Scaleup of wet granulation processes: science not art

Significant advances have been made in the last decade to quantify the process of wet granulation. The attributes of product granules from the granulation process are controlled by a combination of three groups of processes occurring in the granulator: (1) wetting and nucleation, (2) growth and consolidation and (3) breakage and attrition. For the first two of these processes, the key controlling dimensionless groups are defined and regime maps are presented and validated with data from tumbling and mixer granulators. Granulation is an example of particle design. For quantitative analysis, both careful characterisation of the feed formulation and knowledge of operating parameters are required. A key thesis of this paper is that the design, scaleup and operation of granulation processes can now be considered as quantitative engineering rather than a black art. Résumé

Cracks of higher modes in Cosserat continua

Rotational degrees of freedom in Cosserat continua give rise to higher fracture modes. Three new fracture modes correspond to the cracks that are surfaces of discontinuities in the corresponding components of independent Cosserat rotations. We develop a generalisation of J- integral that includes these additional degrees of freedom. The obtained path-independent integrals are used to develop a criterion of crack propagation for a special type of failure in layered materials with sliding layers. This fracture propagates as a progressive bending failure of layers – a “bending crack that is, a crack that can be represented as a distribution of discontinuities in the layer bending. This situation is analysed using a 2D Cosserat continuum model. Semi-infinite bending crack normal to layering is considered. The moment stress concentrates along the line that is a continuation of the crack and has a singularity of the power − 1/4. A model of process zone is proposed for the case when the breakage of layers in the process of bending crack propagation is caused by a crack (microcrack in our description) growing across the layer adjacent to the crack tip. This growth is unstable (in the moment-controlled loading), which results in a typical descending branch of moment stress – rotation discontinuity relationship and hence in emergence of a Barenblatt-type process zone at the tip of the bending crack.

Fibre agglomerate transport in a horizontal flow

An experimental and theoretical study of the transport of mineral wool fibre agglomerates in nuclear power plant containment sumps is being performed. A racetrack channel was devised to provide data for the validation of numerical models, which are intended to model the transport of fibre agglomerates. The racetrack channel provides near uniform and steady conditions that lead to either the sedimentation or suspension of the agglomerates. Various experimental techniques were used to determine the velocity conditions and the distribution of the fibre agglomerates in the channel. The fibre agglomerates are modelled as fluid particles in the Eulerian reference frame. Simulations of pure sedimentation of a known mass and volume of agglomerations show that the transport of the fibre agglomerates can be replicated. The suspension of the fibres is also replicated in the simulations; however, the definition of the fibre agglomerate phase is strongly dependent on the selected density and diameter. Detailed information on the morphology of the fibre agglomerates is lacking for the suspension conditions, as the fibre agglomerates may undergo breakage and erosion. Therefore, ongoing work, which is described here, is being pursued to improve the experimental characterisation of the suspended transport of the fibre agglomerates.

Synthesis of sulforaphane and inhibition of cytochrome P450 enzymes as a basis for antigenotoxicity

Many dietary factors have been associated with a decreased risk of developing cancer. One potential mechanism by which these factors, chemopreventors, protect against cancer may be via alteration of carcinogen metabolism. The broccoli constituent sulforaphane (1-isothiocyanate-4-methylsulinylbutane) (CH3-S0-(CH2)4-NCS) has been isolated as a potential inducer of phase II detoxification enzymes and also protects rodents against 9,10-dimethyl-1,2-benz[aJanthracene-induced mammary tumours. The ability of sulforaphane to also modulate phase I activation enzymes (cytochrome P450) (CYP450) was studied here. Sulforaphane was synthesised with an overall yield of 15%, essentially via 1-methylsulfinylphthalimidobutane, which was oxidised to the sulfoxide moiety. Deprotective removal of phthalimide yielded the amine, which was converted into sulforaphane by reaction with N,N'-thionocarbonyldiimidazole. Purity (95 %) was checked by 1H-NMR,13C-NMR and infrared and mass spectrometry.Sulforaphane was a competitive inhibitor of CYP2E1 in acetone-induced Sprague-Dawley rat microsomes (Ki 37.9 ± 4.5μM), as measured by the p-nitrophenol hydroxylase assay. Ethoxyresorufin deethylase activity (EROD), a measurement of CYP1A activity, was also inhibited by sulforaphane (100μM) but was not competitive, and a preincubation time-dependence was observed. In view of these results, the capacity of sulforaphane to inhibit N-nitrosodimethylamine (NDMA)-induced genotoxicity (CYP2E1-mediated) was studied using mouse liver activation systems. Sulforaphane (>0.8μM) inhibited the mutagenicity of NDMA (4.4 mg/plate) in Salmonella typhimurium strain TA100 after pre-incubation for 45 min with acetone-induced liver 9000 g supernatants from Balb/c mice. Unscheduled DNA synthesis induced by NDMA (33μ5 M) in mouse hepatocytes was also reduced by sulforaphane in a concentration-dependent manner (0.064-20μM). Sulforaphane was not genotoxic itself in any of these systems and cytotoxic only at high concentrations (>0.5 mM and > 40μM respectively). The ability of sulforaphane to modulate the orthologous human enzymes was studied using a human epithelial liver cell line (THLE) expressing individual human CYP450 isoenzymes. Using the Comet assay (a measurement of DNA strand breakage under alkaline conditions), NDMA (0.01-1μg/ml) and IQ (0.1-10μg/ml) were used to produce strand breaks in T5-2E1 cells (expressing human CYP2E1) and T5-1A2 cells (expressing human CYP1A2) respectively, however no response was observed in T5-neo cells (without CYP450 cDNA transfection). Sulforaphane inhibited both NDMA and IQ-induced DNA strand breakage in a concentration-dependent manner (0.1-10μM).The inhibition of metabolic activation as a basis for the antigenotoxic action of sulforaphane in these systems (bacteria, rodent hepatocytes and human cells) is further supported by the lack of this chemopreventor to influence NaN3 mutagenicity in S. typhimurium and H202-induced DNA strand breakage in T5-neo cells. These findings suggest that inhibition of CYP2E1 and CYP1A by sulforaphane may contribute to its chemoprotective potential.

An age-related increase in resistance to DNA damage-induced apoptotic cell death is associated with development of DNA repair mechanisms

Neurons in the developing brain die via apoptosis after DNA damage, while neurons in the adult brain are generally resistant to these insults. The basis for this resistance is a matter of conjecture. We report here that cerebellar granule neurons (CGNs) in culture lose their competence to die in response to DNA damage as a function of time in culture. CGNs at either 1 day in vitro (DIV) or 7 DIV were treated with the DNA damaging agents camptothecin, UV or gamma-irradiation and neuronal survival measured. The younger neurons were effectively killed by these agents, while the older neurons displayed a significant resistance to killing. Neuronal survival did not change with time in culture when cells were treated with C2-ceramide or staurosporine, agents which do not target DNA. The resistance to UV irradiation developed over time in culture and was not due to changes in mitotic rate. Increases in DNA strand breakage, up-regulation of the levels of both p53 and its phosphorylated form and nuclear translocation of p53 were equivalent in both older and younger neurons, indicating a comparable p53 stress response. In addition, we show that treatment of older neurons with pharmacological inhibitors of distinct components of the DNA repair machinery promotes the accumulation of DNA damage and sensitizes these cells to the toxic effects of UV exposure. These data demonstrate that older neurons appear to be more proficient in DNA repair in comparison to their younger counterparts, and that this leads to increased survival after DNA damage.

Micromechanics of agglomerate damage processes

This thesis reports a detailed investigation of the micromechanics of agglomerate behaviour under free-fall impact, double (punch) impact and diametrical compression tests using the simulation software TRUBAL. The software is based on the discrete element method (DEM) which incorporates the Newtonian equations of motion and contact mechanics theory to model the interparticle interactions. Four agglomerates have been used: three dense (differing in interface energy and contact density) and one loose. Although the simulated agglomerates are relatively coarse-grained, the results obtained are in good agreement with laboratory test results reported in the literature. The computer simulation results show that, in all three types of test, the loose agglomerate cannot fracture as it is unable to store sufficient elastic energy. Instead, it becomes flattened for low loading-rates and shattered or crushed at higher loading-rates. In impact tests, the dense agglomerates experience only local damage at low impact velocities. Semi-brittle fracture and fragmentation are produced over a range of higher impact velocities and at very high impact velocities shattering occurs. The dense agglomerates fracture in two or three large fragments in the diametrical compression tests. Local damage at the agglomerate-platen interface always occurs prior to fracture and consists of local bond breakage (microcrack formation) and local dislocations (compaction). The fracture process is dynamic and much more complex than that suggested by continuum fracture mechanics theory. Cracks are always initiated from the contact zones and propagate towards the agglomerate centre. Fracture occurs a short time after the start of unloading when a fracture crack "selection" process takes place. The detailed investigation of the agglomerate damage processes includes an examination of the evolution of the fracture surface. Detailed comparisons of the behaviour of the same agglomerate in all three types of test are presented. The particle size distribution curves of the debris are also examined, for both free-fall and double impact tests.

Numerical modelling of agglomerate degradation

In the processing industries particulate materials are often in the form of powders which themselves are agglomerations of much smaller sized particles. During powder processing operations agglomerate degradation occurs primarily as a result of collisions between agglomerates and between agglomerates and the process equipment. Due to the small size of the agglomerates and the very short duration of the collisions it is currently not possible to obtain sufficiently detailed quantitative information from real experiments to provide a sound theoretically based strategy for designing particles to prevent or guarantee breakage. However, with the aid of computer simulated experiments, the micro-examination of these short duration dynamic events is made possible. This thesis presents the results of computer simulated experiments on a 2D monodisperse agglomerate in which the algorithms used to model the particle-particle interactions have been derived from contact mechanics theories and, necessarily, incorporate contact adhesion. A detailed description of the theoretical background is included in the thesis. The results of the agglomerate impact simulations show three types of behaviour depending on whether the initial impact velocity is high, moderate or low. It is demonstrated that high velocity impacts produce extensive plastic deformation which leads to subsequent shattering of the agglomerate. At moderate impact velocities semi-brittle fracture is observed and there is a threshold velocity below which the agglomerate bounces off the wall with little or no visible damage. The micromechanical processes controlling these different types of behaviour are discussed and illustrated by computer graphics. Further work is reported to demonstrate the effect of impact velocity and bond strength on the damage produced. Empirical relationships between impact velocity, bond strength and damage are presented and their relevance to attrition and comminution is discussed. The particle size distribution curves resulting from the agglomerate impacts are also provided. Computer simulated diametrical compression tests on the same agglomerate have also been carried out. Simulations were performed for different platen velocities and different bond strengths. The results show that high platen velocities produce extensive plastic deformation and crushing. Low platen velocities produce semi-brittle failure in which cracks propagate from the platens inwards towards the centre of the agglomerate. The results are compared with the results of the agglomerate impact tests in terms of work input, applied velocity and damage produced.

Discrete element modelling of a rotating drum and drum granulation

This thesis reports the results of DEM (Discrete Element Method) simulations of rotating drums operated in a number of different flow regimes. DEM simulations of drum granulation have also been conducted. The aim was to demonstrate that a realistic simulation is possible, and further understanding of the particle motion and granulation processes in a rotating drum. The simulation model has shown good qualitative and quantitative agreement with other published experimental results. A two-dimensional bed of 5000 disc particles, with properties similar to glass has been simulated in the rolling mode (Froude number 0.0076) with a fractional drum fill of approximately 30%. Particle velocity fields in the cascading layer, bed cross-section, and at the drum wall have shown good agreement with experimental PEPT data. Particle avalanches in the cascading layer have been shown to be consistent with single layers of particles cascading down the free surface towards the drum wall. Particle slip at the drum wall has been shown to depend on angular position, and ranged from 20% at the toe and shoulder, to less than 1% at the mid-point. Three-dimensional DEM simulations of a moderately cascading bed of 50,000 spherical elastic particles (Froude number 0.83) with a fractional fill of approximately 30% have also been performed. The drum axis was inclined by 50 to the horizontal with periodic boundaries at the ends of the drum. The mean period of bed circulation was found to be 0.28s. A liquid binder was added to the system using a spray model based on the concept of a wet surface energy. Granule formation and breakage processes have been demonstrated in the system.

A molecular dynamics model of the atomic structure of dysprosium alumino-phosphate glass

Molecular dynamics (MD) has been used to identify the relative distribution of dysprosium in the phosphate glass DyAl0.30P3.05O9.62. The MD model has been compared directly with experimental data obtained from neutron diffraction to enable a detailed comparison beyond the total structure factor level. The MD simulation gives Dy ... Dy correlations at 3.80(5) and 6.40(5) angstrom with relative coordination numbers of 0.8(1) and 7.3(5), thus providing evidence of minority rare-earth clustering within these glasses. The nearest neighbour Dy-O peak occurs at 2.30 angstrom with each Dy atom having on average 5.8 nearest neighbour oxygen atoms. The MD simulation is consistent with the phosphate network model based on interlinked PO4 tetrahedra where the addition of network modifiers Dy3+ depolymerizes the phosphate network through the breakage of P-(O)-P bonds whilst leaving the tetrahedral units intact. The role of aluminium within the network has been taken into explicit account, and A1 is found to be predominantly (78 tetrahedrally coordinated. In fact all four A1 bonds are found to be to P (via an oxygen atom) with negligible amounts of Al-O-Dy bonds present. This provides an important insight into the role of Al additives in improving the mechanical properties of these glasses.

Editorial

The year so far has been a slow start for many businesses, but at least we have not seen the collapse of as many businesses that we were seeing around two years ago. We are, however, still well and truly in the midst of a global recession. Interest rates are still at an all time low, UK house prices seem to be showing little signs of increase (except in London where everyone still seems to want to live!) and for the ardent shopper there are bargains to be had everywhere. It seems strange that prices on the high street do not seem to have increased in over ten years. Mobile phones, DVD players even furniture seems to be cheaper than they used to be. Whist much of this is down to cheaper manufacturing and the rest could probably be explained by competition within the market place. Does this mean that quality suffered too? Now that we live in a world when if a television is not working it is thrown away and replaced. There was a time when you would take it to some odd looking man that your father would know who could fix it for you. (I remember our local television fix-it man, with his thick rimmed bifocal spectacles and a poor comb-over; he had cardboard boxes full of resistors and electrical wires on the floor of his front room that smelt of soldering irons!) Is this consumerism at an extreme or has this move to disposability made us a better society? Before you think these are just ramblings there is a point to this. According to latest global figures of contact lens sales the vast majority of contact lenses fitted around the world are daily, fortnightly or monthly disposable hydrogel lenses. Certainly in the UK over 90% of lenses are disposable (with daily disposables being the most popular, having a market share of over 50%). This begs the question – is this a good thing? Maybe more importantly, do our patients benefit? I think it is worth reminding ourselves why we went down the disposability route with contact lenses in the first place, and unlike electrical goods it was not just so we did not have to take them for repair! There are the obvious advantages of overcoming problems of breakage and tearing of lenses and the lens deterioration with age. The lenses are less likely to be contaminated and the disinfection is either easier or not required at all (in the case of daily disposable lenses). Probably the landmark paper in the field was the work more commonly known as the ‘Gothenburg Study’. The paper, entitled ‘Strategies for minimizing the Ocular Effects of Extended Contact Lens Wear’ published in the American Journal of Optometry in 1987 (volume 64, pages 781-789) by Holden, B.A., Swarbrick, H.A., Sweeney, D.F., Ho, A., Efron, N., Vannas, A., Nilsson, K.T. They suggested that contact lens induced ocular effects were minimised by: •More frequently removed contact lenses •More regularly replaced contact lenses •A lens that was more mobile on the eye (to allow better removal of debris) •Better flow of oxygen through the lens All of these issues seem to be solved with disposability, except the oxygen issue which has been solved with the advent of silicone hydrogel materials. Newer issues have arisen and most can be solved in practice by the eye care practitioner. The emphasis now seems to be on making lenses more comfortable. The problems of contact lens related dry eyes symptoms seem to be ever present and maybe this would explain why in the UK we have a pretty constant contact lens wearing population of just over three million but every year we have over a million dropouts! That means we must be attracting a million new wearers every year (well done to the marketing departments!) but we are also losing a million wearers every year. We certainly are not losing them all to the refractive surgery clinics. We know that almost anyone can now wear a contact lens and we know that some lenses will solve problems of sharper vision, some will aid comfort, and some will be useful for patients with dry eyes. So if we still have so many dropouts then we must be doing something wrong! I think the take home message has to be ‘must try harder’! I must end with an apology for two errors in my editorial of issue 1 earlier this year. Firstly there was a typo in the first sentence; I meant to state that it was 40 years not 30 years since the first commercial soft lens was available in the UK. The second error was one that I was unaware of until colleagues Geoff Wilson (Birmingham, UK) and Tim Bowden (London, UK) wrote to me to explain that soft lenses were actually available in the UK before 1971 (please see their ‘Letters to the Editor’ in this issue). I am grateful to both of them for correcting the mistake.

A compartmental CFD-PBM model of high shear wet granulation

The conventional, geometrically lumped description of the physical processes inside a high shear granulator is not reliable for process design and scale-up. In this study, a compartmental Population Balance Model (PBM) with spatial dependence is developed and validated in two lab-scale high shear granulation processes using a 1.9L MiPro granulator and 4L DIOSNA granulator. The compartmental structure is built using a heuristic approach based on computational fluid dynamics (CFD) analysis, which includes the overall flow pattern, velocity and solids concentration. The constant volume Monte Carlo approach is implemented to solve the multi-compartment population balance equations. Different spatial dependent mechanisms are included in the compartmental PBM to describe granule growth. It is concluded that for both cases (low and high liquid content), the adjustment of parameters (e.g. layering, coalescence and breakage rate) can provide a quantitative prediction of the granulation process.

Directionality based preventive link maintenance scheme for mobile ad hoc networks

The purpose of this study was to design a preventive scheme using directional antennas to improve the performance of mobile ad hoc networks. In this dissertation, a novel Directionality based Preventive Link Maintenance (DPLM) Scheme is proposed to characterize the performance gain [JaY06a, JaY06b, JCY06] by extending the life of link. In order to maintain the link and take preventive action, signal strength of data packets is measured. Moreover, location information or angle of arrival information is collected during communication and saved in the table. When measured signal strength is below orientation threshold , an orientation warning is generated towards the previous hop node. Once orientation warning is received by previous hop (adjacent) node, it verifies the correctness of orientation warning with few hello pings and initiates high quality directional link (a link above the threshold) and immediately switches to it, avoiding a link break altogether. The location information is utilized to create a directional link by orienting neighboring nodes antennas towards each other. We call this operation an orientation handoff, which is similar to soft-handoff in cellular networks. ^ Signal strength is the indicating factor, which represents the health of the link and helps to predict the link failure. In other words, link breakage happens due to node movement and subsequently reducing signal strength of receiving packets. DPLM scheme helps ad hoc networks to avoid or postpone costly operation of route rediscovery in on-demand routing protocols by taking above-mentioned preventive action. ^ This dissertation advocates close but simple collaboration between the routing, medium access control and physical layers. In order to extend the link, the Dynamic Source Routing (DSR) and IEEE 802.11 MAC protocols were modified to use the ability of directional antennas to transmit over longer distance. A directional antenna module is implemented in OPNET simulator with two separate modes of operations: omnidirectional and directional. The antenna module has been incorporated in wireless node model and simulations are performed to characterize the performance improvement of mobile ad hoc networks. Extensive simulations have shown that without affecting the behavior of the routing protocol noticeably, aggregate throughput, packet delivery ratio, end-to-end delay (latency), routing overhead, number of data packets dropped, and number of path breaks are improved considerably. We have done the analysis of the results in different scenarios to evaluate that the use of directional antennas with proposed DPLM scheme has been found promising to improve the performance of mobile ad hoc networks. ^

Tool cutting force modeling and wear estimation of micro -end-milling operations

The applications of micro-end-milling operations have increased recently. A Micro-End-Milling Operation Guide and Research Tool (MOGART) package has been developed for the study and monitoring of micro-end-milling operations. It includes an analytical cutting force model, neural network based data mapping and forecasting processes, and genetic algorithms based optimization routines. MOGART uses neural networks to estimate tool machinability and forecast tool wear from the experimental cutting force data, and genetic algorithms with the analytical model to monitor tool wear, breakage, run-out, cutting conditions from the cutting force profiles. ^ The performance of MOGART has been tested on the experimental data of over 800 experimental cases and very good agreement has been observed between the theoretical and experimental results. The MOGART package has been applied to the micro-end-milling operation study of Engineering Prototype Center of Radio Technology Division of Motorola Inc. ^

An experimental study of micro-end-milling operations

Cutting tools less than 2mm diameter can be considered as micro-tool. Microtools are used in variety of applications where precision and accuracy are indispensable. In micro-machining operations, a small amount of material is removed and very small cutting forces are created. The small cross sectional area of the micro-tools drastically reduces their strength and makes their useful life short and unpredictable; so cutting parameters should be selected carefully to avoid premature tool breakage. The main objective of this study is to develop new techniques to select the optimal cutting conditions with minimum number of experiments and to evaluate the tool wear in machining operations. Several experimental setups were prepared and used to investigate the characteristics of cutting force and AE signals during the micro-end-milling of different materials including steel, aluminum and graphite electrodes. The proposed optimal cutting condition selection method required fewer experiments than conventional approaches and avoided premature tool breakage. The developed tool wear monitoring technique estimated the used tool life with ±10% accuracy from the machining data collected during the end-milling of non-metal materials.