAspirin Loaded MCM-41 Samples. 13C CP MAS experimentswere conducted on all of the samples and on a physical mixture ofaspirin and MCM-41. Representative 13C NMR spectra areshown in Figure6. Characteristic resonances corresponding to

aspirin were observed in the spectra. The peak at 170 ppm wasassigned to the carbonyls of the carboxylic acid and ester groupsof the aspirin. The peaks in the region from 116 to 150 ppm wereassigned to the aromatic carbons of the phenyl ring in aspirin.The peak from the methyl group of aspirin was observed at 19ppm with two additional peaks coming from the propyl chain ofthe APTES moiety for the APTES functionalized MCM-41samples. The phenyl ring carbon peaks for all of the aspirinloaded samples (Figure 6be) are shifted for the MCM-41samples relative to the physical mixture (Figure6a), indicatingthat the phenyl ring interacts with the MCM-41 surface. A similarshift has been observed for aspirin loaded in polymeric hosts andwas attributed to an aspirin/host interaction.54 In addition, thepeak due to thephenyl group carbon bonded to the oxygen of theester group (150 ppm) is broadened and shifted for the APTESfunctionalized MCM-41 samples (Figure 6d,e) relative to thephysical mixture.

In contrast, for the parent MCM-41, resonances due to thecarbonyl carbons do not appear in the CP MAS NMR spectrum(Figure6b). In previous NMR studies of drug molecules, such asibuprofen, incorporated into porous materials, this missingcarbonyl peak has been attributed to the high mobility of the drugmolecules in the pores which results in a decreased efficiency ofthe CP due to a decrease in the 13C1H dipolar coupling.14,5557

To support this interpretation of the data, the single pulse MAS13C NMR spectrum with proton decoupling was obtained and isshown in Figure6c. The carbonyl carbon signals due to both thecarbonyl in the carboxylic acid and inthe ester are observed intheNMR spectrum at 170 ppm. The increased broadening in the13C NMR data for aspirin in the APTES-functionalized MCM-41samples suggests that these samples undergo substantially lessmotion relative to aspirin in the parent MCM-41 sample, mostlikely due to the interaction between aspirin and the aminefunctional group.

The FTIR spectra of MCM-41 and aspirin are shown in Figure7. In the case of parent MCM-41 sample (Figure 7a, black), thereare several large peaks in the 10001250 cm1 range that areattributed to SiO vibrations.9,11,31Another prominent peak is

present at

1636 cm

1

and is due to water physisorbed onMCM-41. After aspirin loading (Figure7a, red), a peak at 1700cm1 is observed which is assigned to the carbonyl carbon.Relatively weaker peaks are also observed at 1486, 1425, and1368 cm1, and these are attributed to aspirin phenyl groupvibrations.

For the APTES functionalized MCM-41 sample, MCM-PS-1(Figure7b), a characteristic peak assigned to the NH bendingmode of the amine group is observed at1565 cm1 for both co-condensed and postsynthesis modication samples. Strongvibrational peaks are observed in the CH stretching regionaround 2900 cm1. After loading the sample with aspirin, onlysmall changes are observed in the FTIR spectra due to theoverlapping vibrational bands of the APTES and aspirin. Thecarbonyl vibration at 1700 cm1 is not observed, and this isattributed to the strong interaction of the carbonyl carbon of thecarboxylic acid with the amine groups. This lack of a carbonylvibration at1700 cm1 has been observed in previous studies ofaspirin on various mesoporous silica functionalized materials andhas been attributed to the formation of a carboxylatespecies.9,11,31 The FTIR spectra for all of the APTES function-alized samples (included in theSupporting Information) havecharacteristics similar to Figure 7b. The 13C NMR spectraprovide evidence that the carboxylic acid groups are present inthe aspirin loaded samples even though they are not directlyobserved in the FTIR spectra.

Molecular Dynamics Simulation of Aspirin in MCM-41.The results of the molecular dynamics simulation of aspirin inmesoporous silica are shown in Figure 8. Figure8a shows anaspirin molecule located in the center of the 3 nm pore at thebeginning of the molecular dynamics simulation. After 400 ps,the aspirin is oriented along the pore wall, such that the phenylgroup of the aspirin is parallel to the pore wall (Figure8b). Themolecular dynamics results provide further support for the 13CNMR results which show that the peaks assigned to the phenylcarbons are shifted relative to the pure aspirin, suggesting that thephenyl group of aspirin interacts with the pore walls.

Aspirin Release from MCM-41. The aspirin release prolesfor the MCM-41 and APTES modied MCM-41 are shown inFigure9. Drug release from porous media can follow severaldifferent models. In some cases, the release process is governedby Ficks diffusion and can be described using a simplied

Figure 6.13C NMR spectra of (a) physical mixture of mesoporous silicaand aspirin (CP MAS), (b) MCM-41 with aspirin (CP MAS), (c)MCM-41 with aspirin (SP with decoupling), (d) MCM-CC-1 withaspirin (CP MAS), and (e) MCM-PS-1 with aspirin (CP MAS). Thepeak at 60 ppm in (b) and (c) is due to residual solvent (ether).



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Higuchi model, Q = KHt0.5, where Q is the amount of drug

release,KH is the Higuchi dissolution constant, and tisthe time.58

The KorsmeyerPeppas model is similar except that a release

exponent, n, is introduced into the model such that Q= atn,

whereais a constant.58 This equation can be modied to include

a burst effect (b), such that

= +Q at bn

(3)

Figure 7.FTIR spectra of (a) MCM-41 and (b) MCM-PS-1 with (red) and without (black) aspirin loaded. The FTIR spectra before and after loadinghave been scaled to the strong framework SiO vibration from 10001200 cm1 for display purposes.

Figure 8.Results of the molecular dynamics simulation showing (a) the starting conguration with aspirin in the center of the 3 nm mesopore and (b)after 400 ps with the phenyl ring of aspirin orientated parallel to the pore wall.

Figure 9.Aspirin release kinetics from MCM-CC-1 (lled square), MCM-CC-2 (open square), MCM-PS-1 (open circle), MCM-PS-2 (lled circle),and MCM-41 (lled triangle) are shown. The least-squares ts to eqs4and3are shown by the solid and dashed lines, respectively.



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which is also called the power law.58 In other cases, the drugrelease follows the rst-order kinetic exponential decaymodel,36,58with the equation represented as

= Q Q k t (1 exp( ))max 1 (4)

where Q is the amount of drug released in time t, Qmax is themaximum amount of drug released, and k1 is the rst-order

release constant. For unmodied mesoporous silica materialssuch as MCM-41, the drug release is often governed byFicksdiffusion and can be described using the Higuchi model.30 TheKorsmeyerPeppas model has been used to describethe releaseof aspirin from bimodal mesoporous silica materials.9,11,12 Foramine-modied MCM-41 and SBA-15, the drug release foribuprofen and sodium alendronate has beendescribed using therst-order kinetic model described by eq4.15,36 Based on theprevious work, the data from this study were analyzed using therst-order kinetic model for the functionalized samples and thepower law for the parent MCM-41.

The release proles for aspirin from MCM-41 and MCM-CCand MCM-PS samples are plotted in Figure9. Initially, all of therelease proles weretted using the rst-order kinetic model (eq

4), and the

ts to the data are indicated by the solid curves. Theparameters Qmaxand k1 obtained aftertting this release data witheq4are listed in Table2. The parent MCM-41 release data donot t this model very well as indicated by the R2 value of 0.81compared to 0.90 for all of the other samples.

The parent MCM-41 data could be t better using the powerlaw model withn= 0.5, indicating Fickian diffusion and with ay-intercept which indicates a burst effect. The data and the t (a=1.37 and b = 64.5; R2 = 0.85) are shown in Figure 9c. Thediffusion of the drug molecules from the pores is largelydependent on the nature of the interaction of the drug moleculewith the pore and the intrinsic mobility of the drug moleculesinside the pores. The modication of the samples with functionalgroups causes steric hindrance as a result of which the diffusiondeviates from Ficks law.

From the release data shown in Table2, it can be concludedthat the total amine group loading and the method of loading(co-condensation or postsynthesis modication) both effect therelease of the aspirin. The rst-order rate constant, k1, isapproximately the same (1.4 min1) for all of the samples,except for MCM-PS-2 in which the k1 is smaller (0.78 min

1).The reason for this may have to do with the higher loading of theamine group leading to increased pore blocking, but it shouldalso be noted that theR2value has also declined for MCM-PS-2,suggesting that the goodness of t has also declined. For thesamples prepared by co-condensation, the maximum release(Qmax) of the drug decreased from 71 to 50% most likely due toincreased pore blocking due to the higher APTES content. Incase of postsynthesis grafting, the Qmaxwas not correlated with

the loading of amine groups, which is attributed to the presenceof amine groups at the pore entrances, which is similar for thepostsynthesis samples, independent of the overall amine loading.

DISCUSSIONA comparison of the loading and release for the different samplesis provided in Figure 10. The loading of aspirin into APTES

functionalized MCM-41 was enhanced by 2070% relative tothe unfunctionalized MCM-41. The increase in aspirin loading inthe amine functionalized MCM-41 materials is attributed to thefavorable amine group and aspirin interaction. If the APTESloadings are further increased (data not shown), the aspirinloading declines due to pore blocking in both co-condensed andpostsynthesis modication samples. The highest overall aspirinloading is achieved for the MCM-CC-2 sample. The literaturesuggests that the functional groups in MCM-41 samplesprepared via co-condensation are more accessible and less likelyto cause pore blocking relativeto comparable samples preparedby postsynthesis modication.2 This accounts for the higheraspirin loading for the co-condensed sample with comparableAPTES loading relative to the postsynthesis prepared sample.The data reported here are consistent with this view in that thehigher APTES loading observed for MCM-PS-2 does not resultin increased aspirin loading under these conditions. So while theaspirin loadings are comparable due to the favorable interactionswith the amine group, the distribution and amount of functionalgroups also impacts the aspirin loading and release properties.

The spectroscopic studies (FTIR and solid-state NMR)indicate that the aspirin molecules are loaded intact into theMCM-41 samples. The spectroscopic data also indicate thataspirin is more weakly bound in MCM-41 relative to APTESfunctionalized MCM-CC and MCM-PS samples. In FTIRspectroscopy, the carbonyl band is observed for MCM-41 butis not observed for APTES functionalized MCM-41 samples,suggesting a weak interaction with the parent and a strongerinteraction between the APTES functionalized MCM-41 and theaspirin. The NMR data support this interpretation as well in thatthe cross-polarization is not very efficient for aspirin on MCM-41, and this is attributed to motion of the aspirin in the porewhich suggests weak interactions with the framework consistentwith hydrogen bonding to the silanol groups of the mesoporoussilica. The MCM-CC and MCM-PS 13C NMR spectra are

Table 2. Fitted Kinetic Release Parameters for Aspirin Releasefrom MCM-41a

sample Qmax(%) k1(min1) R2

MCM-41 75 1 1.0 0.3 0.81

MCM-CC-1 71.4 0.4 1.4 0.2 0.98

MCM-CC-2 50.4 0.3 1.4 0.2 0.98

MCM-PS-1 56.6 0.4 1.3 0.2 0.96

MCM-PS-2 57.3 0.6 0.78 0.1 0.90aQmax= maximum aspirin released (%); k1= release rate constant.

Figure 10. Aspirin loading (pink) and release (blue) from MCM-41samples.



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broadened relative to the physical mixture of MCM-41 andaspirin, and also the carbonyl carbon peak is observed in the13C1H CP MAS experiments. These observations indicate thatthe motion is restricted in the amine functionalized MCM-41samples relative to the parent MCM-41. Previous NMR studiesof ibuprofen on mesoporous materials exhibit similar behaviorwith respect to the 13C1H cross-polarization NMR.14,5557 A

shift of the

13

C phenyl group carbon resonances of aspirin is alsoobserved in the 13C NMR, suggesting that the phenyl group ofaspirin interacts with the MCM-41 host. The MD simulationssupport the idea from the 13C NMR data that the phenyl ring ofaspirin interacts with the pore walls as shown in Figure 8b.

The release data can be understood by considering themolecular level details revealed in the FTIR and NMRexperiments. The aspirin in the parent MCM-41 is weaklybound to silanol groups, and the release follows Ficks diffusion.For the APTES functionalized MCM-41 samples, the aspirinundergoes a stronger interaction with the amine group and isreleased to a lesser extent relative to theparent MCM-41. Fortheco-condensed MCM-41 samples with aspirin loaded, a 71%release of the aspirin in 4 h is observed whereas with higherloadings the release decreases to 50% after 4 h. In case ofpostsynthesis MCM-41 samples, the release reaches a plateau at57% aspirin release for both samples. A similar effect has beenobserved previously for sodium alendronate loaded on SBA-15functionalized with APTES in two different ways.38 In that study,theQmaxdecreased for the samples functionalized by a catalyticmethod, and the loading increased with increasing functionaliza-tion similar to our co-condensed sample. For the sampleprepared by anhydrous postsynthesis modication, the drugloading and Qmax remained about the same independent ofAPTES loading. This is consistent with the hypothesizedlocation of amine functional groups at the pore mouth for thesamples prepared by postsynthesis modication independent ofloading.2 The functional group content and distribution offunctional groups in the pores are both important factorsgoverning the loading and release of aspirin from MCM-41.

CONCLUSIONSThis integrated experimental and computational study of aspirinloading and release from MCM-41 and amine functionalizedMCM-41 provided insight into the molecular level interactionsof aspirin with the mesoporous host. These insights were used tounderstand the loading and release data. The ndings show thatthe distribution and loading of the functional groups are bothimportant factors. In this study, the aspirin loading wasmaximized for APTES functionalized MCM-41 samplesprepared by the co-condensation method because the functionalgroups are more evenly distributed in this method relative to thepostsynthesis modication method. The aspirin release data forthe parent MCM-41 was tted using the power law, which is amodied form of the KorsmeyerPeppas model for a diffusionbased process that also takes into account a burst release. Therelease proles for the APTES functionalized MCM-41 sampleswere tted using a rst-order kinetic exponential decay model.The difference in release models was explained by the relativelyweaker interaction of aspirin with the parent MCM-41 relative tothe APTES functionalized samples. Solid-state NMR and FTIRprovided detailed molecular information about the aspirinbinding to the mesoporous silica host that supported theseconclusions. MD simulations indicated that the phenyl group ofthe aspirin was oriented parallel to the pore wall in agreementwith the NMR data.

ASSOCIATED CONTENT*S Supporting InformationTEM images, nitrogen adsorption isotherm data, TGA data, andcomplete FTIR spectra. This material is available free of chargevia the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

NotesThe authors declare no competing nancial interest.

ACKNOWLEDGMENTSThis material is based upon work partially supported by theNational Science Foundation under Grant CHE-0847974 andCHE-0840371. Izz El-Maazawi was supported by NSF CHE-0754738.

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