Investigation of the swelling behavior of Dome Matrix drug delivery modules by high-resolution X-ray computed tomography

Transcription

1 J. DRUG DEL. SCI. TECH., 23 (2) Investigation of the swelling behavior of Dome Matrix drug delivery E. Losi 1, N.A. Peppas 2, R.A. Ketcham 3, G. Colombo 4, R. Bettini 1, F. Sonvico 1, P. Colombo 1 * 1 Interdepartmental Center, Biopharmanet-TEC, University of Parma, Parco Area delle Scienze 27/a, Parma, Italy 2 Dept. of Biomedical Engineering, 3 Dept. of Geological Sciences, The University of Texas at Austin, 1 University Station C1100, Austin, TX United States 4 Dept. of Life Sciences and Biotechnology, University of Ferrara, Via Fossato di Mortara 17/19, Ferrara, Italy Present address: Chiesi Farmaceutici SpA, Largo F. Belloli, 11/a, 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 studies. 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 defined as 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 approach for solution of pharmaceutical application problems. Thus, development of new pharmaceutical formulations is based on classical 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 therapeutic 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 associated 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 swelling 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 thermodynamic point of view, the most important parameters that define the behavior of these swollen hydrogels are the polymer volume fraction in the swollen state, υ 2,S, the average molecular weight of the polymer chains between cross-linked points, M c, 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. 165

2 J. DRUG DEL. SCI. TECH., 23 (2) Investigation of the swelling behavior of Dome Matrix drug delivery 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 (Xray 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 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 and the powder fraction passing through the sieve Mesh No 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 (concaveconvex) of 7.4 mm diameter. The total matrix 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 middle 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. 4. Volume swelling ratio Investigation of the water uptake was done by the conventional gravimetric method. Pre-weighed specimens were placed in a stainlesssteel 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 = V s /V d Eq. 1 where V s is the volume of the swollen matrix, and V d 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 quantification. 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 specimen, 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 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 166

3 Investigation of the swelling behavior of Dome Matrix drug delivery J. DRUG DEL. SCI. TECH., 23 (2) 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 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 exhibited 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 swelling 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 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 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 investigated 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 Peppas 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 167

4 J. DRUG DEL. SCI. TECH., 23 (2) Investigation of the swelling behavior of Dome Matrix drug delivery 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 particles 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 undergoing 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 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 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 µm). 168

5 Investigation of the swelling behavior of Dome Matrix drug delivery J. DRUG DEL. SCI. TECH., 23 (2) Figure 7 - Reconstruction of the solid part (glassy core) of the dome-shaped disc matrix (particle size fraction of drug and polymer between 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 mm 2 ) higher than the flat base disc matrix (147 mm 2 ) [16]. Concerning the volume of the solid part of the matrix, it decreased as the swelling process occurred, but no difference between the two types of matrices was observed (Figure 9). Photographs of the matrices 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 instantaneous 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 domeshaped disc matrix in distilled water at 37 C (particle size fraction of drug and polymer between µm). * 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). 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. 169

6 J. DRUG DEL. SCI. TECH., 23 (2) Investigation of the swelling behavior of Dome Matrix drug delivery 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 defined 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. REFERENCES 1. Colombo P., Sonvico F., Colombo G., Bettini R. - Novel platforms for oral drug delivery. - Pharm. Res., 26, , Colombo P., Santi P., Siepmann J., Colombo G., Sonvico F., Rossi A., Strusi O.L. - Swellable and rigid matrices: controlled release matrices with cellulose ethers. - In: Pharmaceutical Dosage Forms: Tablets, 3 rd ed., Vol. 2, Augsburger L.L., Hoag S.W. (Eds.), Informa Healthcare USA, Inc., New York, 2008, p Bettini R., Colombo P., Massimo G., Catellani P.L., Vitali T. - Swelling and drug release in hydrogel matrices: polymer viscosity and matrix porosity effects. - Eur. J. Pharm. Sci., 2, , Bettini R., Catellani P.L., Santi P., Massimo G., Peppas N.A., Colombo P. - Translocation of drug particles in HPMC matrix gel layer: effect of drug solubility and influence on release rate. - J. Control. Release, 70, , Karasulu H.Y., Ertan G., Köse T. - Modeling of theophylline release from different geometrical erodible tablets. - Eur. J. Pharm. Biopharm., 49, , Petrović J., Jocković J., Ibrić S., Durić Z. - Modelling of diclofenac sodium diffusion from swellable and water-soluble polyethylene oxide matrices. - J. Pharm. Pharmacol., 61, , Siepmann J., Peppas N.A. - Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). - Adv. Drug Deliv. Rev., 48, , Siepmann J., Podual K., Sriwongjanya M., Peppas N.A., Bodmeier R. - A new model describing the swelling and drug release kinetics from hydroxypropyl methylcellulose tablets. - J. Pharm. Sci., 88, 65-72, Siepmann J., Peppas N.A. - Hydrophilic matrices for controlled drug delivery: an improved mathematical model to predict the resulting drug release kinetics (the sequential layer model). - Pharm. Res., 17, , Baumgartner S., Kristl J., Peppas N.A. - Network structure of cellulose ethers used in pharmaceutical applications during swelling and at equilibrium. - Pharm. Res., 19, , Colombo P., Bettini R., Peppas N.A. - Observation of swelling process and diffusion front position during swelling in hydroxypropyl methyl cellulose (HPMC) matrices containing a soluble drug. - J. Control. Release, 61, 83-91, Rajabi-Siahboomi A.R., Bowtell R.W., Mansfield P., Henderson A., Davies M.C., Melia C.D. - Structure and behavior in hydrophilic matrix sustained release dosage form. 2. NMR-imaging studies of dimensional changes in the gel layer and core of HPMC tablets undergoing hydration. - J. Control. Release, 31, , Yang L., Johnson B., Fassihi R. - Determination of continuous changes in the gel layer thickness of poly(ethylene oxide) and HPMC tablets undergoing hydration: a texture analysis study. - Pharm. Res., 15, , Colombo P., Bettini R., Catellani P.L., Santi P., Peppas N.A. - Drug volume fraction profile in the gel phase and drug release kinetics in hydroxypropylmethyl cellulose matrices containing a soluble drug. - Eur. J. Pharm. Sci., 9, 33-40, Ferrero C., Massuelle D., Doelker E. - Towards elucidation of the drug release mechanism from compressed hydrophilic matrices made of cellulose ethers. II. Evaluation of a possible swelling-controlled drug release mechanism using dimensionless analysis. - J. Control. Release, 141, , Losi E., Bettini R., Santi P., Sonvico F., Colombo G., Lofthus K., Colombo P., Peppas N.A. - Assemblage of novel release modules for the development of adaptable drug delivery systems. - J. Control. Release, 111, , Strusi O.L., Sonvico F., Bettini R., Santi P., Colombo G., Barata P., Oliveira A., Santos D., Colombo P. - Module assemblage technology for floating systems: in vitro flotation and in vivo gastro-retention. - J. Control. Release, 129, 88-92, Casas M., Strusi O.L., Jiménez-Castellanos M.R., Colombo P. - Tapioca starch graft copolymers and Dome Matrix modules assembling technology. I. Effect of module shape on drug release. - Eur. J. Pharm. Biopharm., 75, 42-47, Hascicek C., Rossi A., Colombo P., Massimo G., Strusi O.L., Colombo G. - Assemblage of drug release modules: effect of module shape and position in the assembled systems on floating behavior and release rate. - Eur. J. Pharm. Biopharm., 77, , Oliveira P.R., Bernardi L.S., Strusi O.L., Mercuri S., Segatto Silva M.A., Colombo P., Sonvico F. - Assembled modules technology for site-specific prolonged delivery of norfloxacin. - Int. J. Pharm., 405, 90-96, Colombo P., Colombo G., Cahyadi C. - Geometric release systems: principles, release mechanisms, kinetics, polymer science and release-modifying material. - In: Controlled Release in Oral Drug Delivery, Advances in Delivery Science and Technology, Wilson C.G., Crowley P.J. (Eds.), Springer and CRS, New York, 2011, p Young P.M., Nguyen K., Jones A.S., Traini D. - Microstructural analysis of porous composite materials: dynamic imaging of drug dissolution and diffusion through porous matrices. - AAPS J., 10, , Wang Y., Wertheim D.F., Jones A.S., Coombes A.G. - Micro-CT in drug delivery. - Eur. J. Pharm. Biopharm., 74, 41-49, Ketcham R.A. - Computational methods for quantitative analysis of three-dimensional features in geological specimens. - Geosphere, 1, 32-41, Lee PI. - Controlled drug release from polymeric matrices involving moving boundaries. - In: Controlled Release of Pesticides and Pharmaceuticals, Levis D.H. (Ed.), Plenum, New York, 1981, p Siepmann J., Streubel A., Peppas N.A. - Understanding and predicting drug delivery from hydrophilic matrix tablets using the sequential layer model. - Pharm. Res., 19, , 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