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The pharmaceutical field is currently moving towards continuous manufacturing pursuing reduced waste, consistency, and automation. During continuous manufacturing, it is important to understand how both operating conditions and material properties throughout the process affect the final properties of the product to optimise and control production. In this study of a continuous wet granulation line, the liquid to solid ratio (L/S) and drying times were varied to investigate the effect of the final granule moisture content and the liquid to solid ratio on the properties of the granules during tabletting and the final tensile strength of the tablets. Both variables (L/S and granule moisture) affected the tablet tensile strength with the moisture content having a larger impact. Further analysis using a compaction model, showed that the compactability of the granules was largely unaffected by both L/S and moisture content while the compressibility was influenced by these variables, leading to a difference in the final tablet strength and porosity. The granule porosity was linked to the L/S ratio and used instead for the model fitting. The effect of moisture content and granule porosity was added to the model using a 3d plane relationship between the compressibility constant, the moisture content and porosity of the granules. The tablet tensile strength model, considering the effect of moisture and granule porosity, performed well averaging a root mean squared error across the different conditions of 0.17 MPa., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Reconstitution of dairy powders is strongly influenced by the presence and physical state of fat on the particle surface. The present study investigates the effect of a micronized lactose coating on the physical state of the fat and the reconstitution kinetics of whole milk powder at four different temperatures (4/21/40/60 °C) and two stirring rates (400/800 rpm). For this purpose, two types of micronized lactose were used as coating materials: crystalline and amorphous. At 4 °C and 21 °C, the coated powders sink and are reconstituted faster than pure whole milk powder, regardless of the stirring rate applied. At 40/60 °C and 400 rpm, although the amorphous micronized lactose coating leads to a significant decrease in the reconstitution time, the crystalline coating has the opposite effect (or no effect). This discrepancy is related to the large differences in terms of dissolution enthalpy between the two micronized lactose physical states. It is posited that the dissolution of the coating material causes a temperature shift at the powder-water interface which could hamper the complete melting of surface fat and influence its viscosity, thereby affecting wetting and sinking. These differences are overcome at a high stirring rate (800 rpm) or if agglomerated whole milk powder is used as the host material., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The fill level is defined as the volume occupied by the powder and granules inside the twin-screw granulator in proportion to the maximum barrel channel void 'free' volume. In literature, the fill level is one of the key factors that determine the final granule properties as it relies on several factors such as the screw speed, screw element geometry, mass flow rate and barrel length. However, quantitative prediction of the fill level in twin-screw granulation (TSG) is still a developing area, which is required to enable effective development of process design space, to yield a product with desired quality attributes for all process scale levels (small to large equipment). In this study, a simple geometrical model is presented that predicts the barrel channel fill level in TSG. This model relates the volumetric flow rate to the forward volumetric conveying rate of the screws when they advance in the axial direction. Experimentation was conducted to validate the model by analytically measuring mass hold-up, the amount of material remaining in the barrel after steady state was reached, as the fill level is proportional to mass hold-up. Furthermore, the trends in the extent of granulation with the proposed model were investigated. Good agreement was found between the proposed fill level model and the mass hold-up for various screw elements, therefore the model provides a more practical measure of the fill level in TSG., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Roller compaction is a continuous dry granulation process, in which powder is compressed by two counter-rotating rollers. During this process, the powder feeding to the compaction zone has a significant effect on product quality. This work investigates the flow of powder from the feeding zone to the compaction zone using online infrared thermography as Process Analytical Technology (PAT) which is achieved via a specially built cheek plate (side-sealing). The powder undergoes increasing stress from the rollers when it is approaching the minimum gap of the compaction zone, which can be indirectly monitored by measuring the powder temperature. The online monitoring of the powder flow during the roller compaction helps locate the nip region and identify the effect of different roller forces on the temperature of the feeding powder. The results show that the nip region can be identified by analysing the temperature profiles from the feeding to the compaction zone. The increase of roller force results in an increasing slope of the powder temperature profile. In addition, offline X-ray CT measurement results show the increase of density along the feeding to the compaction direction, which is compared with Johanson theory under different roller forces in the roller compaction process., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Roller compaction is a continuous dry granulation process, where the powder is compressed between two counter-rotating rollers and compacted into ribbons. The quality and homogeneity of the granulate is determined by the uniformity and porosity of the ribbon, which depends on the feeding process of the primary powder to the rollers, the flow properties of the primary powder and process parameters such as roller forces. Previous work was conducted to improve the powder flow and distribution in the feeding zone by developing new feeding guiders, which are located in the feeding zone close to the rollers on the lab-scale roller compactor Alexanderwerk WP120 Pharma (Yu et al., 2018). These new feeding guiders were used to reduce the amount of powder that is delivered to the centre of the rollers and increase the amount of powder that is delivered to the sides of the rollers, in comparison to the original feeding guiders. This modified concept using new feeding guiders has been applied to the large-scale roller compactor Alexanderwerk WP200 Pharma in the present work. In order to evaluate the homogeneity of the ribbon properties across the ribbon width, the temperature profile and porosity distribution across the ribbon width were measured. The new feeding guiders resulted in ribbons being produced with a more uniform temperature profile and porosity distribution across the ribbon width when using the small and large scale roller compactors at different process parameters., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The wetting process involved when a liquid droplet comes into contact with a mixture of particles is a complex phenomenon which is often understood by reference to Cassie-Baxter theory. However, various authors have applied the Cassie-Baxter theory for the prediction of contact angles on two-component mixtures without success. We hypothesise that the main difficulty in applying the Cassie-Baxter theory to mixtures is that if the particles differ in size, it is possible for the small particles to coat the large particles, so reducing the available surface area of the large particles. This leads to the view that bulk volume fractions are not good estimates of surface fractions of the components within the mixture. We argue that the Cassie-Baxter theory over represents the influence of large particles and that below a certain critical volume fraction they exert no influence. We present a simple geometrical model that relates the critical surface coverage volume fraction to the Sauter mean particle size of the binary mixture components. As a consequence, the wetting behaviour can be determined from the bulk volume fractions and the calculated critical surface coverage volume fraction, by means of a simple geometric model. We show that the simple model describes the five two-components systems reported here and a further four systems reported in the literature, irrespective of whether the larger or small particles are hydrophobic/hydrophilic. With this model, it is possible to predict the wetting behaviour of mixtures of particles that coat each other using very simple characterisation methods, so reducing the development time in the creation of formulations in the pharmaceutical industry., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In the present study the application of near-infrared chemical imaging (NIR-CI) for assessing particle segregation in granules from continuous twin screw granulation (TSG) granules, were the complex attributes of the machinery configuration in relation to particle segregation is not well understood was investigated. Experiments were performed along the compartmental length of the TSG barrel channel by varying the screw element type and liquid binder viscosity. Examination of the data showed a direct correlation between dispersion due to shear force and de-mixing of particles, which allowed for identification of fundamental granule segregation mechanisms affecting content uniformity in TSG. Particle segregation behavior was linked to dispersion due to shear force through a proposed regime mapping approach which links de-mixing potential to controlling granule formation mechanisms with a new dimensionless mixing number. This was carried out in order to provide a general guideline of how particles segregate along the length of the TSG barrel channel., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Roller compaction is the main technique employed in dry granulation. Ribbon sticking and splitting are among the major factors that can hinder the use of this process for some formulations. Ribbon splitting can occur either transversally (through the ribbon thickness) or longitudinally (through the ribbon width). It was observed that transverse splitting is commonly associated with sticking of the split ribbons to the rollers and results in an inferior performance of the process. Longitudinal splitting is associated with an across-width distribution of the ribbon density so that there may an adverse effect on the mechanical strength and dissolution properties of the tablets formed from the milled granules. The aim of the current work was to elucidate the mechanisms of splitting by an experimental study involving single component powders with a range of yield strengths, including those that are commonly used as excipients. Both smooth and knurled rollers were employed without and with lubrication by applying magnesium stearate to the rollers. The minimum gap was fixed and the maximum roll stress was varied. The observed trends for the smooth rollers were rationalised in terms of a splitting index, which is a measure of the residual stresses driving crack growth relative to the tensile strength of the ribbons. There was a lower limit at which splitting was observed but the occurrence of transverse splitting decreased and that for longitudinal splitting increased with increasing values of the index, which was accompanied by an increase in mixed transverse-longitudinal splitting. Transverse splitting was always associated with sticking to the rollers and was prevented by external lubrication. The main difference with the knurled rollers was that in some cases transverse splitting occurred without sticking to the rollers. A detailed discussion of the mechanisms involved is presented., (Copyright © 2019 Elsevier B.V. All rights reserved.)

During roller compaction, not only the properties of the primary powder affect the product quality but also the process parameters. Any change in the process parameters during roller compaction will result in changing the properties of the ribbon. In this study, the temperature of the ribbon during production was monitored online using a thermal camera. The information from the thermal camera was used to explain the differences in ribbon properties at varying process parameters. Lactose powder was used as a primary powder, and ribbons were produced at different process parameters. The surface temperature of the ribbon during production was found to increase with increasing both the gap between the two rollers and the roller speed. This was attributed to the screw feeder speed, which increased to feed additional powder as required to adjust to the change in process parameters. Increasing the roller gap resulted in wider ribbons and decreased the percentage of fines in the product, which was a signature of better powder distribution across the roller width. The results were also supported by the uniform temperature distribution recorded across the ribbon width. It was found that increasing the roller speed during roller compaction decreased the width of the ribbon while increasing the percentage of fines in the product. The feeder screw speed was found to have a similar effect as the roller gap.

Understanding the compaction behaviour of the primary powder in the roller compaction process is necessary to be able to better control the quality of the product. In this study, the plastic deformation of the primary particles was evaluated by determining two mechanical properties: the nano-indentation hardness and the viscoelasticity of the primary powder. The nano-indentation hardness of eight different materials with a wide range of mechanical properties was determined by indenting the surface of the single primary particle, whereas the viscoelasticity was evaluated for a powder bed using the creep test. These were linked to fundamental ribbon properties such as ribbon strength and width in addition to the amount of fines. It was identified that the plastic deformation of the material had the potential to provide an indication for the ability of the primary powder to produce a good ribbon. For the range of the investigated process parameters, the optimum hardness range that produced ribbons with ideal properties and small amount of fines was suggested.

In the roller compaction process, powder flow properties have a significant influence on the uniformity of the ribbon properties. The objective of this work was to improve the powder flow in the feeding zone by developing novel feeding guiders which are located in the feeding zone close to the rollers in the roller compactor (side sealing system). Three novel feeding guiders were designed by 3D printing and used in the roller compactor, aiming to control the amount of powder passing across the roller width. The new feeding guiders were used to guide more powder to the sides between the rollers and less powder to the centre comparing to the original feeding elements. Temperature profile and porosity across the ribbon width indicated the uniformity of the ribbon properties. Using the novel feeding guiders resulted in producing ribbons with uniform temperature profile and porosity distribution across the ribbon width. The design of the feeding guiders contributed to improving the tensile strength of the ribbons produced from the compaction stage as well as reducing the fines produced from the crushing stage., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Lactose and mannitol are some of the most commonly used powders in the pharmaceutical industry. The limited research published so far highlights the effects of process and formulation parameters on the properties of the granules and the tablets produced using these two types of powders separately. However, the comparison of the performance of these two types of powders during twin screw wet granulation has received no attention. The present research is focused on understanding the granulation mechanism of different grades of two pharmaceutical powders with varying properties (i.e., primary particle size, structure, and compressibility). Three grades each of lactose and mannitol were granulated at varying liquid to solid ratios (L/S) and screw speed. It was noticed that primary powder morphology plays an important role in determining the granule size and structure, and tablet tensile strength. It was indicated that the processed powders such as spray-dried and granulated lactose and mannitol can be used in formulation for wet granulation where flowability of active pharmaceutical ingredient (API) is poor.

This paper focuses on investigating the influence of varying barrel fill levels on the mean residence time, granule properties (median size, size distribution, and shape), and tensile strength of tablets. Specific feed load (SFL) (powder feed rate divided by screw speed) and powder feed number (PFN) (i.e., powder mass flow rate divided by the product of screw speed, screw diameter, and the material density in the denominator) were considered as surrogates for the barrel fill level. Two type of powders (lactose and microcrystalline cellulose (MCC)) were granulated separately at varying fill levels at different liquid-to-solid ratios (L/S). It was observed that by controlling the barrel fill level, the granule size, shape, and tablet tensile strength can be maintained at specific L/S. It was also noticed that the mean residence time decreased with increasing fill levels in the case of both lactose and MCC powder. However, it was only found to be related to the change in granule size in case of granulating microcrystalline cellulose at varying fill levels. At very high fill levels, granule size decreased, owing to a limited interaction between MCC powder and liquid at high throughput force and short residence time.

In this research, a new systematic modelling framework which uses machine learning for describing the granulation process is presented. First, an interval type-2 fuzzy model is elicited in order to predict the properties of the granules produced by twin screw granulation (TSG) in the pharmaceutical industry. Second, a Gaussian mixture model (GMM) is integrated in the framework in order to characterize the error residuals emanating from the fuzzy model. This is done to refine the model by taking into account uncertainties and/or any other unmodelled behaviour, stochastic or otherwise. All proposed modelling algorithms were validated via a series of Laboratory-scale experiments. The size of the granules produced by TSG was successfully predicted, where most of the predictions fit within a 95% confidence interval., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The effect of storage at different relative humidity conditions, for various types of lactose, on roller compaction behaviour was investigated. Three types of lactose were used in this study: anhydrous lactose (SuperTab21AN), spray dried lactose (SuperTab11SD) and α-lactose monohydrate 200M. These powders differ in their amorphous contents, due to different manufacturing processes. The powders were stored in a climatic chamber at different relative humidity values ranging from 10% to 80% RH. It was found that the roller compaction behaviour and ribbon properties were different for powders conditioned to different relative humidities. The amount of fines produced, which is undesirable in roller compaction, was found to be different at different relative humidity. The minimum amount of fines produced was found to be for powders conditioned at 20-40% RH. The maximum amount of fines was produced for powders conditioned at 80% RH. This was attributed to the decrease in powder flowability, as indicated by the flow function coefficient ffc and the angle of repose. Particle Image Velocimetry (PIV) was also applied to determine the velocity of primary particles during ribbon production, and it was found that the velocity of the powder during the roller compaction decreased with powders stored at high RH. This resulted in less powder being present in the compaction zone at the edges of the rollers, which resulted in ribbons with a smaller overall width. The relative humidity for the storage of powders has shown to have minimal effect on the ribbon tensile strength at low RH conditions (10-20%). The lowest tensile strength of ribbons produced from lactose 200M and SD was for powders conditioned at 80% RH, whereas, ribbons produced from lactose 21AN at the same condition of 80% RH showed the highest tensile strength. The storage RH range 20-40% was found to be an optimum condition for roll compacting three lactose powders, as it resulted in a minimum amount of fines in the product., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Tablet disintegration is a fundamental parameter that is tested in vitro before a product is released to the market, to give confidence that the tablet will break up in vivo and that active drug will be available for absorption. Variations in tablet properties cause variation in disintegration behaviour. While the standardised pharmacopeial disintegration test can show differences in the speed of disintegration of different tablets, it does not give any mechanistic information about the underlying cause of the difference. With quantifiable disintegration data, and consequently an improved understanding into tablet disintegration, a more knowledge-based approach could be applied to the research and development of future tablet formulations. The aim of the present research was to introduce an alternative method which will enable a better understanding of tablet disintegration using a particle imaging approach. A purpose-built flow cell was employed capable of online observation of tablet disintegration, which can provide information about the changing tablet dimensions and the particles released with time. This additional information can improve the understanding of how different materials and process parameters affect tablet disintegration. Standard USP analysis was also carried out to evaluate and determine whether the flow cell method can suitably differentiate the disintegration behaviour of tablets produced using different processing parameters. Placebo tablets were produced with varying ratios of insoluble and soluble filler (mannitol and MCC, respectively) so that the effect of variation in the formulation can be investigated. To determine the effect of the stress applied during granulation and tableting on tablet disintegration behaviour, analysis was carried out on tablets produced using granular material compressed at 20 or 50bar, where a tableting load of either 15 or 25kN was used. By doing this the tablet disintegration was examined in terms of the tablet porosity by monitoring the tablet area and particle release. It was found that when 20 and 50bar roller compaction pressure was used the USP analysis showed almost identical disintegration times for the consequent tablets. With the flow cell method a greater tablet swelling was observed for the lower pressure followed by steady tablet erosion. Additionally, more particles were released during disintegration due to the smaller granule size distribution within the tablet. When a higher tableting pressure was applied the tablet exhibited a delay in the time taken to reach the maximum swelling area, and slower tablet erosion and particle release were also observed, largely due to the tablet being much denser causing slower water uptake. This was in agreement with the USP analysis data. Overall it was confirmed by using both the standard USP analysis and flow cell method that the tablet porosity affects the tablet disintegration, whereby a more porous tablet disintegrates more slowly. But a more in-depth understanding was obtained using the flow cell method as it was determined that tablets will swell to varying degrees and release particles at different rates depending on the roller compaction and tableting pressure used., (Copyright © 2016 Elsevier B.V. All rights reserved.)

This work focuses on monitoring the behaviour and the mass of the built up/caking of powder during wet granulation using Twin Screw Granulator (TSG). The variables changed during this work are; powder (α-lactose monohydrate and microcrystalline cellulose (MCC)), the screw configuration (conveying and kneading elements) and the weight percentage of hydroxypropyl-methyl cellulose (HPMC) dissolved in the granulation liquid (i.e. changing liquid viscosity). Additionally, the effect of these variables on the size distribution, of the granules produced, was determined. The experiments were conducted using an acrylic transparent barrel. A stainless steel barrel was then used to conduct the two extreme granulation liquid viscosities with two different screw configurations, using lactose only. This was done to compare the findings to those obtained from the transparent barrel for validation purpose. These variables showed to affect the behaviour and the mass of the powder caking as well as the size distribution of granules. Overall, the use of kneading element resulted in uniform behaviour in caking with higher mass. Furthermore, increasing the amount of HPMC resulted in a reduction of the mass of powder caking for lactose, while showing inconsistent trend for MCC. Furthermore, lactose showed to have a greater tendency to cake in comparison to MCC. The results, for lactose, obtained from the stainless steel barrel compared well with their corresponding conditions from the transparent barrel, as the screw configuration and HPMC mass varied., (Copyright © 2015 Elsevier B.V. All rights reserved.)

In this study, the nano-indentation hardness of a single primary particle was measured for six different materials; microcrystalline cellulose, hydroxypropyl methylcellulose, maltodextrin, lactose, sodium carbonate and calcium carbonate. This was linked to the properties of the ribbons produced by roller compactor at different hydraulic pressures in the range of 30-230 bar. The main investigated ribbon properties were strength, porosity and width. For the range of materials that were tested, it was found that the lower the nano-indentation hardness of the powder particles, the higher the strength, width and lower the ribbon porosity. This is because the applied pressure by the rollers was enough to plastically deform the particles and create bonds between them. A method was suggested to predict the workability of the powder in roller compactor by using the data of nano-indentation for three materials., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The effect of morphology and amorphous content, of three types of lactose, on the properties of ribbon produced using roller compaction was investigated. The three types of lactose powders were; anhydrous SuperTab21AN, α-lactose monohydrate 200 M, and spray dried lactose SuperTab11SD. The morphology of the primary particles was identified using scanning electron microscopy (SEM) and the powder amorphous content was quantified using NIR technique. SEM images showed that 21AN and SD are agglomerated type of lactose whereas the 200 M is a non-agglomerated type. During ribbon production, an online thermal imaging technique was used to monitor the surface temperature of the ribbon. It was found that the morphology and the amorphous content of lactose powders have significant effects on the roller compaction behaviour and on ribbon properties. The agglomerated types of lactose produced ribbon with higher surface temperature and tensile strength, larger fragment size, lower porosity and lesser fines percentages than the non-agglomerated type of lactose. The lactose powder with the highest amorphous content showed to result in a better binding ability between the primary particles. This type of lactose produced ribbons with the highest temperature and tensile strength, and the lowest porosity and amount of fines in the product. It also produced ribbon with more smooth surfaces in comparison to the other two types of lactose. It was noticed that there is a relationship between the surface temperature of the ribbon during production and the tensile strength of the ribbon; the higher the temperature of the ribbon during production the higher the tensile strength of the ribbon., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The effects of three ways of binder delivery into the twin screw granulator (TSG) on the residence time, torque, properties of granules (size, shape, strength) and binder distribution were studied. The binder distribution was visualised through the transparent barrel using high speed imaging as well as quantified using offline technique. Furthermore, the effect of binder delivery and the change of screw configuration (conveying elements only and conveying elements with kneading elements) on the surface velocity of granules across the screw channel were investigated using particle image velocimetry (PIV). The binder was delivered in three ways; all solid binder incorporated with powder mixture, 50% of solid binder mixed with powder mixture and 50% mixed with water, all the solid binder dissolved in water. Incorporation of all solid binder with powder mixture resulted in the relatively longer residence time and higher torque, narrower granule size distribution, more spherical granules, weaker big-sized granules, stronger small-sized granules and better binder distribution compared to that in other two ways. The surface velocity of granules showed variation from one screw to another as a result of uneven liquid distribution as well as shown a reduction while introducing the kneading elements into the screw configuration., (Copyright © 2015. Published by Elsevier B.V.)

The application of twin screw granulation in the pharmaceutical industry has generated increasing interest due to its suitability for continuous processing. However, an understanding of the impact of formulation properties such as hydrophobicity on intermediate and finished product quality has not yet been established. Hence, the current work investigated the granulation behaviour of three formulations containing increasing amounts of hydrophobic components using a Consigma™-1 twin screw granulator. Process conditions including powder feed rate, liquid to solid ratio, granulation liquid composition and screw configuration were also evaluated. The size of the wet granules was measured in order to enable exploration of granulation behaviour in isolation without confounding effects from downstream processes such as drying. The experimental observations indicated that the granulation process was not sensitive to the powder feed rate. The hydrophobicity led to heterogeneous liquid distribution and hence a relatively large proportion of un-wetted particles. Increasing numbers of kneading elements led to high shear and prolonged residence time, which acted to enhance the distribution of liquid and feeding materials. The bimodal size distributions considered to be characteristic of twin screw granulation were primarily ascribed to the breakage of relatively large granules by the kneading elements., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The present work focuses on the study of the progression of granules in different compartments along the length of screws in a twin screw granulator (TSG). The effects of varying powder feed rate; liquid to solid ratio and viscosity of granulation liquid on properties of granules was studied. The bigger granules produced at the start of the process were found to change in terms of size, shape and strength along the screw length at all the conditions investigated. The granules became more spherical and their strength increased along the screw length. Tracer granules were also introduced in order to understand the role of kneading and conveying elements in the TSG. The kneading elements promoted consolidation and breakage while the conveying elements led to coalescence, breakage and some consolidation. The results presented here help to provide a qualitative and quantitative understanding of the twin screw granulation process., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Being able to predict the properties of granules from the knowledge of the process and formulation variables is what most industries are striving for. This research uses experimental design to investigate the effect of process variables and formulation variables on mechanical properties of pharmaceutical granules manufactured from a classical blend of lactose and starch using hydroxypropyl cellulose (HPC) as the binder. The process parameters investigated were granulation time and impeller speed whilst the formulation variables were starch-to-lactose ratio and HPC concentration. The granule properties investigated include granule packing coefficient and granule strength. The effect of some components of the formulation on mechanical properties would also depend on the process variables used in granulation process. This implies that by subjecting the same formulation to different process conditions results in products with different properties., (Copyright © 2012 Elsevier B.V. All rights reserved.)