.1016j.apsusc.2018.02.260 [624028]

Accepted Manuscript
Full Length Article
Ordered cubic nanoporous silica support MCM-48 for delivery of poorly soluble
drug indomethacin
Vladimír Zeleň ák, Dá ša Halamová, Miroslav Almá ši, Luká š Žid, Adriána
Zeleň áková, Ondrej Kapusta
PII: S0169-4332(18)30623-8
DOI: https://doi.org/10.1016/j.apsusc.2018.02.260
Reference: APSUSC 38718
To appear in: Applied Surface Science
Received Date: 24 November 2017
Revised Date: 24 February 2018
Accepted Date: 26 February 2018
Please cite this article as: V. Zele ň ák, D. Halamov á, M. Alm á ši, L. Žid, A. Zele ň áková , O. Kapusta, Ordered cubic
nanoporous silica support MCM-48 for delivery of poorly soluble drug indomethacin, Applied Surface Science
(2018), doi: https://doi.org/10.1016/j.apsusc.2018.02.260
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Ordered cubic nanoporous silica support MCM -48 for delivery of poorly soluble drug
indomethacin

Vladimír Zeleňák1*, Dáša Halamová1, Miroslav Alm áši1, Lukáš Žid1, Adriána Zeleňáková2,
Ondrej Kapusta2
1Institute of Chemistry , Faculty of Science, P.J. Šafári k University in Košice, Moyzesova 11,
SK-041 54 Košice, Slovak ia
2Institute of Physics, P. J. Šafárik University, Park Angelinum 9, 04001 Košice, Slovakia

*Corresponding author:
Assoc. Prof. Vladimír Zeleňák, PhD .
Department of Inorganic Chemistry
Facul ty of Science
P. J. Šafárik University in Košice
Moyzesova 11
SK-041 54 Košice, Slovak Republic
e-mail: vladimir.zelenak @upjs.sk

Ordered cubic nanoporous silica support MCM -48 for delivery of poorly soluble drug
indomethacin
Vladimír Ze leňák1*, Dáša Halamová1, Miroslav Alm áši1, Lukáš Žid1, Adriána Zeleňáková2,
Ondrej Kapusta2
1Institute of Chemistry , Faculty of Science, P.J. Šafárik University in Košice , Moyzesova 11,
SK-041 54 Košice, Slovak ia
2Institute of Physics, P. J. Šafárik Univer sity, Park Angelinum 9, 04001 Košice, Slovakia
*Corresponding author, e-mail: vladimir.zelenak @upjs.sk

Abstract
Ordered MCM -48 nano porous silica (SBET = 92 3(3) m2.g-1, VP = 0.63(2) cm3.g-1) with cubic
Ia3d symmetry was used as a support for drug delivery of anti-inflammatory poorly soluble
drug indomethacin. The delivery from parent, unmodified MCM -48, and 3-aminopropyl
modified silica carrier was studied into the simulated body fluid s with the pH =2 and pH =7.4.
The studied samples were characterized by thermal analysis (TG/DTG -DTA), N 2
adsorption /desorption, infrared spectroscopy (FT -IR), powder XRD , SEM, HRTEM methods
and measurements of zeta potential () and dynamic light scattering (DLS) . The determined
content of indomethacin in pure MCM -48 was 21 wt. % and in the amin e-modified silic a
MCM -48A-I was 45 wt. %. The release profile of the drug, in the time period up to 72 hours,
was monitored by TLC chromatographic method. It as shown, that by the modificat ion of the
surface , the drug release can be controlled. The slower release of indomethacin was observed
from amino modified sample MCM -48A-I in the both type s of studied simulated body fluids
(slightly alkaline intravenous solution with pH=7.4 and acidic gastric fluid with pH=2 ), which
was supported and explained by zeta potential and DLS measurements . The amount of the
released indomethacin into the fluids with various pH was different. The maximum released
amount of the drug was 97% for sample containing unmodified s ilica, MCM -48-I at pH = 7.4
and lowest released amount, 57%, for amine modified sample MCM -48A-I at pH = 2 . To
compare the indomethacin release profile four kinetic models were tested. Results showed,
that that the drug release based on diffusi on Higuchi model , mainly govern s the rel ease.

Keywords: Nanoporous silica, MCM -48, drug de livery, indomethacin , drug release kinetics.

1. Introduction
Drug delivery is a process of administering pharmaceutical compound s to achieve a best
therapeutic effect in organism. Most common routes of administration of the drugs to the
organism include the non -invasive , per oral , topical, transmucosal and inhalation routes.
Many drugs may not be delivered using these rout es because they may be susceptible to
enzymatic degradation or cannot be absorbed into the systematic circulation efficiently.
Current efforts in the area of the drug delivery focus on the development of targeted drug
delivery , in which the drug is only active in the target area of the body as well as t he
development of sustained release formulations in which the drug is released over a period of
the time and in the controlled manner from a carrier [1, 2]. Prolonged delivery is interesting
for drugs that are rapidly metabolized and eliminated from the bo dy after administration .
Recently, periodic nanoporous silica materials has been suggested as biocompatible
matrices for drug delivery [3]. Compared with amorphous colloidal and nonporous silica,
nano porous silica materials exhib it higher loading of the drugs and provide a better control of
the drug release. Moreover, the periodic nanoporous silica may be used for delivery of
hydrophobic drug molecules with lack of water solubility , which lead patients to take high
doses of the drug to achieve sufficient t herapeutic effects.
Periodic nano porous matrices were used as carrier s of different substances such as
vitamins [4], analgetics [5-7], antibiotics [8, 9], antihypertensive agents [ 10] anti-cancer drugs
[11], anti-depressants [12], steroids [13], antiviral substances [14] and antimicrobial agents
[15- 17].
It was found that drug loading and release rate could be adjusted by organic
functionalization of the nano porous materials. Modification of surface by different organic
groups such as amino, carboxyl, ch loropropyl, benzyl, butyl, mercaptopropyl, cyanopropyl
improve the drug loading due to the interactions with the functional groups of the drug [18].
For example Tang et al. observed , that the release rate of the model drug could be delayed by
grafting trim ethylsil yl groups onto MCM -41 materials [19]. Song et al. desc ribed that the
animopropyl -modified SBA -15 showed larger drug loading capacity tha n that of pure SBA -15
[20].
From the drug delivery point of view, an interesting mesoporous material , as a drug
carrier, is MCM -48 silica . In contrast to MCM -41 and SBA -15 counterparts , having t he
unidirectional channels of p6mm symmetry , cubic structure of MCM -48 with space group
Ia3d has recently attracted much attention due to its unique penetrating channels net work ,
which is very useful for applications requiring easy molecular accessibility and fast molecular

transport . MCM -48 mesoporous silica material has a discontinuous structure centered on
gyroid minimal surface that allocates available pore space into two non-intersecting sub-
volumes . The structure of MCM -48 makes the mass -transfer faster in comparison with MCM –
41 mesoporous material , which makes MCM -48 as a p romising material for many
applications.
In spite of the presented properties of the cubic mesopo rous silica MCM -48, only a
few works h ave been reported to study this material as a drug delivery support. Izquiedo –
Barba et al. reported adsorption and release of model drugs ibuprofen and erythromycin , using
mesoporous silica MCM -48 [21]. Their results s howed, that the delivery rate of the studie d
drugs decreased with the pore size of the matrix and chemical modification of pore s. A
comparative study o series of pure and functionalized mesostructured silica s, which belong to
MCM -41, MCM -48, SBA -15 family were studied by Ber ger et al. [ 22]. They used antibiotic s
amikacin and kanam ycin as drug molecules . From all mesostructures the lowest amount was
released from MCM -48-kanam ycin system . From XRD results a partial loss of the mesophase
ordering was observed . The degradation of the mesostructure of MCM -48 framework aut hors
explained by thinner pore walls that are less stable in aqueous solution in comparison with
SBA -15 silica . Nath studied the MCM -48 modified by hexamethy ldisilazine and the a ntibiotic
drug ampicillin [1] and they showed that MCM -48 is a good carrier for this drug (75% of
ampicillin w as released after 8 hours).
Different silica materials such as MCM -41, MCM -48 and SBA -15 were load ed by
water insoluble antitumor drug model – diorganotin (IV) di chloride complex [23]. Among
them, nanoporous silica MCM -48, with cage -like pores showed highe st capacity and l owest
release rate which were emphasized are the positive points of MCM -48 for being a good drug
carrier system . The effect of chemical structure and molecular size of the anticancer drugs 5 –
fluorouracil and 7 -hydroxycoumarine on release properties of mesoporous carrier MCM -48
was demonstrated by Hamdallah et al. [ 24]. The release experiments were conducted in acidic
buffer media at pH=5. 2. The rel ease of 5 -fluorouracil was almost complete in 2 hours from
beginning of release . However the release of 7 -hydroxycoumarine , which has a larger
molecular size and higher acidity , took place over a period of 12 hours.
In our previous work we have studied nap roxen uptake an d release from hexagonal
nanoporous silica MCM -41 and SBA -15 [2, 5, 6]. As a continuation of these works, i n the
present study we have used cubic nanoporous MCM -48 silica as a drug delivery system for
delivery of i ndomethacin , [1-(4-chlorobe nzoyl) -5-methoxy -2-methylindol -3-yl]acetic acid
(see Fig. 1) . Indomethacin is an anti -inflammatory drug and in our study it was used as

representing example of poorly soluble (hydrophobic) drug (solubility 7-9 μg/ml at 35°C in
water ), which dissolution rate is consequently very slow. Indometh acin has two main
polymorphs (α, γ) [25]. It is a nonselective inhibitor of cyclooxygenase (COX -1 and COX -2),
enzymes that participate in prostaglandin synthesis from ar achidonic acid in stomach and
intestines, which maintain the mucous lining of the gastrointestinal tract . This drug has
strongly analgesic, antireumatic , antipyretic properties and it is commonly used for
osteoporosis treatment [ 26]. The drug has also negative effect s, like exacerbation of the
gastrointerstinal mucosa [27]. Some articles described the reduction of the si de effects by
esterification of the carboxyl groups of indomethacin [28]. The side effects may be reduced
using the formulations, where dru g is released slowly, in a controlled manner.
In this article we descr ibe release of indomethacin from unmodified and aminopropyl
modified mesoporous silica material MCM -48 into two types of simulated body fluids with
different pH values (slightly alkalin e intravenous physiological solution with pH=7 .4 and
simulated gastric fluid with pH=2). The differences in the release behavior of the studied drug
into the media are presented. Moreover, kinetics of i ndomethacin release was studied using
different kineti c models.

Fig. 1 View of molecular structure of indomethacin , with the approximate molecular sizes
1.36 nm x 0.82 nm x 0.56 nm.

2. Experimental section
2.1. Chemicals and Materials
Cetyltrimethylammonium bromide (CTAB ) was used as the structure directi ng agent
and t etraethyl orthosilicate (TEOS , 97%) was selected as a source of silica . 3-aminopropyl –
triethoxysilane was chosen for silica modification. All chemicals were obtained from Sigma –

Aldrich and used without further purification . Physiological solut ion (intravenous infusion
solution of 0.9% NaCl) was obtained from Braun Company (Germany).

2.2. Synthesis
2.2.1 Synthesis of the mesoporous silica MCM -48
Cubic mesoporous silica MCM -48 was synthesis ed according to the modified
procedure describe d in [29]. The molar ratio of reactants was 1 TEOS / 0.6 CTAB / 0.1 NaF /
60 H2O / 0.5 NaOH. In the typical synthesis tetraethylorthosilicate (TEOS , 5g, 20 mmol ) as
silica source, cetyl trimethyl ammonium bromide (CTAB , 4.35g, 12 mmol ) as surfactant,
sodium hydroxi de (NaOH , 0,39g, 10 mmol ) as alkali source and sodium floride (NaF , 0.085g,
2mmol ) as mineralizer were used . NaOH and NaF were dissolved in distilled water (21.5 cm3)
to form clear solution and heated to 35°C . TEOS was added dropwise under stirring. After 15
min of stirring , CTAB was added to the reaction mixture . Prepared suspension was placed in
Parr Teflon -lined stainless -steel autoclave, heated to 120°C with heating rate of 2°C /min-1 and
kept at this temperature for 24 h. After this time, the reaction m ixture was stepwise cooled
down to room temperature at 1°C.min-1. White powder of templated MCM -48 was collected
by filtration, washed by distilled water and dried. To remove the template from prepared
MCM -48 material calcination was performed . The 2g of t emplated silica w ere placed in an
oven with thermolegulator under stream of air , heated to 150°C with heating rate 2°C.min-1
and kept at this temperature for 2h (dehydratation). After this time, the temperature was
increased to 550°C with heating rate 1°C. min-1 and the sample was kept at this temperature
for 7h. Finally MCM -48 was cooled down to room temperature with cooling rate 3°C.min-1.
The prepared mesoporous matrix was characterized and used for amino -modification or drug
loading.

2.2.3. Modifica tion of MCM -48 silica
The surface modification of MCM -48 silica by 3-aminopropyl ligands was carried out
by grafting method . Before grafting , the silica matrix was thermally treated at 200 °C for 3
hours. During the grafting procedure, the 1g of pre-heated nanoporous silica was dispersed in
50 cm3 of dry toluene (toluene was dried and purified before use according to standard
procedure s and stored over zeolite molecular sieves) . In the next step , 3 cm3 of 3 –
aminopropyltriethoxysilane were added to the suspe nsion of MCM -48 in dry toluene and
refluxed for 20 hours . The solid product was filtered off , washed with toluene and dried at
laboratory temperature . The sample was denoted as MCM -48A.

2.2.4. Indomethacin adsorption and release study
For th e loading of MCM -48 with indome thacin, 400 mg of sample MCM -48 or MCM –
48A was suspended at laboratory temperature in 10 cm3 of ethanol solution of indomethacin
with the concentration 1mg/mL and stirred for 24 hours. The obtained products were filtered
off, gently washe d with ethanol and dried at laboratory temperature. The respectiv e samples
were denoted as MCM -48-I and MCM -48A-I. The amount of the loaded indomethacin was
assessed by thermogravimetry .
For the study of the drug release, 150 mg of the sample MCM -48-I or MCM -48A-I
was soaked into 10 cm3 of physiological solution (pH=7 .4, intravenous infusion solution ) and
into the simulated gastric fluid solution (pH=2, prepared using HCl) at room temperature
under stirring. The released amount of the drug was determined in predefined times intervals
in 1, 3, 5, 7, 24, 48 and 72 hours .

2.3. Characterisation
2.3.1. Characterization of prepared mesoporous matrices
Nitrogen adsorption /desorption measurements were performed on a Quantachrome
NOVA 1200e analyzer at -197°C. Before the experiment, th e samples were outgassed at 110
°C for 12 hours under vacuum (10-2 Torr). The specific surface area (SBET) for each sample
was estimated using the Brunauer -Emmett -Teller (BET), pore size distribution was calculated
from adsorp tion branches of the nitrogen isotherms using BHJ method (theor y of Barrett,
Joyner, Halenda) and pore volumes were calculated also applying BHJ method. For the
reproducibility, each sample was measured twice.
Infrared spectra were recorded on Avatar 6700 FT-IR spectrometer in the range 4000 –
500 cm-1. The samples were prepared in KBr pellets with a sample/KBr weight ratio of 1:100.
Before IR measurements, KBr was dried at 600°C for 2h in an oven and cooled in desiccator.
Thermogravimetric analysis (TG/DT G) with simultaneous differential thermal
analysis (DTA) of the samples were carried out in air atmo sphere (flow rate 30 cm3.min-1).
The samples with weight of 25 mg were placed in Al 2O3 crucible s and heated with heating
rate of 9 °C.min-1 using Netzsch 409 PC instrument in the temperature range 25 – 900°C.
X-ray powder diffraction (XRD) was used to verify the long range ordering of the
prepared materials as well as its symmetry. The XRD patterns were measured on a powder X –
ray diffraction (Bruker AXS D8 Ad vance) , using C uK radiation.
The HRTEM micrographs were taken with a JEOL JEM 3010 (LaB 6 cathode)
microscope operated at 300 kV. Copper grid coated with a holey carbon support film was

used to prepare samples for the TEM observation. A powdered sample was dispersed in
ethanol and the suspension was treated in an ultrasonic bath for 10 min.
SEM micrographs were taken with using a scanning electron microscope (SEM)
Tescan, model VEGA. The accelerating voltage was 30 kV .
The zeta potential of the studied samples and mean diam eter were determined by
Dynamic Light Scattering (DLS) using a Zetasizer NANO -ZS (Malvern Instrument). The
particles size and zeta potential were analysed using a dilute suspension of particles in an
aqueous solution from pH = 2 to pH = 10 and sonicated fo r 5 min before measurement.
Measurements were carried out at temperature 25°C. In Malvern ZetaSizer`s software, the
Henry equation and Smoluchowski approximation was used to calculate Zeta potential from
particles mobility.

2.3.2. Chromatographic analysis of released indomethacin
Chromatographic analysis was performed on a Silufol alumina background TLC plates
(Pre-coated TLC sheets ALUGRAM Xtra Sil G/UV 254, Macherey Nagel ). The samples were
spotted using a 2 μL microsyring. The plates were developed at room temperature in the
vertical trou gh glass developing chamber (20 cm x 20 cm) with benzene -tetrachlormethane –
acetic acid -ethylacetate (30: 6 : 5,5: 1 v/v/v /v) as mobile ph ase to the distance of 8 cm.
Visualiza tion was performed by illumination with UV light source (254 nm) using UV
scanner (Krüss, Germany). Densitometric analysis was performed at 260 nm by Shimadzu
CS-930 TLC Scanner in the absorbance mode. The obtained peak areas served for
quantita tive evalua tion of the drug in the physiological solution and gastric body fluid with
help of calibration curve of standards.
Calibration standards were prepared by diluting solution of indomethacin (1mg/mL of
ethanol) to yield concentrations of 25, 50, 100, 300, 5 00 ng per spot of indome thacin . These
standards were used to construct calibration curve. This curve was constructed by plotting the
peak area against the corresponding concentrations of the analyte by means of the least -square
method.

2.3.3. Kinetic of i ndomethacin release
To investigate the kinetics of drug release , the m odel dependent methods , based on
different mathematical functions describ ing the dissolution were used [ 30]. In order to
determine the suitable drug release kinetic model describing the dissolution profile, the
nonlinear regression module of Origin 8.1 was applied. In our work we tested the zero order,

first order, Higuchi and Korsmeyer -Peppas models to calculate the release profile of the drug
from nanoporous MCM -48.

Zero -order model
The model can be used to describe drug dissolution of several types of modified
release pharmaceutical dosage forms e.g. matrices with low soluble drugs . Drug dissolution
from dosage forms that do not disaggregate and release the drug slowly can be represe nted by
the equation:
Qt = Q 0 + k0t (1)
where Q t is the amount of drug dissolved in time t, Q 0 is the initial amount of drug in the
solution (most times, Q 0 = 0) and k0 is the zero order release constant expressed in units of
concentration/time. To stu dy the release kinetics, data obtained from in vitro drug release
studies were plotted as cumulative amount of drug released versus time [ 30].

First order model
This model can be used to describe the drug dissolution in pharmaceutical dosage
forms containing water -soluble drugs in porous matrices. The release of the drug which
followed first order kinetics can be expressed by the eq uation:
log C = log C 0 – k1t / 2.303 (2)
where C 0 is the initial concentration of drug, k 1 is the first orde r rate constant expressed in
units of time , and t is the time [ 30].

Higuchi model
The example of a mathematical model aimed to describe drug release from a matrix
system proposed by H iguchi [30,31] to describe the drug dissolution from several types of
modified release pharmaceutical dosage forms, like some transdermal systems and matrix
tablets. The model expression is given by the equation:
21
tk QH t
(3)
where Q is the amount of drug released in time t per unit area. Constant kH is Hi guchi rate
constant expressed in units of time.

Korsmeyer -Peppas model
Korsmeyer et al. (1983) derived a simple relationship which described drug release

from a polymeric system using the equation :

n
KPttkQQ
 (4)
where Qt / Q ∞ is a fraction of drug released at time t, k is the release rate constant and n is the
release exponent. The value of n characterizes the release mechanism of drug. The case of n ≤
0.45 corresponds to a Fickian diffusion mechanism, 0.45 < n < 0.89 to non -Fickian transport,
n = 0.89 to Case II ( relaxation ) transport, and n > 0.89 to super case II transport [30].

3. Results and discussion
3.1. HR TEM micrographs
The high -resolution transmission electron microscopy images of MCM -48 sample
(Fig. 1a) reveal th at the sample is composed of uniform pore system with average pore
diameter about 3.5 nm. The HRTEM micrographs confirm cubic symmetry of the pores,
typical for MCM -48 material. The modification of the sample aby amine ligand (Fig. 1b) and
loading of the i buprofen into the pores (Fig. 1c,d) did not influence the porous structure, even
after ibuprofen loading small pore alterations could be observed supposedly due to the
treatment of the samples in the solvents during the loading of the drug.

a b c d
Fig. 1 HRTEM micrographs of the samples a.) MCM -48, b.) MCM -48A, c.) MCM -48-I and
d.) MCM -48A-I.

3.2. SEM micrographs
Scanning electron microscopy (SEM) is used to determine the particle shape, morphology
and particle size of the samples. The SEM micr ographs are shown in Figure 2. From the
figures it can be observed, that the MCM -48 silica has spherical morphology, with the size of
the particles about 9 0 – 120 nm. This spherical particle morphology may be due to the
presence of ammonium hydroxide in th e synthesis, which is known as a morphology catalyst
[32, 33]. Visual inspection of the images (Fig. 2 a -d) indicate that the spherical morphology
was not changed after amine functionalisation of silica. Some change in the surface roughness

upon indomethac in loading was observed (Fig. 2 c,d) . However, the mean diameter of the
particles was not changed.

a b c d
Fig. 2 SEM micrographs of the samples a.) MCM -48, b.) MCM -48A, c.) MCM -48-I and d.)
MCM -48A-I.

3.3. XRD study
In addition to HRTEM, t he pe riodicity of the samples was also reflected by XRD
patter ns. The XRD patterns of the unmodified sample MCM -48 and indomethacin loaded
samples MCM -48-I and MCM -48A-I in the range 2  = 1.5-4° are displayed in Fig. 3. The
sample MCM -48 show two peaks, the mor e intensive one at 2  value about 2.73° and weaker
one at 2 value about 3. 13°. The peaks can be indexed as (211) and (220) in cubic Ia3d space
group with respective d-spacings of ca. 32.3 and 28.2 Å, respectively.
1,5 2,0 2,5 3,0 3,5 4,0(220) Intensity / a.u.
2 / deg1
2
3
(211)

Fig. 3. XRD pattern of unmodified MCM -48 mesoporous silica (curve 1) and indomethacin
loaded samples MCM -48-I (curve 2) and MCM -48A-I (curve 3).

The unit cell parameter, calculated according to the equation a=
6hkld using (211)
reflection, is 79 Å. The diffraction peaks of the indomethacin loaded samples occur at same

2 values as in unmodified MCM -48 silica, which indicates that no change of structural
arrangement during the modification took place. However, after the indomethacin loading, the
second peak indexed as (220) was less pronounced in the drug loaded samples .

3.4. Thermal analysis
The thermal stability and determination of the amount of grafted 3 -aminopropyl
ligands and the drug loading into the modified/unmodified porous matrix was performed by
thermogravimetric analysis (TG/DTA) in air atmosphere. Fig. 4 sho ws TG/DTA curves of the
samples MCM -48, MCM -48A, MCM -48-I and MCM -48A-I. The initial weight loss, in all
samples, in the temperature range from 25°C to 150°C, corresponds to the desorption of water
or toluene molecules from mesoporous matrix, adsorbed duri ng the grafting. The solvent
desorption from the samples was accompanied by endothermic peaks on DTA curves in the
range 80 – 120°C.
After the dehydration (8 wt%), the pure silica MCM -48 matrix is thermally stable in
full studied temperature range, from 1 50 to 900°C (curve a in Fig. 4). Thermogravimetric
analysis of amine modified sample, MCM -48A (curve b in Fig. 4), shows weight loss of 12 %
in the temperature range from 300 to 900°C corresponding to the thermal decomposition of
aminopropyl ligands. The d ecomposition of the ligand was accompanied by the exothermic
peak at 315°C.
The presence of the loaded indomethacin molecules in the sample MCM -48-I was
reflected on DTA curve by the endothermic peak at the temperature of 155°C, which
corresponds to the m elting point of this drug (curve c in Fig. 4) . At higher temperatures,
during thermal decomposition of indomethacin, two exothermic peaks at 337°C and 585°C
were observed on the DTA curve of the sample MCM -48-I. The total mass loss in the
temperature range 300-900°C, corresponding to the indomethacin decomposition, was 21%
(see curve c in Fig. 4), which represents 210 mg of drug in one gram of the sample.
For the sample MCM -48A-I also an endothermic peak at temper ature 155oC was
observed , corresponding to t he melting point of indomethacin. At higher temperatures, after
the indomethacin decomposition, the other exothermic peaks were observed on DTA curve at
the temperatures 342°C, 40 7°C and 580°C. These three steps correspon ded to the
simul taneous decompositi on of indomethacin and amine ligands. The mass loss in the
temperature range 300 – 900°C represented 57% (see curve d in Fig. 4) . From the balance of
the mass loss ob served for the samples MCM -48A and MCM -48A-I in the temperature range
300-900 °C (12% and 57%, respectively) we can conclude that the sam ple MCM -48A-I

contained 45 wt. % of indomethacin, which corresponds to 450 mg of indomet hacin in one
gram of the sample MCM -48A-I.
To sum up, the modification of MCM -48 by amine ligands led to the larger amount of
the loading of the indomethacin. In the non -modified sample MCM -48-I, the loading was
21%, while in the modified sample, MCM -48A-I, the loading represented 45%.
200 400 600 8002030405060708090100012-3-2-10

m / %
Temperature / °C MCM-48A-I
MCM-48-I
MCM-48A
MCM-48a
b
c
d DTA / mV.mg-1

a bc d DTG / %.min-1

Fig. 4 TG and DTA curves of the samples MCM -48 (curve a), MCM -48A (curve b), MCM –
48-I (curve c) and MCM -48A-I (curve d).

3.5. FT-IR spectra
Infrared spectra pure MCM -48 silica matrix and amine modified and /or indomethacin
loaded samples are shown in Fig. 5. The mesoporous silica matrix was reflected in IR spectra
by stretching Si-O-Si bands observed at 1100 cm-1 (asymmetric Si -O-Si stretch ), 790 cm-1
(symmetric Si -O-Si stretch ) and by the bending vibrations, (Si-O-Si), observed at 460 cm-1
(see Fig. 5a, curve 1). Bands around 3400 and 1620 cm-1 were attributed to the stretching and
deformat ion vibrations of physisorbed water , respectively .
The aminopropyl -modified samples were characterized bands of C -H stretching
vibrations of propyl chains observed at about 2930 cm-1 and deformation (C-H) vibrations in
the range of 1500 – 1350 cm-1 (Fig. 5 b, c).
The loading of the indomethacin was reflected by the bands of the carbonyl stretching
vibration ν( C=O) of carboxylic group at 1690 cm-1, the breathing vibrations of the aromatic

rings observed in the spectra in the range 1600 -1500 cm-1. In the region below to the 900 cm-1
the (C-H) vibrations of indomethacin were observed (spectra c, d in Fig. 5a and e, f in Fig.
5b). For the sample MCM -48A-I, also the C-H stretching vibrations of indome thacin , ν(C-H),
at 2980 – 2840 cm-1 were observed. Moreove r, after indomethacin adsorption on amine –
modified mesoporous silica MCM -48 characteristic vibration at 1550cm-1, corresponding to
stretching vibrations of ionized carboxylic groups , were observed. These observations
confirm the ionic character of the drug -carrier interactions .
4000 3500 3000 2500 2000 1500 1000 500
aTransmitance / a.u
Wavenumber / cm-1b

c
4000 3500 3000 2500 2000 1500 1000 500d
Transmitance / a.u
Wavenumber / cm-1e
f

Fig. 5 FTIR spectra of the samples MCM -48 (a), MCM -48A (b), MCM -48A-I (c, f),
indomethacin (d) and sample MCM -48-I (e).

From the results of thermal analysis (see paragraph 3.4 ) it followed, that higher
amount of the indomethacin was loaded into the amine -modified sample MCM -48A-I (45 %)
than into the amine unmodified sample MCM -48-I (21 %). These differences were also
reflected in IR spectra by different intensity of the bands corresponding to the vibrations of
the indomethacin (se e Fig. 5b, curves e, f). Different intensity of the IR bands of
indomethacin in both samples can be also explained by partial immobilization of the
indomethacin on external surface of the amine modified MCM -48 silica.

3.6. Nitrogen adsorption/desorption s tudies
For the assessment of the mesoporosity and evaluation of the textural properties in the
studied materials, the nitrogen adsorption -desorption measurements at 77 K were used. The
calculated textural parameters are summarized in Table 1 and N2 isother ms for the parent
MCM -48 and its amino -modified and drug -loaded a nalogues are shown in the Fig. 6.

The isotherms show t ypical shape of type IV isotherms a s defined by IUPAC [34]
without hysteresis. The initial part of the adsorption isotherms corresponds t o the adsorption
in micropores. The microporosity is highest in parent MCM -48, after amine modification
and/or drug loading the microporosity significantly decreases. In the range of the relative
pressures between 0.25 – 0.4 the adsorption in mesopores tak es place. The mesoporous step is
well pronounced in the samples MCM -48 and MCM -48A. After the drug loading and filling
of the mesopores with indomethacin, the mesoporous adsorption step disappeared, indicating
the successful filling of the pores by the dru g molecules. For the sample MCM -48A-I even no
adsorption was observed after indomethacin loading . We suppose that this can be explained
by pore blocking due to interaction of indomethacin molecules, containing carboxylate
group s, with the amine groups poin ting into pore entrances and subsequent blockage of the
pores.
0,0 0,2 0,4 0,6 0,8 1,00100200300400500
MCM-48
MCM-48A
MCM-48-I
MCM-48A-I
Adsorbed volume / cm3.g-1 @ STP
p/p01
2
3
4

Fig. 6 Nitrogen adsorption/desorption isotherms of parent silica MCM -48 (curve 1), amino –
modified silica MCM -48A (curve 2) and indomethacin loaded samples MCM -48-I (curve 3)
and MCM -48A-I (curve 4).

The n itrogen adsorption isotherms enable the calculation of the specific surface area ,
pore volume, mesopore size distribution and external surface area. The Brunauer -Emmett –
Teller (BET) surfac e area was calculated using experimental points betwe en the relative
pressure ranges of p/p 0 0.05 – 0.3. The pore size distribution was calculated from the
adsorption branch of N 2 isothe rms using the conventional BHJ method. For the calculation of

the e xternal surface area the t-plot method was used . The tex tural properties are summarized
in Table 1.

Table 1 . Structural information and indomethacin loading capacity of studied mesoporous
silica samples
Sample SBET (m2/g) SEXT. (m2/g) VP (cm3/g) DP (nm) Indomethacin
loading(mg/g)
MCM -48
MCM -48A
MCM -48-I
MCM -48A-I 923(3)
410(2)
204(2)
8(1) 77(2)
48(1)
21(1)
5(1) 0.63(2)
0.46(3)
0.24(2)
0.01(1) 3.8(2)
2.8(2)
2.0(1)
– –
–
210
450
SBET – BET surface area, V P – pore volume, D P – pore diameter, S EXT – external surface area. For the
reproducibility, each sample wa s measured twice.

The functionalization of silica and indomethacin loading led to the decrease of textural
properties , change of shape of isotherms and reduc tion of capillary conde nsation step of the
samples MCM -48A, MCM -48-I and MCM -48A-I (Tab. 1 , Fig. 2). The significant change of
BET surface area and pore volume was observed from parent MCM -48 (SBET = 923(3) m2.g-1,
VP = 0.63(2) cm3.g-1) through MCM -48A (SBET = 410(2) m2.g-1, VP = 0.46(3) cm3.g-1), MCM –
48-I (SBET = 204(2) m2.g-1, VP = 0.24(2) cm3.g-1) to MCM -48A-I (SBET = 8(1) m2.g-1, VP =
0.01(1) cm3.g-1). The significant decrease of pore surface and pore volume in the sample
MCM -48A-I is related to the filling of the pores by aminopropyl groups and indomethacin
molecules. We suppose, that t he molecul es of the drug and aminopropyl ligands blocked
pores and no N2 adsorption was observed.

3.7. Surface characteristics, zeta potenital and isoelectric point
Zeta () potential measurements were performed in aqueous suspensions as a function
of pH to determi ne the electrokinetic charge of the materials . The corresponding curves are
shown in Fig . 7. For the pure, unmodified MCM -48 the zeta potential of + 26.47 mV was
recorded at pH near 2, corresponding to the protonation of Si-OH surface hydroxyls . The zero
point of charge (isoelectric point, IEP) of the unmodified silica was determined to be 2.98, in
accordance with literature values for amorphous and mesoporous silica [ 35, 36 ]. With pH
increasing , the  potential becomes more negative as a result of progres sive dissociation of Si –
OH groups, reaching the values of -58,6 mV at pH close to 10 . These results are in
accordance with the data obtained for other silica -based surfaces [ 35, 36 ].

The effect of amine modification and presence of basic amine groups on th e surface of
the sample MCM -48A is reflected in the high zeta potential values (140 mV at pH close to 2),
corresponding to the protonation of amines on the surface and formation of fully protonated
state with the presence of -NH 3+ groups. The functionalisa tion also causes a shift of IEP to
higher pH value (IEP for MCM -48A is 5.3). The isoelectric point of amine modified sample is
close to the basicity constant of aminopropyl ligand ( pKB ~ 4) [37]. Above the isoelectric
point the deprotonation of the surface occurs, leading to the drop in zeta pot ential and
negative surface charge observed for the sample MCM -48A ( -80.3 mV at pH close to 9).
The loading of the indomethacine influenced the zeta potential of the samples, as a ll
surface functions have impact on t he final zeta potential of particles. The indomethacin is
a weak acid (pKa = 4.5) [38] so its protonation/deprotonation influences the surface charge of
the particles together with Si -OH surface hydroxyls , and in case of the MCM -48A-I sample ,
also together with amine -NH 2 groups . The introduction of the indomethacin , as a weak acid ,
into the particles MCM -48 and MCM -48A resulted to the change in the zeta potentials and
IEP observed for the samples MCM -48-I and MCM -48A-I (Fig. 7b) in comparison with the
samp les MCM -48 and MCM -48A. After the indomethacin loading the IEP moved from 2.98
to 2.63 for modified MCM -48A and from 5.3 to 4.17 for amine modified sample (see Fig. 7
a,b).
Together with the zeta potential, dynamic light scattering ( DLS ) measurements were
performed simultaneously by conducting electrokinetic titrations, where particle size was
measured in relation to the changing pH . The results of DLS measurements for the respective
samples are shown in Fig. 7 c, d. As it can be seen, for all the samples the particles showed
good colloidal dispersability in the alkaline pH region . The determined particle size in the
basic conditions using DL S measurements was about 1 10 nm for all four samples. This result
is in a good agreement with the SEM results and syn thesis route. The MCM -48 like materials
are synthesised in the alkaline conditions using the ammonium hydroxide as a morphology
catalyst (see SEM results) [32, 33 ]. Thus in these alkaline conditions the particles are stable
and have no tendency to agglomer ation, as shown by DL S measurements. However, at acidic
conditions the particles start to agglomerat e and increase their size . The agglomeration for the
amine modified samples (MCM -48A and MCM -48A-I) was larger in comparison with the on
modified samples, w hich reflects higher positive charge on the amine modified particles. The
nonmodifed samples MCM -48 and MCM -48-I start to agglomerate at pH below 3.5, while the
amine modified samples MCM -48A and MCM -48A-I increase their size due to agglomeration
at higher pH, below pH = 4.5 -5.0.

2 3 4 5 6 7 8 9-50050100150
IEP= 2.98
(mV)
pH MCM-48
MCM-48A
IEP= 5.3
2 3 4 5 6 7 8 9 10-100-80-60-40-20020406080100
(mV)
pH MCM-48-I
MCM-48A-I
IEP = 4.17
IEP = 2.63
a b

2 3 4 5 6 7 8 9 10050010001500200025003000
Size (nm)
pH MCM-48-I
MCM-48A-I
c d
Fig. 7. Simultaneous electrokinetic titration for the determination of the particle zeta potential
of the samples MCM -48. MCM -48A, MCM -48-I, MCM -48A-I (a, b) and dynamic light
scattering (DSL) for the measureme nt of the particle size (c, d).

3.8. Drug release
The in vitro release of indomethacin from both , non-modified and amino -modified
types of mesoporous supports (MCM -48-I and MCM -48A-I), was investigated in two media,
simulated intestinal body flui d with pH of 7.4 and simulated gastric fluid with pH of 2. The
profiles of cumulative release of indomethacin from the samples MCM -48-I and MCM -48A-I
are shown in Fig . 8.
Slower drug release of indomethacin f rom both types of mesoporous materials was
observed in si mulated gastric fluid . The pH -dependence of release process can be explained
by acidity of indomethacin. Indomethacin is a weak acid ( pKa = 4.5), and therefore its
solubility is higher at slightly alkaline medium than acidic and the release in alkaline med ia
was higher . Moreover, another factor influencing the lower release of the drug in the acidic
media may be agglomeration of the particles at acidic pH , as shown by DLS measurements

(see section 3.7., Fig. 7d ). Due to the agglomeration of the silica parti cles at pH = 2, the
release of the indomethacin from the pores of the agglomerated particles can be hindered,
which results to higher release in the alkaline medium. The results showed, that a t pH=7.4,
95% of indomethacin was released from the sample MCM -48-I after 72 hours and 83 % from
the sample MCM -48A-I. For comparison, at pH = 2, 67% of indomethacin was released from
the sample MCM -48-I after 72 hours and 5 7% from the sample MCM -48A-I (see Fig. 8).
Moreover, the difference in the indomethacin release f rom amine modified sample
MCM -48A-I and non -modified sample was observed. The difference can be explained by the
interactions of indomethacin functional groups (Cl, COOH -), with MCM -48 surface
functional groups. In amine modified sample strong hydrogen bon ding interactions are
present ( –NH 2/–NH 3+…HOOC – or -NH 2–NH 3+…Cl -), which decrease rate of indomethacin
release , especially in the first hours of release. These results were also confirmed by zeta
potential measurements (see section 3.7., Fig. 7a, b), where at pH = 2 and pH = 7.4 the amine
modified samples showed higher surface charge (positive and negative, respectively) in
comparison with the unmodified materials. The higher charge results in stronger interactions
with protonated/deprotonated indomethacine drug either through coulombic interactions or
the hydrogen bonds. Moreover, t he organic functional groups (amines) bonded on the silica
surface can block the pore entrance of MCM -48, which can be another factor influencing a
slower drug release rate in am ine modified sample MCM -48A-I.
In both, alkaline and acidic media, the most of the drug was released in first 10 hours .
In first 10 hours it was released at pH = 7.4 76% of indomethacin from the sample MCM -48-I
and 50% at pH = 2. In the amine modified samp le MCM -48A-I, the functionalization slowed
down the rate of the release . After 10 hours 60% of indomethacin was released at pH = 7.4
and 36% at pH = 2. This first stage of the release was supposedly driven by wetting and the
dissolution of the drug molecul es present on surface and near surface regions . As suggested
by Salomen et al. [ 39] or Hu et al . [40], the non-modif ied silica is more hydrophilic , and more
easily wetted so the fast er dissolution and release of the drug from the sample MCM -48-I than
MCM -48A-I took place. Moreover, the influence of pore blocking by amines and different
surface charge may influence the release of the indomethacin from modi fied and nonmodified
sample, as it was mentioned in the paragraph above.
In the time interval 10 -72 hour s the slopes of the release curves changed (see Fig. 8).
We suppose, that release in this time interval is driven by two factors: wettability of the silica
surface and diffusion of the solvents and drug molecules into/from porous structure. The
organic fun ctional groups (amines) bonded on the silica surface decrease its hydrophilicity

and wettability and increase the surface charge (see Fig. 7), which leads to slower r elease rate
in amine modified sample MCM -48A-I, than nonmodified sample MCM -48-I [40]. The lower
wettability influences slower diffusion of water inside MCM -48A-I sample under in vitro
conditions, when compared to MCM -48-I.
0 10 20 30 40 50 60 70020406080100
MCM-48-I
Time / hrsCumulative release / %

1
2

0 10 20 30 40 50 60 70020406080100
2
Time / hrs
Cumulative release / %
MCM-48A-I1
A b
Fig. 8 Profiles of cumulative releas e of indomethacin from : a.) sample MCM -48-I into the
simulated body fluid wi th pH=7.4 (curve 1) and into the simulated gastric fluid with pH=2
(curve 2). b.) sample MCM -48A-I into the simulated body fluid with pH=7.4 (curve 1) and
into the simulated gastric fluid with pH=2 (curve 2).

3.9. Kinetics of the drug release
To study the mechanism of indomethacin release from amine modified and
unmodified mesoporous silicas , the in-vitro release data (Fig. 8 ) were fitted to various kinetic
models, namely zero order, first order, diffusion Higuchi’s model or Korsmeyer -Peppas
model (see se ction 2.3.3.) [30]. R2 (coefficient of correlation) values were calculated from
regression analysis of the above plots. Based on correlation coefficients listed in Table 2, is
apparent that the drug release from the samples MCM -48-I and MCM -48A-I mainly fo llows a
model based on diffusion (Higuchi model ) and Korsmeyer -Peppas , whereas the zero order
and firs order model seem to be inconvenient for description of indomethacin release kinetics.
For the Higuchi model it can be seen that the lowest constant (k H) 0.20364 was
observed for the sample MCM -48A-I studied at pH=2 and the highest Higuchi constant was
observed for the sample MCM -48A-I at pH=7 .4.
The lowest Korsmeyer -Peppas constant (k KP) 0.23792 was observed for the sample
MCM -48A-I with release of the dru g from in acidic media with pH=2 , while for samples
MCM -48-I at pH= 2 and 7.4 and MCM -48A-I at pH=7.4 the higher highest k KP values were

observed ( 0.30462 , 0.31062 and 0.31311 , respectively ). Moreover, the values of n ≤ 0.45
showed on to a Fickian diffusion mechanism [30].

Table 2 . Models to describe the re lease kinetics of indomethacin from MCM -48-I and MCM –
48A-I matri ces.
Release
model Parameter Formulation (dosage form)
MCM -48-I MCM -48A-I
pH = 2 pH = 7.4 pH = 2 pH = 7.4
Zero order k0 (mol.dm-3.h-1) 0.43805 (3) 0.64135 (8) 0.42781 (4) 0.43297 (5)
r2 0.89837 (8) 0.76773 (3) 0.95036 (11) 0.62741 (8)
First order k1 (h-1) 0.45742 (5) 0.48738 (4) 0.30948 (5) 0.67579 (6)
r2 0.84659 (7) 0.88025 (9) 0.78518 (8) 0.86763 (3)
Higuchi kH (h-0.5) 0.25659 (6) 0.33401 (2) 0.20364 (7) 0.39704 (9)
r2 0.95565 (1) 0.85882 (7) 0.98839 (8) 0.91164 (7)
Korsmeyer –
Peppas kKP (h-n)
n
r2 0.30462 (1)
0.18 (1)
0.98204 (2) 0.31062 (4)
0.24 (1)
0.97215 (7) 0.23792 (6)
0.20 (1)
0.99343 (3) 0.31311 (4)
0.39 (2)
0.94755 (9)

Conclusion s
The cubic nanoporous silica MCM -48 with bicontinous channel system was prepared
and modified with aminopropyl groups. This mesoporous material was chosen as a drug
delivery support due to its uniqu e structure allowing easy molecular accessibility and fast
molecular transport. The coating of silica with aminopropyl groups decreased the release rate
of the poorly soluble drug indome thacin into the released media due to higher surface charge
of the mod ified samples, as shown by zeta potential measurements , and pore blocing by
amine ligads . Moreover, also the acidity of the released media (acidic with pH=2 or slightly
alkaline with pH=7.4) influenced the drug release rate. Higher drug release was observe d in
simulated intravenous solution, with pH = 7.4. This was due to the higher solubility of the
drug in th e alkaline media (indomethancin is a weak acid) as well as the agglomeration of the
particles in the acidic pH, as shown by DLS measurements, which m ay hinder the drug
release. From the studied k inetic models of drug release it followed , that drug release mainly
follows diffusion Higuchi and Korsmeyer -Peppas dependent kinetics models , with Fickian
diffusion mechanism .

Acknowledgements
This work was s upported by the Slovak Research and Development Agency under the
contract APVV -15-0520 and by the Scientific Grant Agency of the Slovak Republic (VEGA)
project no. 1/0745/17. The authors thank the Ministry of Education, Science, Research and
Sport of the S lovak Republic for the financial support of the TRIANGEL team in the frame of
the scheme „Top Research Teams in Slovakia“.

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Highlights
 Cubic MCM -48 nanoporous silica was studied as an indomethacin drug carrier.
 Surface of MCM -48 silica was grafted by amine ligand to change surface chemistry .
 Surface coating resulted into slower indomethacin release.
 Amounts of the released drug depended on pH conditions of the released media.

Graphical abstract

Graphical abstract s ynopsis
Cubic mesoporous silica MCM -48 was studied as drug delivery system . Surface of the silica
was altered by functionalization with amine. Indomethacin release into simulated body fluids,
slightly alkaline intravenous solution with pH=7.4 and acidic gastric fluid with pH=2, was
studied.