British Journal of Pharmaceutical Research

16(6): 1-19, 2017; Article no.BJPR.33553

ISSN: 2231-2919, NLM ID: 101631759

Mesoporous Silica as a Carrier for Amorphous Solid

Dispersion
Smruti P. Chaudhari1* and Anshul Gupte1
1
Mayne Pharma Inc, Greenville, NC, USA.

Authors’ contributions

This work was carried out in collaboration between both authors. Both authors read and approved the
final manuscript.

Article Information

DOI: 10.9734/BJPR/2017/33553
Editor(s):
(1) Mohamed Fathy, Assiut University, Assiut, Egypt.
(2) N. Alyautdin Renad, Chair of The Department of Pharmacology (Pharmaceutical Faculty),
I. M. Sechenov MSMU, Moscow, Russia.
Reviewers:
(1) Parineeta Samant, MGM Medical College, Kamothe, India.
(2) Essien, Enobong Reginald, Bells University of Technology, Nigeria.
(3) S. V. Patil, Ashokrao Mane College of Pharmacy, India.
Complete Peer review History: http://www.sciencedomain.org/review-history/19287

th
Received 20 April 2017
Review Article Accepted 24th May 2017
st
Published 1 June 2017

ABSTRACT

In the past decade, the discovery of active pharmaceutical substances with high therapeutic value
but poor aqueous solubility has increased, thus making it challenging to formulate these
compounds as oral dosage forms. The bioavailability of these drugs can be increased by
formulating these drugs as an amorphous drug delivery system. Use of porous media like
mesoporous silica has been investigated as a potential means to increase the solubility of poorly
soluble drugs and to stabilize the amorphous drug delivery system. These materials have
nanosized capillaries and the large surface area which enable the materials to accommodate high
drug loading and promote the controlled and fast release. Therefore, mesoporous silica has been
used as a carrier in the solid dispersion to form an amorphous solid dispersion (ASD). Mesoporous
silica is also being used as an adsorbent in a conventional solid dispersion, which has many useful
aspects. This review focuses on the use of mesoporous silica in ASD as potential means to
increase the dissolution rate and to provide or increase the stability of the ASD. First, an overview
of mesoporous silica and the classification is discussed. Subsequently, methods of drug
incorporation, the stability of dispersion and, much more are discussed.

_____________________________________________________________________________________________________

*Corresponding author: E-mail: [email protected];

 Chaudhari and Gupte; BJPR, 16(6): 1-19, 2017; Article no.BJPR.33553

Graphical Abstract

Keywords: Mesoporous silica; amorphous solid dispersion; solubility enhancement; stability;

nanoconfinement of drugs; syloid; aerosil.

1. INTRODUCTION amorphous drug and to reduce the conversion

into crystalline form, efforts have been made to
Combinatorial chemistry and high-throughput reduce the driving force of recrystallization by
screening of drugs has led to the discovery of use of precipitation inhibitors [14,15]. The
more and more poorly water soluble drugs [1-3]. chemical potential of the drug in crystalline phase
These are target specific drugs with poor is equal to the chemical potential on the liquid
aqueous solubility, which present a challenge phase at melting point (Tm) of the crystalline
for effective drug delivery. Many strategies drug. However, the chemical potential of the
have been explored to overcome their low amorphous drug is high, which can be lowered
bioavailability because of poor solubility. by the addition of polymer. The drug dispersed in
Converting crystalline drugs into an amorphous an inert water soluble carrier like polymer at the
form is one the most promising tool to overcome solid stage is known as solid dispersion. It is
the problem of poor solubility, as compared to used to improve solubility of amorphous solid
simple micronization of drugs [4] or salt formation dispersion. Hence, the concept of solid
[5], which has many practical limitations. The dispersion is gaining momentum. The concept of
process of amorphization of the drug substance solid dispersion was introduced by Sekiguchi and
involves disruption of the ordered structure of a Obi [16] and it has become the preferred and
crystal which can be achieved by using a most successful method to enhance the drug
process like melt cast, hot melt technology and dissolution and to stabilize the amorphous solid
spray drying [6,7]. Hence, amorphous drug exists dispersion (ASD). To achieve stable ASD, a
at a higher free energy state and has higher single phase system with drug molecules
mobility as compared to their crystalline miscible with the polymer in a single phase
counterpart. The amorphous drug has enhanced forming a glass solution is desired [17-21]. The
thermodynamic properties which lead to higher physical stability of ASD has been attributed to
apparent solubility and dissolution rate [8-10]. several factors. The addition of polymer to ASD
Due to high internal energy and enhanced will help to stabilize the system by reducing the
molecular mobility of amorphous system, it has a mobility of the drug molecules and by increasing
tendency to crystallize during storage and the glass transition temperature of the glass
dissolution [11-13]. In order to benefit from the solutions as compared to pure amorphous drugs,

2
 Chaudhari and Gupte; BJPR, 16(6): 1-19, 2017; Article no.BJPR.33553

and kinetically act as crystallization inhibitors The behavior of drug molecules confined to
[22-24]. Some scientists have also proved that porous media is different than those in bulk. In
the drug-polymer interactions are important for the case of drug molecules confined to porous
stabilization of ASD [22,25,26]. media, the drug molecules have an altered
thermodynamic state which plays an important
Another approach to stabilizing an amorphous role in the physical stability and product
drug delivery system is to use porous media or performance. It may also influence the chemical
adsorbents. Porous media refers to materials stability as well. The purpose of this review is to
with large surface areas (e.g. greater than 500 focus on the use of mesoporous silica in
2
m /g) and pore volumes (e.g. greater than 1 amorphous oral drug delivery system.
cm3/g) [18]. The International Union of Pure and Mesoporous silica can be classified as ordered
Applied Chemistry (IUPAC) classified the porous mesoporous silica and non-ordered mesoporous
media is based on pore size; micropore, silica.
mesopore, and macropore. Micropore has a
mean pore diameter less than 2 nm, mesopores 2. ORDERED MESOPOROUS SILICA
have a pore diameter in between 2- 50 nm and
macropore have a pore diameter greater than 50 Ordered Mesoporous silica (OMS) are porous
nm. materials that exhibit an array of uniform
mesopores. These have a pore diameter
between 2 and 50 nm. OMS exhibit a very high
In the context of Noyes-Whitney equation [27], 2
specific surface area (up to 1500 m /g) and pore
an enhancement of dissolution rate can be 3
volume (up to 1.5 cm /g) and hence they have
achieved by an increase in apparent solubility,
high porosity. OMS (MCM- Mobil Composition of
reduced boundary-layer thickness and higher
Matter) were first synthesized by Mobil Oil
specific surface area [12,28]. Konno T and his
Corporation in 1991. Since then, ordered
co-workers demonstrated the use of porous
mesoporous silica is attracting attention for
media as a potential drug delivery system to
applications in fields such as lasers, sensors,
improve solubility and dissolution rate [29-32].
catalysis and solar cells [37,38]. Due to the
The porous media may be advantageous in
unique features of silica based ordered
enhancing the physical stability of amorphous
mesoporous materials, they are excellent
systems since it has a size constraint effect on
candidates for controlled drug delivery systems
the nucleation and crystal growth. According to
[39]:
the classical theory of homogeneous nucleation,
crystal growth proceeds spontaneously once a • These materials have ordered pore
critical nucleation size is reached. The system network, which is homogeneous in size
will exist in a non-crystalline state if nucleation and allow control of the drug loading and
and growth are prevented. This can be achieved release kinetics for the drug
if spatial constraints of a capillary are imposed • It has a high pore volume which can fit in
[33]. Jackson and McKenna investigated the large amount of pharmaceuticals
mechanism of vitrification using porous
• It has silanol containing surface that can
adsorbents with controlled pore glasses (CPG)
be functionalized to allow better control
with mean pore diameters ranging from 4 to 73
over drug loading and release.
nm and crystalline o-terphenyl as a model
system [34]. Crystallization of o-terphenyl is not Vallet-Regi research team proposed the use of
seen in CPG with 4nm pores, regardless of ordered mesoporous silica as a drug delivery
whether the pores are overfilled or underfilled. system on model drug Ibuprofen [38]. The pore
Since the critical nucleation size is 6.2 nm which channel of MCM-41 was loaded with ibuprofen
is greater than the pore diameter of 4 nm i.e. and this system release the drug in a sustained
there were not enough molecules in the pores to manner. Since then, there has been a
reach the critical nucleus and nucleation could tremendous increase in the use of the
not proceed. Hence, nanoconfinement of drugs mesoporous system as a drug delivery system. A
prevents recrystallization of the drugs thereby significant growth and many efforts have been
stabilizing the amorphous system. It was found devoted to tailoring the nanostructure and
that the drug cannot re-crystallize when the textural properties which allow control over drug
space in which it is confined does not exceed the loading and release kinetics. To confine the large
drug molecule width by at least a factor of 10 [35, size molecule such as protein, Vallet-Regi
36].This unique process can be utilized to deliver developed a method for tailoring pore sizes of
the poorly soluble drugs. Santa Barbara series (SBA-15) mesoporous

3
 Chaudhari and Gupte; BJPR, 16(6): 1-19, 2017; Article no.BJPR.33553

material. They have used hydrothermal treatment dispersion prepared was amorphous in nature
to enlarge the pore diameters. The mesoporous and showed improved dissolution and physical
material synthesized using this novel method stability of the drug.
were named SBA-15-3d, SBA-15-5d, and SBA-
15-7d, the number 3d, 5d and 7d stand for the 2.1 Preparation of Ordered Mesoporous
total time of hydrothermal treatment in the Silica
autoclave [40]. The increasing pore size
increased the drug loading and protein The first ordered mesoporous silica synthesis is
adsorption. based on the use of a surfactant as structure
directing agent for the silica [54,55]. At critical
Various studies have demonstrated enhanced in micelle concentration (CMC) in aqueous solution,
vitro dissolution properties of silica based surfactant molecules start to form aggregates,
materials for a wide variety of compounds. The which are known as micelles. The shape and
mesoporous silicates improve the drug size of the micelle depend on several factors,
absorption by creating supersaturation in vivo such as chemical composition, auxiliary
[41]. In the context of Fick’s first law [42], chemicals, nature of surfactant and reaction
increased intraluminal concentration may conditions such as concentration, pH and
enhance the flux of drug across the temperature. These micelles aggregate to form
gastrointestinal membrane and which eventually supramicellar structures which, depending on the
increases absorption. However, for optimal in conditions, can be cubic, hexagonal or lamellar
vivo performance simply releasing the drug in a to determine the final mesopores framework. The
supersaturated state may not be sufficient, since mechanism of formation of this material takes
rapid precipitation of drugs to more stable place by means of “liquid-crystal templating” (or
crystalline form may jeopardize the absorption cooperative self-assembly), in which the silicate
[43-47]. If we maintain the supersaturated state material forms inorganic walls between ordered
for a sufficient period, it will result in increased surfactant micelles, forming a template
absorption which in turn increases bioavailability. framework. The surfactant is removed by solvent
The addition of excipients which prevent and extraction or calcination process at high
retard precipitation will be beneficial. This type of temperature, this is the last stage of the process.
approach, i.e. in which the formulation As a consequence of template synthesis, a
components generate a supersaturated state of material with narrow pore size distribution and
drug (Spring) and formulation component which ordered distribution of mesopores are achieved.
stabilize the supersaturated solution, A range of new materials with an ordered
precipitation inhibitors (parachute) is known as distribution of mesopores, narrow pore size
Spring and Parachute approach [43,48]. Various distribution, homogeneous pore morphology
dissolution enhancing technologies that are (hexagonal and cubic pores), high surface area
2
associated with the creation of supersaturation (1000m /g), tuneable pore size (2-10 nm) and
3
have been shown to benefit from incorporation of high pore volume (1 cm /g) has been
precipitation inhibitors, for e.g. solid dispersion synthesized. The pore diameter can be varied
[49,50], lipid base systems [44-47] or use of high from 2 to 10 nm by the addition of auxiliary
solubility salts [43]. Speybroeck et al has hydrocarbons such as alkylated benzene or by
demonstrated that the approach of combining changing the alkyl chain length [40]. There are
SBA-15 with an appropriate precipitation inhibitor several types of mesoporous materials
is established as a valuable tool to enhance the discovered, depending on the synthesis
absorption of poorly soluble weak base procedure for e.g. SBA series [56-58], MCM
itraconazole (ITZ) [51]. The pharmaceutical series [55,59-63], KIT-1 (Korea advanced
performances of two precipitation inhibitors institute of Science and Technology no. 1) [64],
(hydroxypropyl methyl cellulose (HPMC) and MSU series (Michigan State University) [65],and
hydroxypropyl methyl cellulose acetate succinate FSM-16 (Folded Sheet Material no.16) [66,67].
(HPMCAS)) were studied. It was found that the Fig. 1 shows the TEM image of most popular
addition of HPMC polymer proved to be a good SBA-15 [68].
stabilizer for ITZ supersaturation in intestinal
media and the addition of HPMC to SBA-15 2.2 Stability of Drug Loaded on Ordered
resulted in more than 60% increase in absorption Mesoporous Silica
[51]. Ambrogi et al investigated the effect of
ordered mesoporous silica like MCM-41 and The stability of ITZ formulation based on ordered
SBA-15 [52,53] on carbamazepine. The mesoporous silica SBA-15 has been studied by

4
 Chaudhari and Gupte; BJPR, 16(6): 1-19, 2017; Article no.BJPR.33553

R. Mellaerts, et al. [69]. Upon contact with the the physical stability of the samples was found
simulated gastric fluid, ITZ is readily liberated satisfactory and drug release performance was
from the pore space of SBA-15 carrier material; a rapid after storage. The dissolution studies
supersaturated ITZ solution is obtained. When revealed the ability of both MCM-41 and SBA-15
this dispersion was stored at 0% RH, the microparticle to improve the dissolution of
performance of the ITZ is maintained. indomethacin by stabilizing it in a disordered
Interestingly, at higher humidity condition of 52% state inside the mesopores and by further
and 97% RH, an even higher supersaturation maintaining this state even during storage in
level is obtained when the aged formulation is accelerated conditions [71]. The chemical
suspended in simulated gastric fluid. This is a analyses show a decrease in the loading degree
very intriguing feature of this formulation. and possible indomethacin degradation product
Conversely, solid dispersion made using polymer formation, especially in MCM-41 based samples
like PVP and HPMC, a decrease release after stressing. The indomethacin SBA-15
performance on storage is observed due to formulation is more stable under stress condition,
crystallization of the drug on storage. Mellaerts R this result is in agreement with the study
demonstrated that under humid conditions, SBA- conducted by Van Speybroeck, et al. [72]. Ten
15 undergoes hydroxylation, which concentrates (10) physicochemically diverse model
the SBA-15 surface more hydrophilic, which compounds were successfully loaded onto SBA-
facilitates the liberation of poorly water soluble 15. In all cases, the adsorbed drug fraction was
ITZ molecules upon competitive adsorption of found to be amorphous, as evidenced by DSC
water molecules in simulated gastric fluid as results. Amorphization of the compounds
shown in Fig. 2 [69]. Thus, it is possible to tune resulted in a significant improvement in the
the release profile of poorly water soluble drugs dissolution rate as compared to the crystalline
by varying SBA-15 hydrophilicity. It is drugs. On the storage of formulation at 25°C and
hypothesized that at high drug loading of ITZ, the 52% RH, no drug crystallization was observed
walls of SBA-15 are coated with drug molecules after 6 months and the pharmaceutical
and thus there are structural changes that occur performance of the SBA-15 formulation was
upon its storage at the humid condition, retained accordingly. The authors concluded that
specifically the void space of SBA-15 are this established the potential of SBA-15 to yield
suppressed and thus the aggregation of physically stable, dissolution enhancing
hydrophobic ITZ is prevented [69]. Limnell et al formulation, irrespective of a drug’s
[70] studied the stability of high drug load physicochemical profile.
indomethacin formulations based on ordered
mesoporous silica, MCM-41, and SBA-15 3. NON-ORDERED MESOPOROUS SILICA
materials. After drug loading, only a small
amount of crystalline materials (<3.0 wt.-%) were Various non-ordered mesoporous silica like
detected by DSC. The physicochemical stability Syloid, Sylysia and aeroperl have been used to
of the high drug load indomethacin formulation improve the dissolution properties of poorly
was found to be variable during prolonged soluble drugs. This mesoporous silica has
storage under stressed conditions. Even though advantages over non-porous high surface area

Fig. 1. TEM images of mesoporous silica SBA-15; Reprinted from reference [68] with
permission from ACS publications

5
 Chaudhari and Gupte; BJPR, 16(6): 1-19, 2017; Article no.BJPR.33553

Fig. 2. Effect of humidity on Ibuprofen loaded SBA-15 surfaces; reprinted from reference [69]
with permission from Elsevier

materials, in which the deposited molecules not dissolution rate by increasing the effective
just are adsorbed on the surface, but also surface area [81]. Another study was conducted
confined to pore that are only a few molecular using poorly soluble drug sulfathiazole and
diameters wide hence preventing recrystallization polyvinyl pyrrolidone as a carrier and Syloid
[73-75]. Takeguchi and coworkers have 244FP as an adsorbent [82]. This method
evaluated the solid dispersion prepared using combined the advantages of conventional solid
porous silica-sylysia 350 like nonporous Aerosil dispersion and surface solid dispersion by
200 on model drug indomethacin [76]. The utilizing the adsorptive nature of porous silica
dissolution rate of indomethacin was faster in the particle and modifying the model drug into
solid dispersion prepared using sylysia as optimal molecular form [82]. This technology
compared to solid dispersion prepared using helps to prevent the recrystallization of the drug
aerosil. A similar study was conducted with on storage by forming strong hydrogen bonds
model drug tolbutamide [77], bicalutamide [78], between the drug and polymer complex, which is
resveratrol [79] and the results were in adsorbed on the porous carrier with further
agreement with the previous study conducted. stabilization effects of silanol group present on
the pore surfaces. Due to the large surface area
3.1 Use of non-ordered Mesoporous of this system, the dispersion is immediately
Silica in Convention Solid Dispersion dispersed as soon as it touches the dissolution
as Adsorbent media and prevents the crystal growth during
dissolution and the higher dissolution rate was
Some scientists had used a combination of melt achieved [82].
granulation and surface adsorption techniques to
enhance the dissolution and tableting properties 3.2 Stability of Drug Loaded on Non-
of poorly soluble drugs like Glibenclamide [80], ordered Mesoporous Silica
Cefuroxime [81]. The solid dispersion of
Cefuroxime used gelucire as melt dispersion Miura et al investigated the stability of poorly
carrier and Sylysia 350 as an adsorbent. The soluble drug K-832 using porous silica Sylysia
surface adsorbent, Sylysia 350 was used not 740 (2.5 nm diameter pores and Sylysia 350
only to impart good flow and compressibility to (21 nm diameter pore) [83]. These formulations
dispersion granules but also to improve the were stored in 60°C and 80% RH in open and

6
 Chaudhari and Gupte; BJPR, 16(6): 1-19, 2017; Article no.BJPR.33553

closed condition. It was observed that al compared the drug incorporation methods
formulation stored in 60°C and 80% RH closed using ordered mesoporous silica SBA-15 and
condition was difficult to crystallize amorphous K- model drugs ibuprofen and ITZ [94]. Three
832 in the mesopores of the silica. However, the loading procedure were studied like adsorption
formulation stored in 60°C and 80% RH in open from solution (solvent method), incipient wetness
conditions showed a diffraction peak at low impregnation and heating of the drug and the
intensities in powder X-Ray diffraction analysis. SBA-15 physical mixture. ITZ was successfully
DSC measurements revealed the difference in dispersed in SBA-15 using adsorption from
heat of fusion of K-832-Sylysia 740 formulation dichloromethane and incipient wetness
increases on storage; however, it is smaller than impregnation method. ITZ molecules were
that of K-832-Sylysia 350 formulation. This result molecularly deposited over micro- and
suggests that K-832 adsorbed on Sylysia 740, mesopores at 20% drug loading. At the higher
which has a smaller pore diameter, has a higher drug loading, an adsorbed layer is formed in
physical stability of amorphous K-832. which ITZ molecules interact in a way similar to
Furthermore, molecular mobility was measured glassy state. The solvent method favors the
13
in relaxation time study using solid state C positioning of ITZ on mesopores wall and the
NMR, revealed that the molecular mobility of K- incipient wetness impregnation methods favor
832 was lower for the 2.5 nm pore than for the 21 positioning in the micropores. The sample
nm pores, thus making the crystallization rate of prepared from solvent method shows fast
amorphous K-832 in the 2.5 nm pores much release kinetics. Ibuprofen was successfully
slower. The result is in agreement with the study incorporated inside the micropores using melt
conducted by Aso, et al. and Masuda, et al. method due to less viscosity in the molten state.
[84,85]. They have correlated crystallization Both ITZ and ibuprofen released fast from SBA -
behavior of amorphous compounds with the 15 when exposed to simulated gastric fluid and
difference in the molecular mobility of amorphous supersaturation solution are easily obtained. The
compounds, which were based on spin-lattice loading of the ibuprofen and ITZ in ordered
relaxation time measured by solid state 13C NMR mesoporous silica by melt method depends on
spectroscopy based on Adams-Gibbs-Veogel the drug molten viscosity, while the ability to form
equation. a homogeneous mixture of drug and silica prior
to the melting step of the process depends on
4. METHOD OF DRUG INCORPORATION the density of the powders and method of
ON MESOPOROUS SILICA blending.

Various methods are available for incorporation Some scientist has used supercritical fluid
of drugs into mesoporous materials like solvent techniques (SCF) to load the drug in mesoporous
deposition methods [86-90], mechanical silica since solvent immersion method often
activation [70,91,92], vapor-phase mediated leads to the pores of mesoporous materials not
mass transfer [32, 93]. In spite, of the preparation be fully utilized, and results in a low drug loading
method, mesoporous silica systems has high efficiency and an increase in dissolution rate [95].
surface area and high surface energy, and Li-hong and coworkers loaded ibuprofen onto
adsorption of the drug molecules on the porous MCM-41 using solvent immersion method and
material allows the system as a whole to supercritical carbon dioxide drug loading
progress to a lower free energy state i.e. Gibbs procedure [95]. It was found that the amount and
free energy is reduced and this type if systems the depth of ibuprofen entered the pores of the
are stable [18]. The drug exists as an amorphous mesoporous silica by SCF technique were larger
material in these systems and crystallization of than those by the solution immersion method. A
amorphous material will take place only if the similar study conducted on Vitamin E [96] and
thermodynamic state of the system is disturbed. results were in agreement with the previous
In addition to thermodynamic factors, crystal study. The drug loading methods like solvent
growth and nucleation is hindered by spatial immersion, supercritical carbon dioxide, and
constraints, i.e. the pores are not able to liquid carbon dioxide, were able to convert
incorporate enough molecules in order for them crystalline drug in the amorphous state [83,97-
to reach a critical nucleation size [18,34,89]. 99]. The spontaneous transition of crystalline to
the amorphous state of drug occurred in physical
The physical state of hydrophobic drug mixes of drug and silica via a vapor phase-
molecules in ordered mesoporous silica is mediated pathway for drugs with a relatively low
influenced by the loading procedure. Mellaerts et vapor pressure [93]. This unique phase

7
 Chaudhari and Gupte; BJPR, 16(6): 1-19, 2017; Article no.BJPR.33553

transformation phenomena are a simple and represent the TEM images of surface
effective way to improve the aqueous solubility functionalized mesoporous silica. It was found
and bioavailability of poor water soluble drugs. that the release rate of ibuprofen functionalized
by post synthesis can be effectively controlled as
5. EFFECT OF SURFACE compared to that from pure SBA-15 and SBA-15
FUNCTIONALIZATION functionalized by one-pot synthesis due to ionic
interaction between the carboxyl group in
The drug loading is governed by interfacial ibuprofen and an amine group on the surface of
interactions between the drug molecules and the SBA-15. However, the release rate of bovine
surface of the mesoporous silica. The surface serum albumin functionalized by one-pot
chemistry of the mesoporous silica determines synthesis is more favorable due to the balance of
the two common mechanisms like physical and electrostatic interaction and hydrophilic
chemical adsorption. Generally, if one seeks interaction between the bovine serum albumin
enhanced drug dissolution, physical adsorption and the functionalized SBA-15 matrix. Similar
like hydrogen bonding, electrostatic and results were observed for mitoxantrone, the
hydrophobic interactions are preferred. The release rate is strongly dependent on the pH of
unmodified mesoporous silica is covered by –OH the release medium and the type of surface
groups, hence hydrogen bonding are the most functional group [101]. Conversely, Vallet-Regi
common interaction [38,39]. Song et al. [100] and co-workers found that ibuprofen loading was
studied the functionalized mesoporous silica higher in non-functionalized MCM-41 silica
SBA-15 with the amine group through post- compared to amine-modified silica [102].
synthesis and one pot synthesis on model drug A similar trend was observed for
ibuprofen and bovine serum albumin. Fig 3 erythromycin [103].

Fig. 3. TEM images of the different surface functionalized mesoporous silica, with their
corresponding size distribution: (a and b) MSN45; (c) MSN90; (d) conventional MSN150;
(e) MSN300; and (f) MSN500. The insets (in a, c, and d) are HRTEM images, reprinted from
reference [104] with permission from Elsevier

8
 Chaudhari and Gupte; BJPR, 16(6): 1-19, 2017; Article no.BJPR.33553

6. EFFECT OF PORE SIZE AND drug loading). Ibuprofen loaded on a carrier with
PARTICLE SIZE 3.6 nm pore size, a monolayer of drug molecules
fully occupied the pore surface and the space in
The pore size can determine how large the middle of the pore was available to allow the
molecules can be loaded to the carrier molecule, drug molecules to freely diffuse as seen in Fig. 4.
and it is very crucial for drug loading because of As the pore size decreased to 2.5 nm, due to
the mesopores in mesoporous silica act as geometrical consideration (steric hindrance) the
sieves. The pore should be accessible for drug close packing of the drug molecule along the
molecule and in general, the pore diameter/drug pore wall was avoided. Zhang et al. [109] studied
molecule size should be >1. For high drug the another poorly soluble drug telmisartan on
loading in the mesoporous material, the ratio of the spherical mesoporous silica, increasing pore
pore diameter/drug molecule size should be size from 3.6 nm to 12.9 nm have increased the
greater than 3. Shen et al. [90] studied the effect drug loading to 59.7% in 12.9 nm pores. Kinnari
of pore size and particle size of ordered et al. [87] studied non-ordered mesoporous silica
mesoporous silica material on model drug (Syloid AL-1 and 244) microparticle as a carrier
ibuprofen. Mesoporous silica material (MCM-41 for a hydrophobic drug ITZ. The drug loading
and SBA-15) with varied pore and particle size was performed by the immersion method, in
was co-spray dried at high drug loading with which the particles were immersed into
ibuprofen. The solid dispersion obtained has a concentration ITZ solution in dichloromethane
significant enhancement in the dissolution rate, (high and low drug concentration). The two
which was affected by physical state and particle syloid showed similar drug loading capacities
size of ibuprofen in mesoporous structure. when low drug concentration was used despite
Amorphous state of ibuprofen was obtained their significant differences in the pore size,
when ibuprofen was co-spray dried with MCM-41 surface area, and pore volume. At high loading
and SBA-15 with a pore size smaller than 10 nm concentrations of ITZ, the loading capacities for
due to nano space confinement. In contrast, syloid AL-1 and 244 was increased to 25.1 and
when ibuprofen is co-spray dried with SBA-15 32.8 w-% respectively. The higher drug loads
with a pore size of above 20 nm nanocrystal observed for the mesoporous silica particles
were obtained and it had a slower dissolution might be attributed to different pore geometry.
than SBA-15 and MCM-41. The particle size of The surface structure of the mesoporous silica
mesoporous silica showed less than a contains a large amount of silanol groups that
pronounced effect on the dissolution of are favorable for interactions with ITZ through
ibuprofen. Vallet-Regi [40] use the hydrothermal hydrogen bonds. ITZ was present in an
effect to make mesoporous silica with different amorphous form which resulted in a significant
pore size by use of different surfactant. The improvement in dissolution. The amorphous form
swelling effect of the surfactant template which of ITZ was confirmed by DSC, XPRD
ultimately leads to increase in pore size of SBA- measurements, SEM. Further, the FTIR
15 has increased from 8.4 mn up to 11.4 nm due investigations revealed that loading process did
to the increase in pressure. Control of the pore not change the chemical structure or morphology
size and morphology of porous silica drug of the particle surface. The release of ITZ at pH
carriers have been found to affect the drug 1.2 from Syloid AL-1 microparticle was found to
dissolution profile [105-107]. The release kinetics be faster than Syloid 244 particles.
of confined drugs depends on pore diameter and
the particle size/morphology, drug release may 7. EFFECT OF SOLVENT
occur in the order of minutes, hours or even
days. Drug loading is influenced by the polarity of the
solvent. Dimethyl sulfoxide (DMSO) is very polar
Horcajada et al. [108] also studied the effect of solvent and it can form competitive adsorption
pore size of mesoporous silica MCM-41 on the with the drug molecules causing a low degree of
drug loading on ibuprofen. MCM-41 was drug loading. Charnay et al. [110] systematically
prepared with different pore sizes by using studied the effect of solvent (DMSO,
surfactant molecules with different lengths of the dimethylformamide (DMF), dimethylacetamide
alkyl chain. Ibuprofen was adsorbed on (DMA), ethanol and hexane) on drug loading of
mesopores of MCM-41 with varying pore size, poorly soluble drugs. It was revealed that
more ibuprofen molecules were loaded into the ibuprofen was not loaded into the MCM-41
carrier with the pore size of 3.6 nm (19% wt drug mesoporous material when DMA is used as a
loading) than with a pore size of 2.5 nm (11% wt solvent, this is the result of the extreme polarity

9
 Chaudhari and Gupte; BJPR, 16(6): 1-19, 2017; Article no.BJPR.33553

of the DMA solvent. However, in hexane, the ibuprofen. The results suggest the presence
loading capacity was up to 37% wt. The solvent hydrogen bonding between the drug and
plays an important role on the drug loading with mesoporous material. Hydrogen bonding is the
mesoporous material based on TiO2 and Al2O3. weak intermolecular forces and hence it does not
control the dissolution of the drug molecules from
8. DRUG RELEASE MECHANISM the mesoporous material. However, Anderson et
al [113] observed two-step release phenomenon
To design the optimal carrier system one must with ordered mesoporous silica carrier according
have a thorough understanding of drug release to the fitting of the release data with Higuchi
kinetics. The release profile of poorly soluble equation due to the degradation of mesoporous
drugs can be fitted with Higuchi equation [111] carrier MCM-41 and SBA-3. Nevertheless, the
(Eq. (1)). deviation from Higuchi equation is less
pronounced for the more stable mesoporous
ܳ = ‫ ݐܭ‬ଵ/ଶ (1) carrier. Similar two step release mechanism was
observed for thermally stabilized PSi (TCPSi,
Where Q is the cumulative amount of drug
thermally carbonized PSi and TOPSi, thermally
release at time t, and K is the Higuchi constant.
oxidized PSi) and non-ordered mesoporous silica
The release of drug molecules from the insoluble (Syloid AL-1 and 244) (Fig. 5) [87]. Kinnari et al
carrier is described by Higuchi equation. Since showed that in the first stage, the physically
the mesoporous materials are manufactured entrapped drug molecule is released faster and
using inorganic solvents and compound, they are in the second stage slower release rate is
not soluble in the aqueous solution under the observed due to chemical bonding between the
biological condition and hence, as suggested by drug and the surface of the mesoporous
Higuchi equation the drug release from inorganic materials which sufficiently agreed with the
material is the diffusion controlled process [111]. Higuchi model (Fig. 5). Some scientist showed
Hence Higuchi equation can be applied to the that the drug molecule located on or near the
carrier of the mesoporous system to explain the surface of the porous material can be released
drug release kinetics [108,112,113]. Zhao et al quickly due to instant dissolution and release in
[112] showed a pure Higuchi type of diffusion medium, whereas the drug molecules packed
driven drug release with hollow magnetic deeper inside the pore network are released
mesoporous silica carrier on model drug slower [72,114].

Fig. 4. Ibuprofen molecules inside the pore channels of different pore sized MCM-4; reprinted
from reference [108] with permission from Elsevier

10
 Chaudhari and Gupte; BJPR, 16(6): 1-19, 2017; Article no.BJPR.33553

Fig. 5. Release of itraconazole at pH 1.2 fitted with Higuchi model; reprinted from reference
[87] with permission from Elsevier

Fig. 6. Release profile of ibuprofen (initial 60%) at pH 5.5 fitted with Korsmeyer–Peppas model;
Reprinted from reference [116] with permission from Elsevier

The drug release kinetics from the mesoporous If n= ½ in Eq. (2), this model is reduced to
carrier can be described in a more Higuchi model describes diffusion controlled
comprehensive way by Korsmeyer –Peppas release. The drug release characteristics of
equation (Eq. ( 2)). ibuprofen loaded TUD-1 and MCM-41 the
release profile is fitted with the Korsmeyer-
ெ௧ Peppas model [116] is shown in Fig. 6. The
‫ = ܨ‬ቀ ቁ = ‫ܭ‬௠ ‫ ݐ‬௡ (2)
ெ kinetic constant of K=10.7 was observed for the
TUD-1 carrier, which is higher than MCM-41
Where, F is the fraction of the drug release at (k=4.7) demonstrated the unrestricted release of
time t, M is the total amount of loaded drug in the the drug from release medium due to high
mesoporous carrier; Km is the kinetic constant accessibility and stability of the TUD-1-1
and n is the release constant which describes the mesoporous network. The modeling of the
drug release mechanism [115]. dissolution curve of the pure crystalline form of

11
 Chaudhari and Gupte; BJPR, 16(6): 1-19, 2017; Article no.BJPR.33553

ibuprofen shows the much slower release of the MSM-microparticle tablet). Fig. 7 shows the in
drug (k=0.6) compared to the mesoporous vivo mean plasma concentration of telmisartan
carrier. The release constant n revealed that the following an oral dose of a Micardis tablet and
ibuprofen release mechanism of the TUD- telmisartan loaded in the nano and microparticles
1(n=0.64) material was more diffusion based of mesoporous silica in beagle dogs. The release
than the MCM-41 material (n=0.71). The highly rate is significantly improved in comparison with
accessible nano reservoir of the TUD-1 material commercially available Micardis. The results
provided a relatively unrestricted release of were confirmed with subsequent in vivo studies
ibuprofen, whereas the long and narrow in dogs. The AUC 0-72 h was approximately 1.29
mesopores pathway of MCM-41 sterically times greater when MSM was administered and
hindered the free diffusion of ibuprofen from the the mean value of Cmax for MSN was 1,24 and
mesopores. However, Korsmeyer-Peppas model 1,13- fold greater than that of the commercially
was found to describe only the first 60% of the tablet and MSM. These results have shown that
drug release [116,117]. use of mesoporous material increases the
bioavailability of the poorly water soluble BCS
The mesoporous silica carrier also affects the class II and IV drugs. The drug loaded in
permeation properties of the drug molecules. The mesoporous silica create a supersaturated drug
mesoporous silicon nanoparticle loaded with solution in vivo which has a tendency to
telmisartan significantly enhance telmisartan crystallize out [41] and hence the addition of
permeability and reduce the drug efflux excipients which reduces precipitation will be
[118]. The cellular uptake of mesoporous silica useful. Some scientists have incorporated
is highly time, concentration and size polymeric materials in amorphous formulations to
dependent. inhibit the precipitation and in vivo studied were
conducted in rats [48]. In this study, combined
9. In vivo STUDIES use of SBA-15 and precipitation inhibitor like
HPMC and HPMCAS was used to improve oral
The poor correlation between in vitro and in vivo absorption of ITZ. In vitro studies indicated that
results emphasizes the importance of animal HPMC and HPMCAS inhibited the crystallization
tests when developing formulations with poorly up to 4 hours. Surprisingly, in vivo studies carried
soluble drugs. The poorly soluble drugs are out showed lower AUC of a formulation
successfully loaded into mesoporous silica as an containing HPMCAS than formulation without
amorphous or disordered form. The enhanced HPMCAS. The formulation with HPMC showed
drug dissolution is observed when using the higher AUC than the formulation without
mesoporous silica as a carrier. Hence we expect HPMC. However, Vandecruys et al showed that
it to have enhanced bioavailability [40,48,97]. precipitation kinetics cannot be effectively
The in vivo performance of ordered mesoporous inhibited by excipients [119]. Further, the
silica as a carrier for ITZ was evaluated in rabbits selection of excipients mediated precipitation
and dogs [40]. After oral administration of inhibition is dealt on the empirical basis [43,119]
ordered mesoporous silica loaded with ITZ to and structure activity relationship is not yet
dogs, the area under the curve 0-8 h (AUC0-8) established. It is well understood that degree of
was 681 ± 566 nM while no systemic ITZ was supersaturation and rate at which
detected when pure crystalline ITZ was supersaturation is created affects the rate and
administered. In rabbits, after oral administration mechanism by which precipitation occurs [120].
of ordered mesoporous silica loaded with ITZ, This phenomenon was studied on model drug
AUC0-24 was increased to 1069 ± 278 nM which fenofibrate in which ordered mesoporous
was double of that of crystalline ITZ. When SBA- silica SBA-15 and MCM-41 of varying
15 is used as a mesoporous carrier, tmax was pore diameters were loaded with fenofibrate.
decreased to 4.2±1.8 h. The pharmacokinetic The in vitro release rate analysis showed
parameters obtained with SBA-15 were that increase in release rate as we increase
comparable to commercially available the pore size. However, the In vivo
Sporanox®. Zhang et al. [109], studied the experiments conducted in rats showed the
release and bioavailability of telmisartan loaded bioavailability of fenofibrate increases as we
in the nano and microparticles of mesoporous decrease the pore size [121]. More
silica, Fig. 7. Both nano and micro particle were understanding is needed to gain a better
compressed into tablets and the drug release understanding.
rate was studied (MSN -nanoparticle tablet and,

12
 Chaudhari and Gupte; BJPR, 16(6): 1-19, 2017; Article no.BJPR.33553

Fig. 7A. Release profile of telmisartan (TEL) from A) TEL-loaded MSN tablet, (B) TEL-loaded
MSM tablet and (C) TEL commercial tablet in Phosphate buffer solution (pH6.8); Reprinted
from reference [118] with permission from ACS publication; Fig. 7B: In vivo mean plasma
concentration versus time curves of TEL following an oral dose of (a) a Micardis tablet,
(b) a TEL-MSM tablet and (c) a TEL-MSN tablet (equivalent to 40 mg of TEL) in beagle dogs.
Each data point represents the mean ± SD (n = 6); Reprinted from reference [118] with
permission from ACS publication

10. CONCLUSION decrease in Gibbs free energy. However, more

work is needed to understand the detailed
Mesoporous silica is a promising candidate to mechanism of interactions of drugs in
improve the release profile of poorly soluble mesoporous silica. There is very little information
drugs. Since the drug loading is taking place by available about the molecular arrangements and
physical adsorption and subsequent pore filling a vibrational spectroscopy, which is used to gain
wide variety of drugs can be used and dosage information on molecular interactions such as
forms can be prepared using a downstream hydrogen bonding and intermolecular forces and
process like compression or capsule filling. bonding between the drug molecule and the
Although several in vitro studies showing the mesoporous material. Commercialization of
enhanced dissolution behavior by use of mesoporous silica formulation is possible if the
mesoporous silica are carried out, but there are mechanism of interaction is studied in dept. Silica
relatively few in vivo studies on this topic. Hence, based material like aerosil have already been
all the features of the mesoporous carrier have used as pharmaceutical excipients for several
not been thoroughly explored. These years and hence the obstacle for
mesoporous carriers not only improve the commercialization of the technology is minimal.
dissolution but also permeation of the drug
across the gastrointestinal membrane. The data CONSENT
in the literature have demonstrated the scientific
and commercial promises of using mesoporous It is not applicable.
silica as an amorphous delivery system.
Amorphization of the drug loaded on the
ETHICAL APPROVAL
mesoporous materials occurs through the
limitation of space i.e. if the pore size of the
mesoporous material is smaller than the critical It is not applicable.
nucleation size which will eventually lead to
stabilization of the amorphous drugs by COMPETING INTERESTS
decreasing mobility of the drug molecule by
incorporating them in the pore of the mesoporous Authors have declared that no competing
material. The system is physically stable due to a interests exist.

13
 Chaudhari and Gupte; BJPR, 16(6): 1-19, 2017; Article no.BJPR.33553

REFERENCES 14. Khougaz K, Clas SD. Crystallization

inhibition in solid dispersions of MK-0591
1. Lipinski CA. Drug-like properties and the and poly (vinylpyrrolidone) polymers. J.
causes of poor solubility and poor Pharm. Sci. 2000;89(10):1325-1334.
permeability. J. Pharmacol. Toxicol. 15. Fort JJ, et al. Inhibitors of crystallization in
Methods. 2000;44(1):235-249. a solid dispersion. Google Patents; 2015.
2. Wenlock MC, et al. A comparison of 16. Sekiguchi K, Obi N. Studies on absorption
physiochemical property profiles of of eutectic mixture. I. A comparison of the
development and marketed oral drugs. J. behavior ofeutectic mixture of sulfathiazole
Med. Chem. 2003;46(7):1250-1256. and that of ordinary sulfathiazolein man.
3. Gribbon P, Andreas S. High-throughput Chem. Pharm. Bull. 1961;9:866-872.
drug discovery. What can we expect from 17. Marsac PJ, Li T, Taylor LS. Estimation of
HTS? Drug Discovery Today. 2005; drug–polymer miscibility and solubility in
10(1):17-22. amorphous solid dispersions using
4. Kesisoglou F, Panmai S, Wu Y. experimentally determined interaction
Nanosizing — oral formulation parameters. Pharm. Res. 2008;26(1):139-
development and biopharmaceutical 151.
evaluation. Advanced Drug Delivery 18. Qian F, Huang J, Hussain MA. Drug-
Reviews. 2007;59(7):631-644. polymer solubility and miscibility: Stability
5. Serajuddin ATM. Salt formation to improve consideration and practical challenges in
drug solubility. Advanced Drug Delivery amorphous solid dispersion development.
Reviews. 2007;59(7):603-616. J. Pharm. Sci. 2012;99(7):2941-2947.
6. Adelli GR, et al. Evaluation of topical 19. Rumondor ACF, et al. Evaluation of drug-
hesperetin matrix film for back-of-the-eye polymer miscibility in amorphous solid
delivery. Eur. J. Pharm. Biopharm. dispersion systems. Pharm. Res.
2015;92:74-82. 2009;26(11):2523-2534.
7. Adelli GR, et al. Diclofenac sodium ion 20. Patil VS, Dziubla TD, Kalika DS. Static and
exchange resin complex loaded melt cast dynamic properties of biodegradable poly
films for sustained release ocular delivery. (antioxidant β-amino ester) networks
Drug Delivery. 2017;24(1):370-379. based on incorporation of curcumin
8. Hancock BC, Zografi G. Characteristics multiacrylate. Polymer. 2015;75:88-96.
and significance of the amorphous state in 21. Mitov MI, et al. In vitro cellular assays for
pharmaceutical systems. J. Pharm. Sci. oxidative stress and biomaterial response.
1997;86(1):1-12. Oxidative Stress and Biomaterials.
9. Kaushal AM, Chakraborti AK, Bansal AK. 2016;145.
FTIR studies on differential intermolecular 22. Janssens S, Van den Mooter G. Review:
association in crystalline and amorphous Physical chemistry of solid dispersions. J.
states of structurally related non-steroidal Pharm. Pharmacol. 2009;61(12):1571-
anti-inflammatory drugs. Molecular 1586.
Pharmaceutics. 2008;5(6):937-945. 23. Van den Mooter G, et al. Physical
10. Yu L. Amorphous pharmaceutical solids: stabilisation of amorphous ketoconazole in
Preparation, characterization and solid dispersions with polyvinylpyrrolidone
stabilization. Advanced Drug Delivery K25. Eur. J. Pharm. Sci. 2001;12(3):261-
Reviews. 2001;48(1):27-42. 269.
11. Jaakko Aaltonen TR. Towards physico- 24. Hancock BC, Shamblin SL, Zografi G.
relevant dissolution testing: The Molecular mobility of amorphous
importance of solid-state analysis in pharmaceutical solids below their glass
dissolution. Dissolution Technologies. transition temperatures. Pharm. Res. 1995;
2009;16(2):47-54. 12(6):799-806.
12. Hancock BC, Parks M. What is the true 25. Matsumoto T, Zografi G. Physical
solubility advantage for amorphous properties of solid molecular dispersions of
pharmaceuticals? Pharm. Res. 2000; indomethacin with poly (vinylpyrrolidone)
17(4):397-404. and Poly (vinylpyrrolidone-co-vinyl-acetate)
13. Kaushal AM, Gupta P, Bansal AK. in relation to indomethacin crystallization.
Amorphous drug delivery systems. Pharm. Res. 1999;16(11):1722-1728.
Molecular Aspects, Design, and 26. Konno H, Taylor LS. Influence of different
Performance. 2004;21(3):62. polymers on the crystallization tendency of

14
 Chaudhari and Gupte; BJPR, 16(6): 1-19, 2017; Article no.BJPR.33553

molecularly dispersed amorphous 37. Horcajada P, et al. Bioactivity in ordered

felodipine. J. Pharm. Sci. 2006;95(12): mesoporous materials. Solid State
2692-2705. Sciences. 2004;6(11):1295-1300.
27. Noyes AA. Whitney WR. The rate of 38. Vallet-Regi M, et al. A new property of
solution of solid substances in their own mcm-41: drug delivery system. Chemistry
solutions. J. Am. Chem. Soc. 1897;19(12): of Materials. 2001;13(2):308-311.
930-934. 39. Salonen J, et al. Mesoporous silicon in
28. Leuner C. Dressman J. Improving drug drug delivery applications. J. Pharm. Sci.
solubility for oral delivery using solid 2008;97(2):632-653.
dispersions. Eur. J. Pharm. Biopharm. 40. Vallet-Regí M, et al. Bone-regenerative
2000;50(1):47-60. bioceramic implants with drug and protein
29. Konno T. Physical and chemical changes controlled delivery capability. Progress in
of medicinals in mixtures with adsorbents Solid State Chemistry. 2008;36(3):163-
in the solid state. IV. Study on reduced- 191.
pressure mixing for practical use of 41. Brouwers J, Brewster ME, Augustijns P.
amorphous mixtures of flufenamic acid. Supersaturating drug delivery systems.
Chem. Pharm. Bull. (Tokyo). 1990; The answer to solubility-limited oral
38(7):2003-2007. bioavailability? J. Pharm. Sci. 2009;98(8):
2549-2572.
30. Konno T. Physical and chemical changes
42. Fick A. Ueber diffusion. Annalen der
of medicinals in mixtures with adsorbents
Physik. 1855;170(1):59-86.
in the solid state. III. Determination of
43. Guzmán HR, et al. Combined use of
vapor pressure of solid drugs by steam
crystalline salt forms and precipitation
distillation. Chem. Pharm. Bull. (Tokyo).
inhibitors to improve oral absorption of
1990;38(4):1032-1034.
celecoxib from solid oral formulations.
31. Konno T. Kinuno K. Physical and Journal of Pharmaceutical Sciences. 2007;
chemical changes of medicinals in 96(10):2686-2702.
mixtures with adsorbents in the solid state. 44. Gao P, et al. Characterization and
II. Application of reduced pressure optimization of AMG 517 supersaturatable
treatment for the improvement of S-SEDDS; Emulsifying drug delivery
dissolution of flufenamic acid. Chem. system (S-SEDDS) for improved oral
Pharm. Bull. (Tokyo). 1989;37(9):2481- absorption. J. Pharm. Sci. 2009;98(2):516-
2484. 528.
32. Konno T, Kinuno K, Kataoka K. Physical 45. Gao P, et al. Enhanced oral bioavailability
and chemical changes of medicinals in of a poorly water soluble drug PNU‐91325
mixtures with adsorbents in the solid state. by supersaturatable formulations. Drug
I. Effect of vapor pressure of the Dev. Ind. Pharm. 2004;30(2):221-229.
medicinals on changes in crystalline 46. Gao P, Morozowich W. Development of
properties. Chem. Pharm. Bull. (Tokyo). supersaturatable self-emulsifying drug
1986;34(1):301-307. delivery system formulations for improving
33. Elber R. Molecular dynamics in restricted the oral absorption of poorly soluble drugs.
geometries. Joseph Klafter, Drake JM. The Expert Opinion on Drug Delivery. 2006;
Quarterly Review of Biology. 1990; 3(1):97-110.
65(4):497-497. 47. Gao P, et al. Development of a
34. Jackson CL, McKenna GB. Vitrification supersaturable SEDDS formulation of
and crystallization of organic liquids paclitaxel with improved oral bioavailability.
confined to nanoscale pores. Chemistry of J. Pharm. Sci. 2003;92(12):2386-2398.
Materials. 1996;8(8):2128-2137. 48. Guzman HTM, Zhang Z,
35. Rengarajan GT, et al. Stabilization of the Ratanabanangkoon P, Shaw P, Gardner
amorphous state of pharmaceuticals in C, Chen H, Moreau J, Almarsson O,
nanopores. Journal of Materials Chemistry. Remenar J. A "spring and parachute"
2008;18(22):2537-2539. approach to designing solid celecoxib
36. Sliwinska-Bartkowiak M, et al. Freezing formulations having enhanced oral
behavior in porous glasses and MCM-41. absorption. AAPS. 2004;J(6: Abstract):
colloids and surfaces. A Physicochemical T2189.
and Engineering Aspects. 2001;187– 49. Chaudhari SP, Dave RH. Evaluating the
188:523-529. effects of different molecular weights of

15
 Chaudhari and Gupte; BJPR, 16(6): 1-19, 2017; Article no.BJPR.33553

polymers in stabilizing supersaturated drug 60. Kaneda M, et al. Structural study of

solutions and formulations using various mesoporous MCM-48 and carbon
methodologies of the model drug. networks synthesized in the spaces of
Fenofibrate. J. Pharm. Sci. Pharmacol. MCM-48 by electron crystallography. The
2015;2(3):259-276. Journal of Physical Chemistry B. 2002;
50. Chaudhari SP, Dave RH. Investigating the 106(6):1256-1266.
effect of molecular weight of 61. Kruk M, et al. Adsorption and
polyvinylpyrrolidone and hydroxypropyl thermogravimetric characterization of
methyl cellulose as potential mesoporous materials with uniform
antiprecipitants on supersaturated drug organic−inorganic frameworks. The
solutions and formulations using weakly Journal of Physical Chemistry B. 2001;
acidic drug. Indomethacin. Int J Pharm Sci 105(3):681-689.
Res. 2016;7(10):3931-3948. 62. Firouzi A, et al. Alkaline lyotropic
51. Van Speybroeck M, et al. Combined use of silicate−surfactant liquid crystals. J. Am.
ordered mesoporous silica and Chem. Soc. 1997;119(15):3596-3610.
precipitation inhibitors for improved oral 63. Sakamoto Y, et al. Direct imaging of the
absorption of the poorly soluble weak base pores and cages of three-dimensional
itraconazole. Eur. J. Pharm. Biopharm. mesoporous materials. Nature. 2000;
2010;75(3):354-365. 408(6811):449-453.
52. Ambrogi V, Marmottini F, Pagano C.
64. Ryoo R, et al. Disordered molecular sieve
Amorphous carbamazepine stabilization by
with branched mesoporous channel
the mesoporous silicate SBA-15.
network. The Journal of Physical
Microporous Mesoporous Mater. 2013;
Chemistry. 1996;100(45):17718-17721.
177:1-7.
53. Wang Z, et al. Increasing the oral 65. Bagshaw SA, Prouzet E, Pinnavaia TJ.
bioavailability of poorly water-soluble Templating of mesoporous molecular
carbamazepine using immediate-release sieves by nonionic polyethylene oxide
surfactants. Science. 1995;269(5228):
pellets supported on SBA-15 mesoporous
silica. International Journal of 1242-1244.
Nanomedicine. 2012;7:5807. 66. Inagaki S, Fukushima Y, Kuroda K.
54. Beck JSCC, Johnson ID, et al. Synthetic Synthesis of highly ordered mesoporous
porous crystalline material, its preparation, materials from a layered polysilicate.
and use; 1991. Journal of the Chemical Society, Chemical
55. Kresge CT, et al. Ordered mesoporous Communications. 1993;(8):680-682.
molecular sieves synthesized by a liquid- 67. Inagaki S, et al. Syntheses of highly
crystal template mechanism. Nature. ordered mesoporous materials, FSM-16,
1992;359(6397):710-712. derived from kanemite. Bull. Chem. Soc.
56. Ravikovitch PI, Neimark AV. Density Jpn. 1996;69(5):1449-1457.
functional theory of adsorption in spherical 68. Maria Chong A. Zhao X. Functionalization
cavities and pore size characterization of of SBA-15 with APTES and
templated nanoporous silicas with cubic characterization of functionalized
and three-dimensional hexagonal materials. The Journal of Physical
structures. Langmuir. 2002;18(5):1550- Chemistry B. 2003;107(46):12650-12657.
1560. 69. Mellaerts R, et al. Aging behavior of
57. Ravikovitch PI, Neimark AV. Experimental pharmaceutical formulations of
confirmation of different mechanisms of itraconazole on SBA-15 ordered
evaporation from ink-bottle type pores. mesoporous silica carrier material.
Equilibrium, Pore Blocking, and Cavitation. Microporous Mesoporous Mater. 2010;
Langmuir. 2002;18(25):9830-9837. 130(1–3):154-161.
58. Zhao D, et al. Triblock copolymer 70. Limnell T, et al. Physicochemical stability
syntheses of mesoporous silica with of high indomethacin payload ordered
periodic 50 to 300 angstrom pores. mesoporous silica MCM-41 and SBA-15
Science. 1998;279(5350):548-552. microparticles. Int. J. Pharm. 2011;416(1):
59. Beck JS, et al. A new family of 242-251.
mesoporous molecular sieves prepared 71. Laitinen R, et al. Emerging trends in the
with liquid crystal templates. J. Am. Chem. stabilization of amorphous drugs. Int. J.
Soc. 1992;114(27):10834-10843. Pharm. 2013;453(1):65-79.

16
 Chaudhari and Gupte; BJPR, 16(6): 1-19, 2017; Article no.BJPR.33553

72. Van Speybroeck M, et al. Ordered porous silica using supercritical carbon
mesoporous silica material SBA-15: A dioxide. Eur. J. Pharm. Biopharm. 2010;
broad-spectrum formulation platform for 76(2):215-221.
poorly soluble drugs. J. Pharm. Sci. 2009; 84. Aso Y, Yoshioka S, Kojima S. Explanation
98(8):2648-2658. of the crystallization rate of amorphous
73. Alba-Simionesco C, et al. Effects of nifedipine and phenobarbital from their
confinement on freezing and melting. molecular mobility as measured by 13 C
Journal of Physics: Condensed Matter. nuclear magnetic resonance relaxation
2006;18(6):R15. time and the relaxation time obtained from
74. Alcoutlabi M, McKenna GB. Effects of the heating rate dependence of the glass
confinement on material behaviour at the transition temperature. J. Pharm. Sci.
nanometre size scale. Journal of Physics: 2001;90(6):798-806.
Condensed Matter. 2005;17(15):R461. 85. Masuda K, et al. Comparison of molecular
75. Azaïs T, et al. Solid-state NMR study of mobility in the glassy state between
ibuprofen confined in MCM-41 material. amorphous indomethacin and salicin
Chemistry of Materials. 2006;18(26):6382- based on spin-lattice relaxation times.
6390. Pharm. Res. 2005;22(5):797-805.
76. Takeuchi H, et al. Solid dispersion particles 86. Hu Y, et al. Facile synthesis of 3D cubic
of amorphous indomethacin with fine mesoporous silica microspheres with a
porous silica particles by using spray- controllable pore size and their application
drying method. Int. J. Pharm. 2005;293(1– for improved delivery of a water-insoluble
2):155-164. drug. J. Colloid Interface Sci. 2011;
77. Takeuchi H, et al. Solid dispersion particles 363(1):410-417.
of tolbutamide prepared with fine silica 87. Kinnari P, et al. Comparison of
particles by the spray-drying method. mesoporous silicon and non-ordered
Powder Technology. 2004;141(3):187-195. mesoporous silica materials as drug
78. Meer T, et al. Solubility modulation of carriers for itraconazole. Int. J. Pharm.
bicalutamide using porous silica. Journal of 2011;414(1–2):148-156.
Pharmaceutical Investigation. 2013;43(4): 88. Mellaerts R, et al. Increasing the oral
279-285. bioavailability of the poorly water soluble
79. Li J, et al. Preparation and characterization drug itraconazole with ordered
of pelletized solid dispersion of resveratrol mesoporous silica. Eur. J. Pharm.
with mesoporous silica microparticles to Biopharm. 2008;69(1):223-230.
improve dissolution by fluid-bed coating 89. Prestidge CA, et al. Mesoporous silicon: A
techniques. Asian Journal of platform for the delivery of therapeutics.
Pharmaceutical Sciences. 2015;11(4):528- Expert Opinion on Drug Delivery.
535. 2007;4(2):101-110.
80. Chauhan B, Shimpi S, Paradkar A. 90. Shen SC, et al. Physical state and
Preparation and evaluation of dissolution of ibuprofen formulated by co-
glibenclamide-polyglycolized glycerides spray drying with mesoporous silica: Effect
solid dispersions with silicon dioxide by of pore and particle size. Int. J. Pharm.
spray drying technique. Eur. J. Pharm. Sci. 2011;410(1–2):188-195.
2005;26(2):219-230. 91. Watanabe T, et al. Solid state radical
81. Sruti J, et al. Improvement in the recombination and charge transfer across
dissolution rate and tableting properties of the boundary between indomethacin and
cefuroxime axetil by melt-granulated silica under mechanical stress. Journal of
dispersion and surface adsorption. Acta Solid State Chemistry. 2002;164(1):27-33.
Pharmaceutica Sinica B. 2013;3(2):113- 92. Watanabe T, et al. Stability of amorphous
122. indomethacin compounded with silica. Int.
82. Patel VI, Dave RH. Evaluation of colloidal J. Pharm. 2001;226(1–2):81-91.
solid dispersions. Physiochemical 93. Qian KK, Bogner RH. Spontaneous
considerations and in vitro release profile. crystalline-to-amorphous phase
AAPS Pharm Sci Tech. 2013;14(2):620- transformation of organic or medicinal
628. compounds in the presence of porous
83. Miura H, et al. Enhancement of dissolution media, part 1: Thermodynamics of
rate and oral absorption of a poorly water- spontaneous amorphization. J. Pharm. Sci.
soluble drug, K-832, by adsorption onto 2011;100(7):2801-2815.

17
 Chaudhari and Gupte; BJPR, 16(6): 1-19, 2017; Article no.BJPR.33553

94. Mellaerts R, et al. Physical state of poorly SBA-15 silica materials. Chemical
water soluble therapeutic molecules Communications. 2007;13:1375-1377.
loaded into SBA-15 ordered mesoporous 106. Aerts CA, et al. Potential of amorphous
silica carriers: A case study with microporous silica for ibuprofen controlled
itraconazole and ibuprofen. Langmuir. release. Int. J. Pharm. 2010;397(1–2):84-
2008;24(16):8651-8659. 91.
95. Li-hong W, et al. A novel strategy to design 107. Izquierdo-Barba I, et al. Release
sustained-release poorly water-soluble evaluation of drugs from ordered three-
drug mesoporous silica microparticles dimensional silica structures. Eur. J.
based on supercritical fluid technique. Int. Pharm. Sci. 2005;26(5):365-373.
J. Pharm. 2013;454(1):135-142.
108. Horcajada P, et al. Influence of pore size
96. Belhadj-Ahmed F, et al. Impregnation of
of MCM-41 matrices on drug delivery rate.
vitamin E acetate on silica mesoporous
Microporous Mesoporous Mater. 2004;
phases using supercritical carbon dioxide.
68(1–3):105-109.
The Journal of Supercritical Fluids. 2009;
51(2):278-286. 109. Zhang Y, et al. Spherical mesoporous
97. Nishiwaki A, et al. Molecular states of silica nanoparticles for loading and release
prednisolone dispersed in folded sheet of the poorly water-soluble drug
mesoporous silica (FSM-16). Int. J. Pharm. telmisartan. J. Controlled Release. 2010;
2009;378(1):17-22. 145(3):257-263.
98. Tozuka Y, Oguchi T, Yamamoto K. 110. Charnay C, Bégu S, Tourné-Péteilh C,
Adsorption and entrapment of salicylamide Nicole L, Lerner DA., Devoisselle JM.
molecules into the mesoporous structure of Inclusion of ibuprofen in mesoporous
folded sheets mesoporous material (FSM- templated silica: drug loading and release
16). Pharm. Res. 2003;20(6):926-930. property. Eur. J. Pharm. Biopharm. 2004;
99. Tozuka Y, et al. Effect of pore size of FSM- 57:533-540.
16 on the entrapment of flurbiprofen in 111. Xu W, Riikonen J, Lehto VP. Mesoporous
mesoporous structures. Chem. Pharm. systems for poorly soluble drugs. Int. J.
Bull. (Tokyo). 2005;53(8):974-977. Pharm. 2013;453(1):181-197.
100. Song SW, K. Hidajat S. Kawi. 112. Zhao W, et al. Uniform rattle-type hollow
functionalized SBA-15 materials as carriers magnetic mesoporous spheres as drug
for controlled drug delivery: influence of delivery carriers and their sustained-
surface properties on matrix−drug release property. Advanced Functional
interactions. Langmuir. 2005;21(21):9568- Materials. 2008;18(18):2780-2788.
9575. 113. Andersson J, et al. Influences of material
101. Wani A, et al. Surface functionalization of characteristics on ibuprofen drug loading
mesoporous silica nanoparticles controls and release profiles from ordered micro-
loading and release behavior of and mesoporous silica matrices. Chemistry
mitoxantrone. Pharm. Res. 2012; of Materials. 2004;16(21):4160-4167.
29(9):2407-2418.
102. Vallet-Regí M. Ordered mesoporous 114. Doadrio AL, et al. Mesoporous SBA-15
materials in the context of drug delivery HPLC evaluation for controlled gentamicin
systems and bone tissue engineering. drug delivery. J. Controlled Release.
Chemistry – A European Journal. 2006; 2004;97(1):125-132.
12(23):5934-5943. 115. Costa P, Sousa Lobo JM. Modeling and
103. Doadrio JC, et al. Functionalization of comparison of dissolution profiles. Eur. J.
mesoporous materials with long alkyl Pharm. Sci. 2001;13(2):123-133.
chains as a strategy for controlling drug 116. Heikkilä T, et al. Mesoporous silica
delivery pattern. Journal of Materials material TUD-1 as a drug delivery system.
Chemistry. 2006;16(5):462-466. Int. J. Pharm. 2007;331(1):133-138.
104. Bouchoucha M, et al. Size-controlled 117. Heikkilä T, et al. Evaluation of mesoporous
functionalized mesoporous silica TCPSi, MCM-41, SBA-15, and TUD-1
nanoparticles for tunable drug release and Materials as API carriers for oral drug
enhanced anti-tumoral activity. Chemistry delivery. Drug Delivery. 2007;14(6):337-
of Materials. 2016;28(12):4243-4258. 347.
105. Mellaerts R, et al. Enhanced release of 118. Zhang Y, et al. Mesoporous Silica
itraconazole from ordered mesoporous nanoparticles for increasing the oral

18
 Chaudhari and Gupte; BJPR, 16(6): 1-19, 2017; Article no.BJPR.33553

bioavailability and permeation of poorly 120. Rodríguez-hornedo N, Murphy D.

water soluble drugs. Molecular Significance of controlling crystallization
Pharmaceutics. 2012;9(3):505-513. mechanisms and kinetics in
119. Vandecruys R, et al. Use of a screening pharmaceutical systems. J. Pharm. Sci.
method to determine excipients which 1999;88(7):651-660.
optimize the extent and stability of 121. Van Speybroeck M, et al. Enhanced
supersaturated drug solutions and absorption of the poorly soluble drug
application of this system to solid fenofibrate by tuning its release rate from
formulation design. Int. J. Pharm. 2007; ordered mesoporous silica. Eur. J. Pharm.
342(1–2):168-175. Sci. 2010;41(5):623-630.

© 2017 Chaudhari and Gupte; This is an Open Access article distributed under the terms of the Creative Commons Attribution
License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.

Peer-review history:
The peer review history for this paper can be accessed here:
http://sciencedomain.org/review-history/19287

19