E. Lahdenpää, O. Antikainen, J.

Yliruusi

J. DRUG DEL. SCI. TECH., 23 (1) 000-000 2013

Investigation of the swelling behavior of Dome Matrix drug

delivery modules by high-resolution X-ray computed tomography
E. Losi1§, N.A. Peppas2, R.A. Ketcham3, G. Colombo4, R. Bettini1, F. Sonvico1†, P. Colombo1*
1
Interdepartmental Center, Biopharmanet-TEC, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy
2
Dept. of Biomedical Engineering, 3Dept. of Geological Sciences,
The University of Texas at Austin, 1 University Station C1100, Austin, TX 78712-1062 United States
4
Dept. of Pharmaceutical Sciences, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy
§
Present address: Chiesi Farmaceutici SpA, Largo F. Belloli, 11/a, 43122 Parma, Italy
†
Present address: School of Pharmacy, University of Technology Sydney, Broadway, NSW 2007, Australia
*Correspondence: farmac2@unipr.it

The swelling behavior of novel Dome Matrix drug delivery modules was investigated using high-resolution X-ray computed tomography stud-
ies. The technique was exploited to investigate the swelling front position and the conditions of the interacting surfaces in situ without removing
the sample from the medium during swelling. Surface and volume evolution of the glassy core under the gel layer were precisely described. Within
the gel formed on the glassy core there were several particles not completely dissolved or swollen, transported from the core by the stresses due
to the polymer swelling. The gel portion, i.e., defined, partially swollen gel, was evidenced on the convex and flat surfaces of tablets, where a
line of fracture in the gel could be observed near the glassy core. In addition, the presence of solid particles in the gel layer confirmed that the
translocation of particles in the swellable system affected the drug and polymer gradient within the system.

Key words: Drug delivery systems – Dome Matrix module – X-ray computed tomography – Controlled release – Swelling – Polymer – HPMC.

In the last fifteen years there has been a significant acceleration
in drug delivery research. In the early days of controlled release,
development of pharmaceutical formulations was more idealized,
with emphasis on the attainment of the illusive “zero-order release
behavior”. Recently, research has returned to a more realistic ap-
proach for solution of pharmaceutical application problems. Thus,
development of new pharmaceutical formulations is based on classi-
cal pharmaceutical technology (e.g., tablets, capsules, powders, FDA
approved excipients), appropriately designed for the achievement
of prolonged release (typically up to 24 h) with controlled, but not
necessarily constant, release rates [1].
Drug delivery has become an integral feature of novel therapeu-
tic formulations. Drug delivery systems (DDS) allow the release of
the necessary drug amount to the correct site and with the desirable
kinetics. The majority of oral drug delivery systems on the market
are swellable or swelling matrices, i.e., monolithic systems triggered
by the process of water transport in the polymer and the associated
drug transport outwards. Swellable matrices respond in the presence
of water or biological fluids by changing dimensions and volume by
water uptake, allowing the drug to diffuse out of the dosage form
[2, 3]. The main component of the swellable matrix is a hydrophilic
polymer, initially in its glassy state. When this matrix is in contact with
the biological fluid, swelling occurs due to an abrupt change from a
glassy to a rubbery state. The individual polymer chains, originally in
the unperturbed state, absorb water so that their end-to-end distance
and radius of gyration expand in the new solvated state. This is due to
the lowering of the typical glass transition temperature of the polymer,
determined by the swelling agent characteristic concentration and
depending on temperature and thermodynamic interactions of the
polymer/solvent system.
A sharp boundary between the glassy and rubbery portions is
observed and the matrix volume increases due to swelling. On a
molecular level, this phenomenon can contribute to convective drug
transport, reinforcing the reproducibility of the diffusive drug transport.
The result is an anomalous (non-Fickian) drug transport due to the
polymer relaxation behind the swelling position that creates osmotic
stresses and convective transport effects [4]. The ensuing carrier is a
hydrogel.
When using a particular hydrogel as the carrier for a drug delivery
system, it is important to know the structure and properties of the as-
sociated polymer network during swelling. Upon contact with water,
a swellable matrix starts to swell with the formation of a gel layer
around the dry glassy core. Chain dissolution may take place at the
gel surface depending upon whether the polymer is cross-linked or
not.
Numerous models have been proposed to describe polymer swell-
ing and erosion as well as drug release [5-7]. Siepmann and Peppas
[8, 9] developed accurate models to describe all of these processes
during drug release from HPMC matrix tablets. From a thermody-
namic point of view, the most important parameters that define the
behavior of these swollen hydrogels are the polymer volume fraction
in the swollen state, υ2,S, the average molecular weight of the polymer
chains between cross-linked points, Mc, and the associated mesh (or
pore) size, ξ. These parameters can be mutually dependent; they are
determined either theoretically or experimentally [10].
From a macroscopic point of view, it is important to know the
behavior of the swellable matrix in terms of front movement, gel
layer thickness and structure. Several techniques have been used to
determine the front position in the matrix under swelling. Optical
colorimetric methods, NMR spectroscopy and texture analysis have
been discussed before [11-13].
In previous papers, the water front movement in cylindrical matrices
was studied by clamping samples in a transparent device that allowed
for water uptake only from the side of the matrix. The main fronts
became visible on the matrix base through the clamping transparent
material as concentric circles and their position could be measured
directly [14, 15].
Recently, Colombo and collaborators [16-21] designed a novel drug
release system based on hydrophilic polymers and other excipients
formulated as discs with two curved bases: one convex and the other
concave. Since the axial section of the system or module appeared as
a dome, the new system was named Dome Matrix.

1
 When analyzing the swelling and release behavior of the Dome
Matrix systems, it was demonstrated that the swelling behavior of
the curved surfaces of the matrices strongly affected the drug release
kinetics. Indeed, the drug release from the convex base is faster and
more linear than from the concave base. For further microscopic and
molecular analysis, it is desirable to measure the dynamics of swelling
evolution and, in particular, the front movement of this curved geometry
that cannot be examined with the optical techniques previously used
with the flat base matrix.
A new technique was proposed for the in situ analysis of the
swelling behavior of Dome Matrix systems. In material analysis,
high-resolution X-ray computed tomography is used largely for the
determination of the density and density distribution of the material.
This method has been recently applied to study solid drug dosage
forms [22, 23]. This new method can be applied on dry and slowly
swelling samples. Since the apparent density of the polymer sample
changes when it hydrates, X-ray computed tomography could have
potential application in the determination of the front movement inside
a matrix undergoing swelling. No special geometry of the sample is
required for this application.
Therefore, in the present work we analyzed the swelling behavior
of the Dome Matrix modules using X-ray computed tomography (X-
ray CT). The aim was to study the gel layer thickness evolution of the
complete hydrophilic dome-shaped disc matrix in order to identify
the position of the relevant fronts and the conditions of the polymer
gel layer due to the curved geometry of the bases. In our studies we
used matrices of hydroxypropyl methylcellulose (HPMC) containing
buflomedil pyridoxalphosphate (BPP) as a model drug. The latter
was used due to its high solubility and the intense yellow color that
facilitates the imaging of the gel layer and glassy core of the matrix.
A comparison was made with flat base disc matrices having the same
mass.
I. Materials and Methods
1. Materials
Buflomedil pyridoxalphosphate (BPP; batch #0500) was a gift from
Lisapharma S.p.A (Erba, CO, Italy). Hydroxypropyl methylcellulose
(HPMC) was supplied by Colorcon (Methocel K100M Premium CR
EP; batch #MJ18012N01; Orpington, UK).
2. Manufacturing of Dome Matrix tablets
Dome Matrix tablets were prepared from 60 % (w/w) of buflomedil
pyridoxalphosphate (solubility in water at 37 °C of about 65 % w/v) and
40 % (w/w) of hydroxypropyl methylcellulose (HPMC). Two particle
size fractions were investigated, that were between 125-250 μm or
lower than 125 μm. Both drug and polymer were sieved by means of
an ASTM sieve series, collecting the powder fractions between the
sieves of Mesh No. 60-120 and the powder fraction passing through
the sieve Mesh No. 120.
Tablets were prepared by direct compression at a constant pressure
of 200 MPa using a reciprocating tableting machine (EKO Korsch,
Berlin, Germany) equipped with special shaped punches (concave-
convex) of 7.4 mm diameter. The total matrices weight was 120 ±
4 mg. For comparative purposes, flat base disc tablets having the same
composition, diameter and mass were manufactured.
Before swelling studies, the thickness and diameter of each tested
tablet were measured using a digital caliper sensitive to 0.01 mm
(Mitutoyo Italia S.r.l., Lainate, MI, Italy).
3. Swelling studies
Swelling studies were carried out using the method first proposed
by Peppas and Baumgartner [10]. Specimens were placed in the mid-
dle of a test tube having a diameter of 7.42 mm. Tablet thickness was
measured directly as a function of time during swelling in the presence
of distilled water at 37 °C. Tubes were kept vertical.
2
4. Volume swelling ratio
Investigation of the water uptake was done by the conventional
gravimetric method. Pre-weighed specimens were placed in a stainless-
steel mesh basket and then immersed in 500 mL of distilled water at
37 °C. Samples were taken out at desired time intervals, mildly dried
with a swab and weighed on a lab scale (Mettler Toledo, Columbus,
OH, United States) with a precision of 1 mg.
Knowing the density of the tablets, the mass data obtained were
translated into volume. Using the following equation (Equation 1), a
volume-swelling ratio, Q, was calculated:
Q = Vs/Vd Eq. 1
where Vs is the volume of the swollen matrix, and Vd is the volume
of the dry matrix.
5. High-resolution X-ray computed tomography
studies
The computed tomography (CT) experiment was carried out at the
High-Resolution X-ray CT Facility in the Department of Geological
Sciences at The University of Texas at Austin. This non-destructive,
high-resolution visualization with X-ray CT was used to follow the
process of swelling and dissolution of the swellable tablets.
The simplest common elements of X-ray radiography are an X-ray
source, an object to be imaged through which the X rays pass and a
series of detectors that measure the extent to which the X-ray signal
has been attenuated by the object. Tomography is a technique for
digitally cutting a specimen open using X rays to reveal its interior
details.
The fundamental principle behind computed tomography is to
acquire multiple projections of an object over a range of angular
orientations, which can then be reconstructed into a series of images.
A single CT image typically corresponds to what would be seen if the
object was sliced along the scan plane and corresponds to a certain
thickness of the object being scanned. A set of slices can encompass
the entire sample volume, allowing 3D visualization and quantifica-
tion.
In our experiment, the tablet was placed in a test tube in which a
polymer support foam was placed on the bottom to support the speci-
men, since it cannot be moved during the scan. The matrix was placed
with the convex base in contact with the foam. The cylindrical tablet
was placed with one of the two flat bases in contact with the foam.
The test tube was then filled with distilled water at 37 °C. The tube
was kept vertically.
Using a 21-23 µm resolution and an average scanning time of 4
minutes, data were collected for these matrices in the dry state and at
zero, 15, 30, 45 and 60 hydration minutes in distilled water.
Calibration was necessary to establish the characteristics of the
X-ray signal as read by the detector. CT data were then collected and
special software was required to reconstruct the raw CT images. In
particular, Amira software (Visualization Sciences Group, Mérignac,
France) was used to obtain three-dimensional image data. Blob 3D,
a specialized software package developed at The University of Texas
at Austin, was employed to calculate the surface area and the volume
of the dry and slowly swollen specimens [24].
II. Results and Discussion
1. Swelling studies of the whole system
The behavior in water of the dome-shaped and flat base HPMC
matrices was studied with the aim of characterizing the intensity of
the swelling produced by the formulation of the delivery module.
The shape of the Dome Matrix release modules studied is shown in
Figure 1.
The possibility of cracks forming or observing delamination of
the matrix under the effect of the swelling was considered, since the
Figure 1 - Sketch of the Dome Matrix release module.
distribution of the stresses during the manufacturing of the curved-base
matrix by axial compression could have led to concentration of high
spots in unusually high friction positions. We measured the thickness
increase of the swollen dome-shaped matrices that occurred in water
at 37 °C, and compared their behavior with the flat base disc matrices.
Swelling experiments lasted until the thickness of gel matrix became
constant. In Figure 2, the matrix thickness is reported as a function
of time.
Figure 2 - Thickness of the dome-shaped disc matrix (filled circle)
and flat base disc matrix (empty circle) as a function of swelling time
(mean ± SD, n = 3) (particle size fraction of drug and polymer between
125-250 µm).
After immersion in water, the dome-shaped matrix swelled very
quickly, showing maximum expansion after about 840 minutes at a
thickness value of almost 14 mm. The flat base matrix exhibited a slower
increase of thickness, reaching a maximum thickness of 12 mm over
the same period of time. No delamination or other macroscopic signs
of possible capping and separation of material were observed. A gel
layer was regularly formed on the glassy core of both the differently
shaped matrices. However, the Dome Matrix developed a larger gel
layer than the flat base matrix, as the curved geometry promoted the
expansion and disentanglement of the polymer hydrating chains.
These data correlated well with the water uptake of the tablets
determined by a gravimetric method through the measurement of
swelling ratio. As shown in Figure 3, the dome-shaped matrix ex-
hibited a significantly higher volume swelling ratio (Q) than the flat
base matrix. Although of the same weight, the two matrices having
the same composition but different shape exhibited different swelling
profiles in water, likely due to the different exposed surfaces.
It had already been observed with this formulation that the swell-
ing of the different faces of the matrix differed [16]. The convex base
swelled more intensely than the flat base or the concave one, since the
3
Figure 3 - Volume swelling ratio of matrices, Q, as a function of time:
dome-shaped disc matrix (filled circle); flat base disc matrix (empty
circle) (mean ± SD, n = 3) (particle size fraction of drug and polymer
between 125-250 µm).
polymer chains could extend more freely off the cupola limit of the
Dome Matrix, leading to less entangled polymer chains compared to
the swelling of the concave or flat bases.
2. Front movement, gel layer and glassy
core evolution
The detailed swelling behavior of the Dome Matrix was investi-
gated by X-ray computed tomography focusing on the movement of
the fronts and considering that the progressive expansion of the gel
has been demonstrated to be the controlling step of drug release from
swellable matrices. Water penetrating into the matrix creates sharp
moving boundaries delimiting different positions inside the matrix
where physical changes of the system take place in correspondence
of the swelling front, diffusion front and erosion fronts [25]. The gel
layer delimited by these fronts has different polymer, drug and water
concentrations as a function of the distance from the glassy core.
In general, matrix swelling is followed by dissolution because
hydrophilic matrix tablets as oral delivery systems have to dissolve
(they are not cross-linked) and the process is homogeneous. This is a
general conclusion of previous studies by numerous investigators that
promoted the idea of a rapid swelling and very homogeneous release.
A molecular explanation for these systems was given before by Pep-
pas et al. [8, 9, 26]. It has been illustrated that, with typical HPMC
polymers, swelling and dissolution are two comparable phenomena
since they occur concomitantly. Before dissolution starts, there is no
macromolecular disentanglement. As water penetrates into the matrix,
a swollen glass layer is observed, but at some positions it changes to
a gel layer that has a characteristic polymer concentration known as
c* in the gel theory. This situation is illustrated in Figure 4 where a
flat base matrix, made of drug and polymer and pictured through two
transparent discs during side water uptake, was paralleled to a sketch
of the molecular situation.
Figure 4 shows clearly the separation front between dry glassy core,
swollen glassy layer and true gel layer that is opaque in proximity to
the swelling front and becomes transparent close to the erosion front.
When no more entanglement is observed, actual dissolution of the gel
takes place. Thus, dissolution takes over and the tablet diminishes in
size until it disappears.
Clearly, if these two gel conditions were observed, they should
have different density than the glassy core. X-ray CT is able to indicate
the portion of the gel that is denser than water. With this technique,
the dry (solid) and swollen phases can be observed and distinguished
as long as there is a difference of density between them. Thus, solid

Figure 4 - Comparison between a proposed sketch of the polymer chain
disentanglement and a real picture of a swellable flat base disc matrix
undergoing radial swelling.
particles or partially swollen particles, with a significant difference
in density with respect to water, are visible with X rays.
The density distribution in a swellable matrix was examined and
Figure 5 shows a series of typical 3D visualizations from X-ray CT
images of the dome-shaped disc matrix scanned before and during
swelling in distilled water at 37 °C, in the conditions above described.
After immersion in the dissolution medium, the module contour
became less definite and some particles detached from the matrix
surface, likely due to a surface disintegration process taking place
before a consistent gel formation (Figure 5A). High molecular weight
HPMC swelling is responsible for this phenomenon. In fact, hydration
and swelling processes for the polymer long chains are slow, thus
the formation of a consistent gel layer is delayed enough to allow
superficial disintegration to occur.
The image sequence of the dome-shaped module shows the dense
core reducing in volume and the gel layer increasing in thickness.
Surprisingly, the gel in correspondence of the convex base contained
several individual particles or aggregates of particles not dissolved or
completely jellified (Figure 5C). Individual particles or aggregates,
detached from the dry core material, remained entrapped in the gel
layer. The particles away from glassy core were not homogeneously
dispersed in the gel layer, but they appeared more concentrated in
Figure 5 - High-resolution X-ray computed tomography images during swelling of dome-shaped disc matrix after 1 min (A), 30 min (B) and 60 min
(C) in distilled water at 37 °C (particle size fraction of drug and polymer between 125-250 µm).
Figure 6 - High-resolution X-ray computed tomography images during swelling of the flat base disc matrix after 1 min (A), 30 min (B) and 60 min (C)
in distilled water at 37 °C (particle size fraction of drug and polymer between 125-250 µm).
4
proximity to the glassy core, defining a layer in which the particles
were densely present. Likely, since the drug is very soluble, these
particles are polymer particles slowly jellifying. Thus, some parti-
cles had a specific time to swell and took longer than few minutes to
completely jellify.
The images in Figure 5 show details of the expansion of the
structure due to swelling in water, indicating an external gel layer with
few particles, a layer with un-swollen particles and a glassy core. In
summary, the presence of some particles detached from the core still
in semi-swollen state confirmed the situation represented in Figure 4,
in which a glassy swollen layer in different experimental conditions
(side water uptake of a flat base cylindrical matrix) was shown.
To verify whether this behavior was linked to the swelling and
dissolution of the matrix and not to a shape effect, conventional flat
base disc matrices having the same composition and mass were scanned
under the same conditions described above. The images, presented in
Figure 6, confirmed the previous analysis.
It was interesting to notice that after 30 min of swelling in water,
the gel portion of the cylindrical matrix showed a layer close to glassy
core “free of particles”. This phenomenon was more evident as release
time increased and was depicted as a dense layer of particles pushed
away from the glassy core by the force of polymer particles undergo-
ing swelling. The flat geometry of the matrix surface, in contrast with
the convex shape of the Dome Matrix module, amplified this swelling
behavior around the glassy core.
Using the computer analysis, the solid dry part (glassy core) of
the dome-shaped disc matrix was reconstructed and the images are
shown in Figure 7.
As the time of swelling/release increased, the glassy core volume
of the matrix decreased. At time zero the solid surface was smooth.
After immersion in water, the picture of the matrix clearly shows that
the swelling front is no longer smooth and that individual particles in
the core take different times to dissolve depending on the solubility and
size. In fact, when the size of polymer and drug particles was reduced
(<125 µm), the glassy core at the swelling front of the dome-shaped
disc matrix appeared definitely smoother than the core surface of the
matrix made with larger particles. This is due to the solvent effect of
water, determining faster drug dissolution and polymer swelling with
smaller particle size (Figure 8).
Figure 7 - Reconstruction of the solid part (glassy core) of the dome-shaped disc matrix (particle size fraction of drug and polymer between 125-
250 µm) during swelling in distilled water.
Figure 8 - Reconstruction of the solid part (glassy core) of the dome-shaped disc matrix (particle size fraction of drug and polymer lower than 125 µm)
during swelling in distilled water.
Using Blob 3D software [24], the surface area and volume of the
dry glassy core during swelling were calculated, allowing a plot of the
surface area and volume as a function of swelling time to be constructed
(Figure 9). The increase observed in the surface area values of the
glassy core was due to the roughness of the surface until a plateau was
reached 60 minutes into the experiment. The surface area of the glassy
core corresponded to that of the swelling front. The surface area of the
Dome Matrix was higher than that of the flat base disc matrix. These
higher values observed for the Dome Matrix could be assigned to its
different initial surface area. In fact, despite having the same mass and
diameter, the dome-shaped disc matrix had an initial release surface
(178 mm2) higher than the flat base disc matrix (147 mm2) [16].
Concerning the volume of the solid part of the matrix, it decreased
as the swelling process occurred, but no difference between the two
Figure 9 - Surface area (circle) and volume (triangle) of the glassy core
as a function of time for dome-shaped disc matrix (filled symbols) and flat
base disc matrix (empty symbols) (samples are those of Figures 5-6).
5
types of matrices was observed (Figure 9). Photographs of the matri-
ces during swelling were also taken with a digital camera in the same
conditions used for the X-ray CT studies. The comparison between
these pictures and the X-ray CT reconstructed images confirmed that
in the gel layer there were particles, likely of polymer, not dissolved
(Figure 10). However, the amount of particles observed in the gel
portion near and beyond the diffusion front was not comparable to the
number evidenced by the X-ray apparatus. One possible explanation
for this discrepancy is that the photographs represent an instantane-
ous view of the experiment, whereas the X-ray CT images required a
4-min acquisition time.
Figure 10 - Photographs showing the swelling progress of the dome-
shaped disc matrix in distilled water at 37 °C (particle size fraction of
drug and polymer between 125-250 µm).
Clear identification of the swelling front position and conditions
of the interacting surface, when the fronts are not directly observable,
was the novel result available using X-ray computed tomography
analytical technique. Surface and volume evolution of the glassy core
underneath the gel layer can be accurately described.
Immersion of the matrix in water provokes a number of particles
disintegrating from the core and dispersing in the medium before the
gel formation.
 In the gel formed on the glassy core there are several particles not
completely dissolved or swollen, pushed away from the core by the
stresses due to the polymer undergoing swelling. The reason for this
phenomenon could be attributed to the particle size distribution of the
polymer powder used, as smaller particles jellify quickly and larger
ones take more time. However, the effect of compression energy used
for manufacturing the tablet cannot to be disregarded.
These particles in the gel layer give rise to the gel portion de-
fined as “partially swollen gel” already observed and described. The
phenomenon was more evident on the convex and flat surfaces on
which a line of fracture within the gel could be observed close to the
glassy core. The same was not observed on the concave base of the
dome matrix since the concavity masked the unswollen particles’
distribution. This observation was not possible by optical means. In
addition, the presence of solid particles in the gel layer confirmed that
the translocation of particles in swellable systems affected the drug
and polymer gradient in the system.
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Acknowledgments
The computer tomography experiments were carried out in the High-
Resolution X-ray CT Facility in the Department of Geological Sciences
at The University of Texas at Austin, TX (USA). Elena Losi performed
this research while she was a Visiting Scientist in the Department of
Chemical Engineering at The University of Texas at Austin.
Manuscript
Received 10 September 2012, accepted for publication 22 October 2012.