Process Analytical Technology Approach on Fluid Bed Granulation and Drying : Identifying Critical Relationships and Constructing the Design Space

Fluid bed granulation is a key pharmaceutical process which improves many of the powder properties for tablet compression. Dry mixing, wetting and drying phases are included in the fluid bed granulation process. Granules of high quality can be obtained by understanding and controlling the critical process parameters by timely measurements. Physical process measurements and particle size data of a fluid bed granulator that are analysed in an integrated manner are included in process analytical technologies (PAT). Recent regulatory guidelines strongly encourage the pharmaceutical industry to apply scientific and risk management approaches to the development of a product and its manufacturing process. The aim of this study was to utilise PAT tools to increase the process understanding of fluid bed granulation and drying. Inlet air humidity levels and granulation liquid feed affect powder moisture during fluid bed granulation. Moisture influences on many process, granule and tablet qualities. The approach in this thesis was to identify sources of variation that are mainly related to moisture. The aim was to determine correlations and relationships, and utilise the PAT and design space concepts for the fluid bed granulation and drying. Monitoring the material behaviour in a fluidised bed has traditionally relied on the observational ability and experience of an operator. There has been a lack of good criteria for characterising material behaviour during spraying and drying phases, even though the entire performance of a process and end product quality are dependent on it. The granules were produced in an instrumented bench-scale Glatt WSG5 fluid bed granulator. The effect of inlet air humidity and granulation liquid feed on the temperature measurements at different locations of a fluid bed granulator system were determined. This revealed dynamic changes in the measurements and enabled finding the most optimal sites for process control. The moisture originating from the granulation liquid and inlet air affected the temperature of the mass and pressure difference over granules. Moreover, the effects of inlet air humidity and granulation liquid feed rate on granule size were evaluated and compensatory techniques used to optimize particle size. Various end-point indication techniques of drying were compared. The ∆T method, which is based on thermodynamic principles, eliminated the effects of humidity variations and resulted in the most precise estimation of the drying end-point. The influence of fluidisation behaviour on drying end-point detection was determined. The feasibility of the ∆T method and thus the similarities of end-point moisture contents were found to be dependent on the variation in fluidisation between manufacturing batches. A novel parameter that describes behaviour of material in a fluid bed was developed. Flow rate of the process air and turbine fan speed were used to calculate this parameter and it was compared to the fluidisation behaviour and the particle size results. The design space process trajectories for smooth fluidisation based on the fluidisation parameters were determined. With this design space it is possible to avoid excessive fluidisation and improper fluidisation and bed collapse. Furthermore, various process phenomena and failure modes were observed with the in-line particle size analyser. Both rapid increase and a decrease in granule size could be monitored in a timely manner. The fluidisation parameter and the pressure difference over filters were also discovered to express particle size when the granules had been formed. The various physical parameters evaluated in this thesis give valuable information of fluid bed process performance and increase the process understanding.

An exploratory study on the commercialisation of heat pump-fluidised bed drying technology

Fluidised bed-heat pump drying technology offers distinctive advantages over the existing drying technology employed in the Australian food industry. However, as is the case with many other examples of innovations that have had clear relative advantages, the rates of adoption and diffusion of this technology have been very slow. "Why does this happen?" is the theme of this research study that has been undertaken with an objective to analyse a range of issues related to the market acceptance of technological innovations. The research methodology included the development of an integrated conceptual model based on an extensive review of literature in the areas of innovation diffusion, technology transfer and industrial marketing. Three major determinants associated with the market acceptance of innovations were identified as the characteristics of the innovation, adopter information processing capability and the influence of the innovation supplier on the adoption process. This was followed by a study involving more than 30 small and medium enterprises identified as potential adopters of fluidised bed-heat pump drying technology in the Australian food industry. The findings revealed that judgment was the key evaluation strategy employed by potential adopters in the particular industry sector. Further, it was evidenced that the innovations were evaluated against a predetermined criteria covering a range of aspects with emphasis on a selected set of attributes of the innovation. Implication of these findings on the commercialisation of fluidised bed-heat pump drying technology was established, and a series of recommendations was made to the innovation supplier (DPI/FT) enabling it to develop an effective commercialisation strategy.

Hydrodynamic pressure on a dam with a periodically corrugated reservoir bed

The problem of determining the hydrodynamic pressure, caused by earthquake forces, on a dam with a vertical upstream face and a periodically corrugated reservoir bed is solved approximately by employing a Fourier cosine transform technique to the linearised equations of inviscid and incompressible flow. A particular case of the present problem giving rise to results valid for dams with flat reservoir beds is shown to produce known results as a check of the method used.

Habitat dynamics in the bed sediments of an intermittent upland stream

The effects of the hydrological regime on temporal changes to physical characteristics of substratum habitat, sediment texture of surface sediments (<10 cm), were investigated in a sub-tropical headwater stream over four years. Surface discharge was measured together with vertical hydraulic gradient and groundwater depth in order to explore features of sediment habitat that extend beyond the streambed surface. Whilst the typical discharge pattern was one of intermittent base flows and infrequent flow events associated with monsoonal rain patterns, the study period also encompassed a drought and a one-in-a-hundred-year flood. Rainfall and discharge did not necessarily reflect the actual conditions in the stream. Although surface waters were persistent long after discharge ceased, the streambed was completely dry on several occasions. Shallow groundwater was present at variable depths throughout the study period, being absent only at the height of the drought. The streambed sediments were mainly gravels, sand and clay. Finer sediment fractions showed a marked change in grain size over time, although bedload movement was limited to a single high discharge event. In response to a low discharge regimen (drought), sediments characteristically showed non-normal distributions and were dominated by finer materials. A high-energy discharge event produced a coarsening of sands and a diminished clay fraction in the streambed. Particulate organic matter from sediments showed trends of build-up and decline with the high and low discharge regimes, respectively. Within the surface sediment intersticies three potential categories of invertebrate habitat were recognised, each with dynamic spatial and temporal boundaries.

Packed bed bioreactor for the isolation and expansion of placental-derived Mesenchymal Stromal Cells

Large numbers of Mesenchymal stem/stromal cells (MSCs) are required for clinical relevant doses to treat a number of diseases. To economically manufacture these MSCs, an automated bioreactor system will be required. Herein we describe the development of a scalable closed-system, packed bed bioreactor suitable for large-scale MSCs expansion. The packed bed was formed from fused polystyrene pellets that were air plasma treated to endow them with a surface chemistry similar to traditional tissue culture plastic. The packed bed was encased within a gas permeable shell to decouple the medium nutrient supply and gas exchange. This enabled a significant reduction in medium flow rates, thus reducing shear and even facilitating single pass medium exchange. The system was optimised in a small-scale bioreactor format (160 cm2) with murine-derived green fluorescent protein-expressing MSCs, and then scaled-up to a 2800 cm2 format. We demonstrated that placental derived MSCs could be isolated directly within the bioreactor and subsequently expanded. Our results demonstrate that the closed system large-scale packed bed bioreactor is an effective and scalable tool for large-scale isolation and expansion of MSCs.

Bed Shear from Velocity Profiles: A New Approach

A new binary law of velocity distribution has been developed to describe the velocity profile for the entire flow region. The law is a combination of logarithmic law, valid in the wall (inner) region, and parabolic law, valid in the core (outer) region of the flow. The validity of the law has been established based on earlier data on flat plates, rough and smooth pipes and experimental data obtained from rigid-walled open channels with plane sand beds. A procedure of estimating bed shear stress from the proposed law of velocity distribution using the measured velocity profile has been evolved. Bed shear estimates made according to this procedure are in agreement with the values obtained from uniform flow analysis in the case of open channel flow over a sediment bed. The proposed method of estimating the bed shear stress from the observed velocity profiles is found to be particularly useful in cases where it is difficult to determine precisely the true bed level, such as in the case of flow over sediment beds.

Stream power criterion and design of sand bed channels at incipient motion

The critical stream power criterion may be used to describe the incipient motion of cohesionless particles of plane sediment beds. The governing equation relating ``critical stream power'' to ``shear Reynolds number'' is developed by using the present experimental data as well as the data from several other sources. Simultaneously, a resistance equation, relating the ``particle Reynolds number'' to the``shear Reynolds number'' is developed for plane sediment beds in wide channels with little or no transport. By making use of these relations, a procedure is developed to design plane sediment beds such that any two of the four design variables, including particle size, energy/friction slope, flow depth, and discharge per unit width in the channel should be known to predict the remaining two variables. Finally, a straightforward design procedure using design tables/design curves and analytical methods is presented to solve six possible design problems.

Freddy, Ursula, Elizabeth, Hal, Walter, and Kurt Gottschalk sharing a bed with their parents.

From left to right: Fred Gottschalk, grandma, Ursula Gottschalk, Elizabeth Gottschalk, grandpa, Hal Gottschalk, Walter Gottschalk, and Kurt Gottschalk

Oxidation Of Sodium Sulfide In A Foam Bed Contactor

Oxidation of sodium sulphide to sodium thiosulphate has been experimentally investigated in a foam bed contactor using air as oxidizing medium. The var.

Oxidation of sodium sulphide in the presence of fine activated carbon particles in a foam bed contactor

The oxidation of sodium sulphide in the presence of fine activated carbon particles (4.33 μm) has been studied at 75°C in a foam bed contactor. The existing single-stage model of a foam bed reactor has been modified to take into account the effect of heterogeneous catalyst particles and the absorption in the storage section. The variables studied are catalyst loading, initial sulphide concentration and the average liquid hold-up in the foam bed. It is seen that the rates of oxidation of sodium sulphide are considerably enhanced by an increase in the loading of activated carbon particles. The rate of conversion of sodium sulphide also increases with an increase in the average liquid hold-up in the foam. The modified model predicts these effects fairly well. The contribution of reaction in the storage section is found to be less than 2% of the overall rate of conversion in the contactor.

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Mass transfer with chemical reaction in a foam bed contactor

On the basis of dodecahedral structure of a foam bed, a model to predict conversion in a foam bed contactor with mass transfer with chemical reaction has been developed. To verify the proposed model, experiments have been carried out in a semi-batch apparatus for the absorption of lean CO2 gas in a foam of sodium hydroxide solution. The proposed model predicts fairly well the experimentally found absorption values.

Intrinsic kinetics of trickle bed reactors

Abstract is not available.

Liquid phase hydrogenation of aniline in a trickle bed reactor

A rate equation is developed for the liquid phase hydrogenation of aniline over cylindrical catalyst pellets of 30% nickel deposited on clay in a trickle bed reactor. The equation takes into account external and internal diffusional limitations, and describes the experimental data adequately. The hydrogenation reaction is first order with respect to hydrogen and zero order with respect to aniline. Effectiveness factors are in the range 0.003-0.03. Apparent activation energy of the reaction is 12.7 kcal/mol and true activation energy is 39.6 kcal/mol.