Particle Size, Moisture, and Fluidization Variations Described by Indirect In-line Physical Measurements of Fluid Bed Granulation

The aim of this study was to evaluate an instrumentation system for a bench scale fluid bed granulator to determine the parameters expressing the changing conditions during the spraying phase of a fluid bed process. The study focused mainly on four in-line measurements (dependent variables): fluidization parameter (calculated by inlet air flow rate and rotor speed), pressure difference over the upper filters, pressure difference over the granules (lower filter), and temperature of the fluidizing mass. In-line particle size measured by the spatial filtering technique was an essential predictor variable. Other physical process measurements of the automated granulation system, 25 direct and 12 derived parameters, were also utilized for multivariate modeling. The correlation and partial least squares analyses revealed significant relationships between various process parameters highlighting the particle size, moisture, and fluidization effect. Fluidization parameter and pressure difference over upper filters were found to correlate with in-line particle size and therefore could be used as estimates of particle size during granulation. The pressure difference over the granules and the temperature of the fluidizing mass expressed the moisture conditions of wet granulation. The instrumentation system evaluated here is an invaluable aid to gaining more control for fluid bed processing to obtain repeatable granules for further processing.     

Process analysis of fluidized bed granulation

This study assesses the fluidized bed granulation process for the optimization of a model formulation using in-line near-infrared (NIR) spectroscopy for moisture determination. The granulation process was analyzed using an automated granulator and optimization of the verapamil hydrochloride formulation was performed using a mixture design. The NIR setup with a fixed wavelength detector was applied for moisture measurement. Information from other process measurements, temperature difference between process inlet air and granules (T_diff), and water content of process air (AH), was also analyzed. The application of in-line NIR provided information related to the amount of water throughout the whole granulation process. This information combined with trend charts of T_diff and AH enabled the analysis of the different process phases. By this means, we can obtain in-line documentation from all the steps of the processing. The choice of the excipient affected the nature of the solid-water interactions; this resulted in varying process times. NIR moisture measurement combined with temperature and humidity measurements provides a tool for the control of water during fluid bed granulation.     

Development and Application of a Process Window for Achieving High-Quality Coating in a Fluidized Bed Coating Process

Next to the coating formulation, process conditions play important roles in determining coating quality. This study aims to develop an operational window that separates layering from agglomeration regimes and, furthermore, the one that leads to the best coating quality in a fluidized bed coater. The bed relative humidity and the droplet size of the coating aerosol were predicted using a set of engineering models. The coating quality was characterized using a quantitative image analysis method, which measures the coating thickness distribution, the total porosity, and the pore size in the coating. The layering regime can be achieved by performing the coating process at a certain excess of the viscous Stokes number (ΔSt _v). This excess is dependent on the given bed relative humidity and droplet size. The higher the bed relative humidity, the higher is the ΔSt _v required to keep the process in the layering regime. Further, it is shown that using bed relative humidity and droplet size alone is not enough to obtain constant coating quality. The changes in bed relative humidity and droplet size have been identified to correlate to the fractional area of particles sprayed per unit of time. This parameter can effectively serve as an additional parameter to be considered for a better control on the coating quality. High coating quality is shown to be achieved by performing the process close to saturation and spraying droplets small enough to obtain high spraying rate, but not too small to cause incomplete coverage of the core particles.     

Temporal Aroma Release Profile of Solid and Liquid Droplet Emulsions

The release kinetics of four model aroma compounds from coarse (d ₃₂ = 1.0 μm) and fine (d ₃₂ = 0.25 μm) eicosane and hydrogenated palm stearin (HPS) emulsions prepared with either solid or liquid lipid droplets were measured using a model mouth instrument. For both lipids, the release of aroma compounds from emulsions with solid droplets was higher than from emulsions with liquid droplets. This difference was greater for less polar aroma compounds. The release from solid eicosane droplets increased with particle size but no such effect was observed for HPS emulsions, however, the release from solid eicosane was higher than solid HPS. The initial aroma release profile of the solid droplet emulsion matches that of a similar liquid oil emulsion but requires much less added aroma. Meeting presentation: Presented at 98th AOCS Annual Meeting and Expo in Quebec City, Canada.     

Monitoring the fluidized bed granulation process based on<Emphasis Type="Italic">S</Emphasis>-statistic analysis of a pressure time series

Pressure fluctuation measurements collected during the fluidized bed granulation of pharmaceutical granule have been analyzed using the attractor comparison technique denoted as theS-statistic. Divergence of the bed state from the reference during granulation is followed by a return to a condition statistically similar to the original state of the dry fluidized ingredients on drying. This suggests insensitivity of theS-statistic technique to the changes in particle size distribution occurring during the granulation process. Consequently, the monitoring of pressure fluctuations alone may provide an easily implemented technique for the tracking of granule moisture and process end-point determination. Published: September 30, 2005     

Difference in the Lubrication Efficiency of Bovine and Vegetable-Derived Magnesium Stearate During Tabletting

The purpose of this work was to evaluate and compare the functionality of bovine fatty acids-derived (MgSt-B) and vegetable fatty acids-derived (MgSt-V) magnesium stearate powders when used for the lubrication of granules prepared by high-shear (HSG) and fluid bed (FBG) wet granulation methods. The work included evaluation of tablet compression and ejection forces during tabletting and dissolution testing of the compressed tablets. Granules prepared by both granulation methods required significantly lower ejection force (p < 0.01) when lubricated with the MgSt-V powder as compared to those lubricated with the MgSt-B powder. Granules prepared by the HSG method and lubricated with the MgSt-V powder also required significantly lower compression force (p < 0.01) to produce tablets of similar weight and hardness as compared to those lubricated with the MgSt-B powder. The dissolution profiles were not affected by these differences and were the same for tablets prepared by same granulation method and lubricated with either magnesium stearate powder. The results indicate significant differences (p < 0.01) between lubrication efficiency of the MgSt-B and the MgSt-V powders and emphasize the importance of functionality testing of the MgSt powders to understand the impact of these differences. The opinions expressed in this work are only of authors, and do not necessarily reflect the policy and statements of the FDA.     

A breakthrough column study for removal of malachite green using coco-peat

Abstract

A continuous adsorption study in a fixed bed column using coco-peat (CP) as an adsorbent was carried out for the removal of toxic malachite green (MG) from contaminated water. Fixed bed column studies were carried out to check field application viability. Various parameters like particle size, pH, concentration, dose and interference were exercised to optimize dye removal. Data obtained from breakthrough column studies were evaluated using Thomas and BDST model. Thomas rate constants K_t (0.22?ml min^?1 mg^?1) and adsorption capacity q_o (181.04?mg g^?1) were estimated and found to favor efficiency of CP. Thomas model was tested with several parameters like flow rate, concentration, and bed depth. Upon increase in input dye concentration, flow rate and bed height, adsorption coefficients increased. According to BDST model, maximum dye uptake of 468.26?mg/l was obtained with an input dye concentration of 5?mg/l. HYBRID and MPSD error functions were tested and found that Thomas model fits best. Dilute hydrochloric acid was found best for desorption. Real wastewater from textile industry was analyzed and confirmed the prospect of large-scale industrial application. In conclusion, coco-peat can be used as a promising bio-sorbent in column bed for scavenging of MG from contaminated water.     

The function of water channels in Chara: The temperature dependence of water and solute flows provides evidence for composite membrane transport and for a slippage of small organic solutes across water channels

Using the cell pressure probe, the effects of temperature on hydraulic conductivity (Lp; osmotic water permeability), solute permeability (permeability coefficient, P_s), and reflection coefficients (σ_s) were measured on internodes of Chara corallina, Klein ex Willd., em R.D.W.. For the first time, complete sets of transport coefficients were obtained in the range between 10 and 35 °C which provided evidence about pathways of water and solutes as they move across the plasma membrane (water channel and bilayer arrays). Test solutes used to check for the selectivity of water channels were monohydric alcohols of different molecular size and shape (ethanol, n-propanol, iso-propanol, and tert-butanol) and heavy water (HDO). Within the limits of accuracy, Q₁₀ values for Lp and for the diffusive water permeability (P_d) were identical (Q₁₀ for Lp = 1.29 ± 0.17 (± SD; n = 15 cells) and Q₁₀ for P_d = 1.25 ± 0.16 (n = 5 cells)). The Q₁₀ values were equivalent to activation energies of E_a = 16.8 ± 6.4 and 16.6 ± 10.0 kJ · mol⁻¹, respectively, which is similar to that of self-diffusion or of viscous flow of water. The Q₁₀ values and activation energies for P_s of the alcohols were significantly larger (ethanol: Q₁₀ = 1.68 ± 0.16, E_a = 37.1 ± 5.9 kJ · mol⁻¹; n-propanol: Q₁₀ =  1.75 ± 0.40, E_a = 43.1 ± 15.3 kJ · mol⁻¹; iso-propanol: Q₁₀ = 2.12 ± 0.42, E_a =  52.2 ± 14.6 kJ · mol⁻¹; tert-butanol: Q₁₀ = 2.13 ± 0.56, E_a = 51.6 ± 17.1 kJ · mol⁻¹; ±SD; n = 5 to 6 cells). Effects of temperature on reflection coefficients were most pronounced. With increasing temperature, σ_s values of the alcohols decreased and those of HDO increased. The data indicate that water and solutes use different pathways when crossing the membrane. Ordinary and isotopic water use water channels and the other test solutes use the bilayer array (composite transport model of membrane). Changes in σ_s values with temperature were found to be a sensitive measure for the open/closed state of water channels. The decrease of σ_s with temperature was theoretically predicted from the temperature dependence of P_s and Lp. Differences between predicted and measured values of σ_s allowed estimation of the bypass flow (slippage) of solutes through water channels which did not completely exclude test solutes. The permeability of channels depended on the structure and size of test solutes. It is concluded that water channels are much less selective than is usually thought. Since water channels represent single-file or no-pass pores, solutes drag along considerable amounts of water as they diffuse across channels. This results in low overall values of σ_s. The σ_s of HDO was extremely low. Its response to temperature was opposite to that for the σ_s of the alcohols. This suggested a stronger effect of temperature on the hydraulic (osmotic) than on the diffusive water flow across individual water channels, i.e. a differential sensitivity of different mechanisms to temperature. Received: 10 October 1996 / Accepted: 2 December 1996     

Transport of Intranasally Instilled Fine Fe2O3 Particles into the Brain: Micro-distribution, Chemical States, and Histopathological Observation

It has been demonstrated that inhaled fine (d < 2.5 μm) and ultrafine (d < 100 nm) particles produce more severe toxicity than coarse particles. Some recent data support the concept that the central nervous system (CNS) may be a target for the inhaled fine particulates. This work describes initial observation of the transport of intranasally instilled fine ferric oxide (Fe₂O₃) particles in animal brain. The iron micro-distribution and chemical state in the mice olfactory bulb and brain stem on day 14 after intranasal instillation of fine Fe₂O₃ particle (280 ± 80 nm) suspension at a single dose of 40 mg/kg body weight were analyzed by synchrotron radiation x-ray fluorescence and x-ray absorption near-edge structure (XANES). The micro-distribution map of iron in the olfactory bulb and brain stem shows an obvious increase of Fe contents in the olfactory nerve and the trigeminus of brain stem, suggesting that Fe₂O₃ particles were possibly transported via uptake by sensory nerve endings of the olfactory nerve and trigeminus. The XANES results indicate that the ratios of Fe (III)/Fe (II) were increased in the olfactory bulb and brain stem. The further histopathological observation showed that the neuron fatty degeneration occurred in the CA3 area of hippocampus. Such results imply an adverse impact of inhalation of fine Fe₂O₃ particles on CNS.     

Prediction of Tablet Film-coating Thickness Using a Rotating Plate Coating System and NIR Spectroscopy

The purpose of this research was to create a calibration model based on near-infrared (NIR) spectroscopy data obtained during a small-scale coating process to predict in-line the coating layer thickness of tablets coated in a side-vented drum coater. The developed setup for the small-scale coating process consisted of a rotating plate with 20 tablets molds that pass a spraying unit, a heating unit, and an in-line NIR spectroscopy probe during one rotation. High-density polyethylene (HDPE) was compressed to flat-faced tablets, and these were coated with a sustained release coating suspension containing Kollicoat IR and Kollicoat SR 30D. The film thickness of these tablets was determined for each tablet individually with a digital micrometer. A calibration model of predicted film thickness versus real-film thickness using PLS regression was developed. This model was tested against in-line NIR data obtained from a coating drum process, in which biconvex HDPE tablets were film-coated with the same film-coating suspension. The model predicted a final coating thickness of 240 μm, while the measured average thickness (n = 100 tablets) was 210 μm. Taking into account the use of a different setup and differently shaped tablets, it was possible to predict the coating thickness with accuracy comparable to the one of the digital micrometer. Thus, the small-scale rotating plate system was found to be an efficient means of preparing calibration model for a tablet-coating drum process.     

Bioprocess in-line monitoring using Raman spectroscopy and Indirect Hard Modeling (IHM): A simple calibration yields a robust model

To increase the process productivity and product quality of bioprocesses, the in-line monitoring of critical process parameters is highly important. For monitoring substrate, metabolite, and product concentrations, Raman spectroscopy is a commonly used Process Analytical Technology (PAT) tool that can be applied in-situ and non-invasively. However, evaluating bioprocess Raman spectra with a robust state-of-the-art statistical model requires effortful model calibration. In the present study, we in-line monitored a glucose to ethanol fermentation by Saccharomyces cerevisiae (S. cerevisiae) using Raman spectroscopy in combination with the physics-based Indirect Hard Modeling (IHM) and showed successfully that IHM is an alternative to statistical models with significantly lower calibration effort. The IHM prediction model was developed and calibrated with only 16 Raman spectra in total, which did not include any process spectra. Nevertheless, IHM's root mean square errors of prediction (RMSEPs) for glucose (3.68 g/L) and ethanol (1.69 g/L) were comparable to the prediction quality of similar studies that used statistical models calibrated with several calibration batches. Despite our simple calibration, we succeeded in developing a robust model for evaluating bioprocess Raman spectra.     

Characterization of a glucose 3-dehydrogenase from the cultivated mushroom (Agaricus bisporus )

An extracellular enzyme with glucose dehydrogenase activity was purified from liquid cultures of the basidiomycete Agaricus bisporus after growth with d-cellobiose or d-glucose as carbon source. The molecular mass was measured as 57 kDa by gel filtration and 55 kDa by sodiumdodecyl sulphate/polyacrylamide gel electrophoresis, while the isoelectric point was at pH 3.6. By analysis of ¹H-NMR spectra in D₂O, the product of d-glucose oxidation was identified as 3-ketoglucose. The substrates oxidized included d-cellobiose, l-arabinose, d-xylose and sucrose, but the specificity parameter (k _cat/K _m) was highest for d-glucose. Two electron acceptors were identified, namely 2,6-dichloroindophenol and p-benzoquinone, but reduction of dioxygen, ferricyanide or cytochrome c was not detectable. The selective C-3 oxidation of d-glucose is well-characterized for Agrobacterium and Flavobacterium, but this is the first report for a fungus. Received: 19 June 1998 / Received revision: 15 September 1998 / Accepted: 17 September 1998     

In-Line Monitoring of a High-Shear Granulation Process Using the Baseline Shift of Near Infrared Spectra

Although near infrared (NIR) spectra are primarily influenced by undesired variations, i.e., baseline shifts and non-linearity, and many applications of NIR spectroscopy to the real-time monitoring of wet granulation processes have been reported, the granulation mechanisms behind these variations have not been fully discussed. These variations of NIR spectra can be canceled out using appropriate pre-processing techniques prior to spectral analysis. The present study assessed the feasibility of directly using baseline shifts in NIR spectra to monitor granulation processes, because such shifts can reflect changes in the physical properties of the granular material, including particle size, shape, density, and refractive index. Specifically, OPUSGRAN^®, a novel granulation technology, was investigated by in-line NIR monitoring. NIR spectra were collected using a NIR diffuse reflectance fiber optic probe immersed in a high-shear granulator while simultaneously examining the morphology, particle size, density, strength, and Raman images of the mixture during granulation. The NIR baseline shift pattern was found to be characteristic of the OPUSGRAN^® technology and was attributed to variations in the light transmittance, reflection, and scattering resulting from changes in the physicochemical properties of the samples during granulation. The baseline shift also exhibited an inflection point around the completion of granulation, and therefore may be used to determine the endpoint of the process. These results suggest that a specific pattern of NIR baseline shifts are associated with the unique OPUSGRAN^® granulation mechanism and can be applied to monitor the manufacturing process and determine the endpoint.     

Influence of the starting microbial nucleus type on the anaerobic granulation dynamics

 The influence of four different granulation precursors, syntroph-enriched methanogenic consortia, Methanosaeta-enriched, Methanosarcina-enriched nuclei and acidogenic flocs, on the time course of complex granule development and the lag time for start-up was investigated in four upflow anaerobic sludge-bed and filter reactors. Although the operational conditions allowed the maintenance of the same specific growth rate of biomass in the four reactors, granulation proceeded rapidly with syntroph/methanogenic consortia, Methanosaeta and Methanosarcina nuclei. However, granulation was significantly retarded when acidogenic flocs were used as precursors. The granule mean Sauter diameter increased rapidly in the reactor inoculated with syntroph/methanogenic consortia, Methanosaeta and Methanosarcina nuclei and reached, at the end of the experiment, 3.1, 2.7 and 2.4 mm compared to 1.1 mm in that inoculated with acidogenic flocs. This corresponded to a rate of granule size increase of 31, 21, 18 μm/day in syntroph/methanogenic consortia, Methanosaeta and Methanosarcina nuclei, respectively, compared to 7 μm/day in acidogenic flocs. Biomass specific activities (i.e. acidogenic, syntrophic and methanogenic activities) increased stepwise in all reactors with time, especially in those inoculated with syntroph/methanogenic consortia and Methanosaeta nuclei. From these results it appears that syntrophs and Methanosaeta spp. play an important role in the anaerobic granulation process. Received: 25 January 1996 / Received revision: 3 September 1996 / Accepted: 13 September 1996     

Modelling of parameters for optimization of maturity in composting trimming residues

In this paper, changes in physico-chemical parameters during trimmings residue composting (cation exchange capacity, germination index, self-heated, NH₄/NO₃ ratio and C_FA/C_HA ratio) in relation to environmental composting parameters (time, aeration, moisture and particle size) of the composting process were studied. A central composite experimental design was used to obtain the polynomial model for each dependent variable. Results of the modelling showed that among the studied range, moisture was the highest influenced parameter in maturity evaluation, with respect to aeration and particle size. An exception was found for CEC evolution. In this parameter, the highest influence was found for particle size. Moreover, a product with acceptable chemical properties entails operating at medium moisture content (55%) and medium-to-high particle size (3–5 cm). Moderate to low aeration (0.2 m³ air kg⁻¹ d⁻¹) would be the best compromise to composting this residue, due to the scarce statistical influence of this independent variable.     

Monitoring of a Hot Melt Coating Process via a Novel Multipoint Near-Infrared Spectrometer

The aim of the present work was to develop a PAT strategy for the supervision of hot melt coating processes. Optical fibers were placed at various positions in the process chamber of a fluid bed device. Experiments were performed to determine the most suitable position for in-line process monitoring, taking into account such requirements as a good signal to noise ratio, the mitigation of dead zones, the ability to monitor the product over the entire process, and reproducibility. The experimental evidence suggested that the position at medium fluid bed height, looking towards the center, i.e., normal to particle movement, proved to be the most reliable position. In this study, the advantages of multipoint monitoring are shown, and an in-line-implementation was created. This enabled the real-time supervision of the process, including the fast detection of inhomogeneities and disturbances in the process chamber, and the compensation of sensor malfunction. In addition, a model for estimating the particle size distribution via NIR was successfully created. This ensures that the quality of the product and the endpoint of the coating process can be determined correctly.     

Next generation fluidized bed granulator automation

A system for fluidized bed granulator automation with in-line multichannel near infrared (NIR) moisture measurement and a unique air flow rate measurement design was assembled, and the information gained was investigated. The multivariate process data collected was analyzed using principal component analysis (PCA). The test materials (theophylline and microcrystalline cellulose) were granulated and the calibration behavior of the multichannel NIR set-up was evaluated against full Fourier Transform (FT) NIR spectra. Accurate and reliable process air flow rate measurement proved critical in controlling the granulation process. The process data describing the state of the process was projected in two dimensions, and the information from various trend charts was outlined simultaneously. The absorbence of test material at correction wavelengths (NIR region) and the nature of material-water interactions affected the detected in-line NIR water signal. This resulted in different calibration models for the test materials. Development of process analytical methods together with new data visualization algorithms creates new tools for in-process control of the fluidized bed granulation.     

Experimental studies and two-dimensional modelling of a packed bed bioreactor used for production of galacto-oligosaccharides (GOS) from milk whey

In the present study, extensive experimental investigations and detailed theoretical analysis of a two-dimensional packed bed bioreactor, employed for the production of galacto-oligosaccharides (GOS) from milk whey were performed. Model equations, in one- and two-dimensions, capable of predicting the substrate concentration distribution in the bioreactor were developed by coupling mass balance equation with appropriate velocity distribution equation and solved numerically. Validation of the proposed model equations was done by a set of experimental data obtained from the bioreactor. The effects of reactor to catalyst particle diameter ratio (d _t/d _p), feed flowrate (10^?6–10^?9 m³ s^?1), and initial lactose concentration (50–200 kg m^?3) on substrate concentration distribution were investigated in detail. While, the distribution of substrate concentration in axial direction was independent of d _t/d _p, it was observed that for d _t/d _p <40, significant radial concentration distribution existed. It was further observed that the substrate conversion and product yield obtained experimentally showed an excellent agreement (97 ± 2 %) with the results predicted by the two-dimensional model equation, whereas, the results predicted by the one-dimensional model equation did not lie within the desired confidence level (<90 %). The results were confirmed by both curve fitting and statistical analysis. The prediction of substrate concentration distribution in axial and radial directions using the developed two-dimensional model equation is necessary for computing the bioreactor volume to achieve the desired GOS yield.     

Laccase production from oil palm industry solid waste: Statistical optimization of selected process parameters

Oil palm frond parenchyma tissue was used as a solid substrate for the production of laccase via solid‐state fermentation using the white rot fungus Pycnoporus sanguineus. With a rectangular aluminium tray as solid‐state fermentation bioreactor, process parameters such as bed height, moisture and supplemented nitrogen (as urea solution) levels were studied and optimized using a statistical design of experiment. The moisture level exerted a significant effect on the process. The interaction effect observed between bed height and supplemented nitrogen level suggested that uniform distribution of supplemented nitrogen into the substrate bed was important. The proposed regression model sufficiently predicted the process response over the experimental range tested. The optimum parameter combination for laccase production was a 3‐cm bed height, 72% w/w moisture and 0.21% w/v supplemented nitrogen. Laccase productivity remained constant when the tray size was increased from 1.4 to 3.4‐fold.     

A dynamic model of motor basal ganglia functions

 Fast aiming movements were measured in a choice reaction paradigm in a healthy control group and in Parkinsonian patients. The patients were tested without (‘off ’) and with 3,4-dihydroxyphenylalanine (‘on’) (L-dopa) medication. The movement trajectories were used to estimate the parameters of a dynamic linear model. The model is based on the functional structure of the basal ganglia-thalamocortical circuit with direct and indirect pathways linking the putamen to the basal ganglia output nuclei (Albin et al. 1989). The output of the circuit is connected to a model for the motor neuron-musculo-skeletal system. The gain k _d for the direct pathway and the gain k _i for the indirect pathway were estimated. They were found to be significantly decreased for Parkinsonian patients in ‘off ’ compared with the control group. L-dopa therapy in Parkinsonian patients increased the gains of the direct and the indirect pathway almost to normal values which implies that the long-term dopamine level in the striatum was excitatory for the direct and for the indirect pathway. This result is restricted to movements of correct size. For movements of diminished size, which are typical for Parkinsonian patients, the model predicts that the dopamine level in the striatum is excitatory for the direct pathway but inhibitory for the indirect pathway. The simulated values for neuronal activities are in agreement with expected values according to the experimental data. The proposed model of the ‘motor’ basal ganglia thalamocortical circuit implies that information about biomechanical properties of the musculo-skeletal system is stored in the ‘motor’ basal ganglia-thalamocortical circuit, and that the basal ganglia are involved in computation of the desired movement amplitude. Received: 24 April 1996/Accepted in revised form: 25 February 1997