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.     

Monitoring Granulation Rate Processes Using Three PAT Tools in a Pilot-Scale Fluidized Bed

The purpose of this research was to analyze and compare the responses of three Process Analytical Technology (PAT) techniques applied simultaneously to monitor a pilot-scale fluidized bed granulation process. Real-time measurements using focused beam reflectance measurement (Lasentec FBRM) and near-infra red spectroscopy (Bruker NIR) were taken by inserting in-line probes into the fluidized bed. Non-intrusive acoustic emission measurements (Physical Acoustic AE) were performed by attaching piezoelectric sensors on the external wall of the fluidized bed. Powder samples were collected at regular intervals during the granulation process and characterized offline using laser diffraction, scanning electron microscopy, stereo-optical microscopy and loss on drying method. PAT data comprising chord length distribution and chord count (from FBRM), absorption spectra (from NIR) and average signal levels and counts (from AE) were compared with the particle properties measured using offline samples. All three PAT techniques were able to detect the three granulation regimes or rate processes (wetting and nucleation, consolidation and growth, breakage) to varying degrees of sensitivity. Being dependent on optical signals, the sensitivities of the FBRM and NIR techniques were susceptible to fouling on probe windows. The AE technique was sensitive to background fluidizing air flows and external interferences. The sensitivity, strengths and weaknesses of the PAT techniques examined may facilitate the selection of suitable PAT tools for process development and scale-up studies.     

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.     

Predicting Particle Size During Fluid Bed Granulation Using Process Measurement Data

In this study, a new concept for particle size prediction during the fluid bed granulation is presented. Using the process measurements data obtained from a design of experimental study, predictive partial least squares models were developed for spraying and drying phases. Measured and calculated process parameters from an instrumented fluid bed granulation environment were used as explaining factors, whereas an in-line particle size data determined by spatial filtering technique were used as response. Modeling was carried out by testing all possible combinations of two to six process parameters (factors) of the total of 41 parameters. Eleven batches were used for model development and four batches for model testing. The selected models predicted particle size (d ₅₀) well, especially during the spraying phase (Q ² = 0.86). While the measured in-line d ₅₀ data were markedly influenced by different process failures, e.g., impaired fluidization activity, the predicted data remained more consistent. This introduced concept can be applied in fluid bed granulation processes if the granulation environment is soundly instrumented and if reliable real-time particle size data from the design of experiment batches are retrieved for the model development.     

Investigation of the Variability of NIR In-line Monitoring of Roller Compaction Process by Using Fast Fourier Transform (FFT) Analysis

The purpose of this research was to investigate the variability of the roller compaction process while monitoring in-line with near-infrared (NIR) spectroscopy. In this paper, a pragmatic method in determining this variability of in-line NIR monitoring roller compaction process was developed and the variability limits were established. Fast Fourier Transform (FFT) analysis was used to study the source of the systematic fluctuations of the NIR spectra. An off-line variability analysis method was developed as well to simulate the in-line monitoring process in order to determine the variability limits of the roller compaction process. For this study, a binary formulation was prepared composed of acetaminophen and microcrystalline cellulose. Different roller compaction parameters such as roll speed and feeding rates were investigated to understand the variability of the process. The best-fit line slope of NIR spectra exhibited frequency dependence only on the roll speed regardless of the feeding rates. The eccentricity of the rolling motion of rollers was identified as the major source of variability and correlated with the fluctuations of the slopes of NIR spectra. The off-line static and dynamic analyses of the compacts defined two different variability of the roller compaction; the variability limits were established. These findings were proved critical in the optimization of the experimental setup of the roller compaction process by minimizing the variability of NIR in-line monitoring.     

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.     

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     

Polymorph Transformation in Paracetamol Monitored by In-line NIR Spectroscopy During a Cooling Crystallization Process

The reliable in-line monitoring of pharmaceutical processes has been regarded as a key tool toward the full implementation of process analytical technology. In this study, near-infrared (NIR) spectroscopy was examined for use as an in-line monitoring method of the paracetamol cooling crystallization process. The drug powder was dissolved in ethanol-based cosolvent at 60°C and was cooled by 1°C/min for crystallization. NIR spectra acquired by in-line measurement were interpreted by principal component analysis combined with off-line characterizations via X-ray diffraction, optical microscopy, and transmission electron microscopy. The whole crystallization process appeared to take place in three steps. A metastable form II polymorph of paracetamol was formed and transformed into the stable form I polymorph on the way to the growth of pure form I by cooling crystallization. These observations are consistent with a previous focused beam reflectance method-based study (Barthe et al., Cryst Growth Des 8:3316–3322, 2008).     

Quantitative analysis of film coating in a pan coater based on in-line sensor measurements

A method was developed that enables in-line analysis of film coating thickness on tablets during a pan coating operation. Real-time measurements were made using a diffusereflectance near-infrared (NIR) probe positioned inside the pan during the coating operation. Real-time spectra of replicate batches were used for modeling film growth. Univariate analysis provided a simple method for in-line monitoring of the coating process using NIR data. An empirical geometric 2-vector volumetric growth model was developed, which accounts for differential growth on the face and band regions of biconvex tablets. The thickness of the film coat was determined by monitoring the decrease of absorption bands characteristic of a component of the tablet core and monitoring the increase of bands characteristic of a component in the coating material. There was good correlation between values estimated from the NIR data and the measured tablet volumetric growth. In-line measurements allow the coating process to be stopped when a predetermined tablet coating thickness is achieved. Published: September 20, 2005     

Fluidized Bed Hot-Melt Granulation as a Tool to Improve Curcuminoid Solubility

Curcumin is the main bioactive component of Curcuma longa L. and has recently aroused growing interest from the scientific community. Unfortunately, the medicinal properties attributed to curcuminoids are impaired by their low oral bioavailability or low solubility in aqueous solutions. Many strategies have been studied to improve curcumin solubility; however, the preparation of granules using hydrophilic materials has never been attempted. The aim of this work was to develop curcumin granules by fluidized bed hot-melt granulation using the hydrophilic carrier Gelucire® 50:13. A two-level factorial design was used to verify the influence of Gelucire® 50:13 and lactose contents found in the granules on their size, morphology, bulk and tapped densities, flow, moisture content, and water activity. The granules obtained were also evaluated by differential scanning calorimetry, thermogravimetric analysis, X-ray powder diffraction, and infrared spectrometry. The curcumin solubility and dissolution rates in water were determined by liquid chromatography. The best formulation provides an increase of curcumin solubility of 4642-fold and 3.8-fold compared to the physical mixture. The dissolution tests showed a maximum drug release from granules after 45 min of 70% at pH 1.2 and 80% at pH 5.8 and 7.4, while for non-granulated curcumin, the release was below 20% in all pH. The solid-state characterization and solubility measurement showed good stability of granules over 9 months. The results attest that the fluidized bed hot-melt granulation with hydrophilic binders is an attractive and promising alternative to obtain solid forms of curcumin with enhanced bioavailability.     

Pellet manufacturing by extrusion-spheronization using process analytical technology

The aim of this study was to investigate the phase transitions occurring in nitrofurantoin and theophylline formulations during pelletization by extrusion-spheronization. An at-line process analytical technology (PAT) approach was used to increase the understanding of the solid-state behavior of the active pharmaceutical ingredients (APIs) during pelletization. Raman spectroscopy, near-infrared (NIR) spectroscopy, and X-ray powder diffraction (XRPD) were used in the characterization of polymorphic changes during the process. Samples were collected at the end of each processing stage (blending, granulation, extrusion, spheronization, and drying). Batches were dried at 3 temperature levels (60°C, 100°C, and 135°C). Water induced a hydrate formation in both model formulations during processing. NIR spectroscopy gave valuable real-time data about the state of water in the system, but it was not able to detect the hydrate formation in the theophylline and nitrofurantoin formulations during the granulation, extrusion, and spheronization stages because of the saturation of the water signal. Raman and XRPD measurement results confirmed the expected pseudopolymorphic changes of the APIs in the wet process stages. The relatively low level of Raman signal with the theophylline formulation complicated the interpretation. The drying temperature had a significant effect on dehydration. For a channel hydrate (theophylline), dehydration occurred at lower drying temperatures. In the case of isolated site hydrate (nitrofurantoin), dehydration was observed at higher temperatures. To reach an understanding of the process and to find the critical process parameters, the use of complementary analytical techniques are absolutely necessary when signals from APIs and different excipients overlap each other. Published: September 30, 2005     

Wet granulation in rotary processor and fluid bed: Comparison of granule and tablet properties

The aim of the present study was to investigate and compare granule and tablet properties of granules prepared by wet granulation in a rotary processor or a conventional fluid bed. For this purpose the working range of selected process variables was determined and a factorial study with 3 factors (equipment type, filler type, and liquid addition rate) and 1 covariate (fluidizing air flow rate) was performed. Two grades of calcium carbonate with different size and shape characteristics were applied, and the liquid addition and fluidizing air flow rates were investigated in the widest possible range. Dry mixtures of microcrystalline cellulose, polyvinyl povidone, calcium carbonate, and riboflavin, in a 10∶5∶84∶1 ratio, were granulated in both types of equipment. The granulation end point was determined manually in the fluid bed and by torque measurements in the rotary processor. The filler type had a more pronounced effect on granular properties in the fluid bed, but the rotary processor showed a higher dependency on the investigated process variables. The rotary processor gave rise to more dense granules with better flow properties, but the fluid bed granules had slightly better compressional properties. Furthermore, the distribution of a low-dose drug was found to be more homogeneous in the rotary processor granules and tablets. Generally, wet granulation in a rotary processor was found to be a good alternative to conventional fluid bed granulation, especially when cohesive powders with poor flow properties or formulations with low drug content are to be granulated by a fluidizing air technique. Published: March 10, 2006     

API Determination by NIR Spectroscopy Across Pharmaceutical Production Process

The purpose of this research was to demonstrate the ability of reflectance near-infrared (NIR) spectroscopy for quantitative analysis of an active ingredient in different production steps of a solid formulation. The drug is quantified at two different steps of a pharmaceutical process: after granulation and after tablet coating. Calibration samples were prepared by mixing pure drug, excipients, and batch samples (75–120 mg/g active ingredient) using a simple methodology that can be easily carried out in a laboratory. Partial least squares calibration models were calculated in second-derivative mode using the wavelength range 1,134–1,798 nm. The error of prediction for granulated samples was 1.01% and 1.63% for tablets. The results prove that NIR spectroscopy is a good alternative to other, more time-consuming means of analysis for pharmaceutical process monitoring.     

Glass transition temperatures of a ready to eat breakfast cereal formulation and its main components determined by DSC and DMTA

The effect of water content on the glass transition temperatures of a ready to eat cereal formulation was determined, as well as for its major components, oat flour, rice flour and an oat–rice flour blend, in the same ratio as they are present in the formulation. All samples were compression moulded at high temperature and were moisture conditioned in a 10–22% interval (dry basis). Glass transition temperatures (T_g) were measured by differential scanning calorimetry (DSC) and the main mechanical relaxation temperatures (T_α), measured by dynamic mechanical thermal analysis (DMTA). The relaxation temperatures taken at tan δ peaks, were found 20–30 °C larger than T_g. Besides the plasticizing effect of water adequately described by the Gordon–Taylor equation, no differences of T_g (and T_α) values between the major components were obtained at a constant moisture content. The T_g and T_α values of the RTE formulation were found to be about 30 °C lower than its components, a result which was attributed to the plasticizing effect of the minor components in the formulation (sugar and malt extract).     

In-Line Film Coating Thickness Estimation of Minitablets in a Fluid-Bed Coating Equipment

Film coating thickness of minitablets was estimated in-line during coating in a fluid-bed equipment by means of visual imaging. An existing, commercially available image acquisition system was used for image acquisition, while dedicated image analysis and data analysis methods were developed for this purpose. The methods were first tested against simulated minitablet’s images and after that examined on a laboratory-scale fluid-bed Wurster coating process. An observation window cleaning mechanism was developed for this purpose. Six batches of minitablets were coated in total, using two different dispersions, where for the second dispersion coating endpoint was determined based on the in-line measurement. Coating thickness estimates were calculated from the increasing size distributions of the minitablet’s major and minor lengths, assessed from the acquired images. Information on both the minitablet’s average band and average cap coating thicknesses was obtained. The in-line coating thickness estimates were compared to the coating thickness weight gain calculations and the optical microscope measurements as a reference method. Average band coating thickness estimate was found the most accurate in comparison to microscope measurements, with root mean square error of 1.30 μm. The window cleaning mechanism was crucial for the accuracy of the in-line measurements as was evident from the corresponding decrease of the root mean square error (9.52 μm, band coating thickness). The presented visual imaging approach exhibits accuracy of at least 2 μm and is not susceptible to coating formulation or color variations. It presents a promising alternative to other existing techniques for the in-line coating thickness estimation.     

Indirect measurement of water content in an aseptic solid substrate cultivation pilot-scale bioreactor

A lack of models and sensors for describing and monitoring large-scale solid substrate cultivation (SSC) bioreactors has hampered industrial development and application of this type of process. This study presents an indirect dynamic measurement model for a 200-kg-capacity fixed-bed SSC bioreactor under periodic agitation. Growth of the filamentous fungus Gibberella fujikuroi on wheat bran was used as a case study. Real data were preprocessed using previously reported methodology. The model uses CO2 production rate and inlet air conditions to estimate average bed water content and average bed temperature. The model adequately reproduces the evolution of the average bed water content and can therefore be used as an on-line estimator in pilot-scale SSC bioreactors. To obtain a reasonable fit of the bed temperature, however, inlet air humidity measurements will have to be adjusted with a data reconciliation algorithm. Good estimation of temperature is important for the future design of improved water content estimation using state observers. The model also provides insight into understanding the complex behavior of the dynamic system, which could prove useful when establishing advanced model-based operational and control strategies.     

Lettuce plant growth and tipburn occurrence as affected by airflow using a multi-fan system in a plant factory with artificial light

A multi-fan system (MFS) for single culture beds was developed to improve the airflow in a plant factory with artificial light. The MFS had seven fans which were installed on both the front and back sides of culture beds to generate airflow from two opposite horizontal directions. The fans that push the air into the culture bed were air inlets while those that pull the air out of the culture bed were air outlets. In this study, three airflow patterns were evaluated: T₁, the front and back sides of the culture bed were air inlets; T₂, the front side was an air inlet and the backside was an air outlet; and T₃, both the front and back sides were air outlets. A culture bed with no MFS was used as a control (T₄). Lettuce growth and tipburn occurrence were evaluated and leaf boundary layer resistance (1/g_bv), sensible heat flux (S_h), and latent heat flux (L_h) of lettuce plants were estimated. The airflow pattern in T₁ improved the air velocity (V_a) by an average of 0.75 m s^-1 and a variation coefficient of 65%. The 1/g_bv decreased significantly with the increase in V_a, and the lowest value of 54.0 s m^-1 was observed in T₁. The low resistance to heat and moisture transfer enhanced the S_h and L_h of lettuce plants. The average S_h and L_h were 40% and 46% higher in T₁ compared with those in T₄. The fresh and dry weights of lettuce plants in T₁ were 1.13 and 1.06 higher than those in T₄, respectively. No tipburn occurrence was observed in lettuce plants grown under the MFS while five leaves per plant were injured with tipburn in T₄. The results indicated that improving the airflow can improve the growth of indoor cultured lettuce and alleviate the occurrence of tipburn due to the decrease in the 1/g_bv and the increase in the transpiration rate.     

Inline Real-Time Near-Infrared Granule Moisture Measurements of a Continuous Granulation–Drying–Milling Process

The purpose of this research was to use inline real-time near-infrared (NIR) to measure the moisture content of granules manufactured using a commercial production scale continuous twin-screw granulator fluid-bed dryer milling process. A central composite response surface statistical design was used to study the effect of inlet air temperature and dew point on granule moisture content. The NIR moisture content was compared to Karl Fischer (KF) and loss on drying (LOD) moisture determinations. Using multivariate analysis, the data showed a statistically significant correlation between the conventional methods and NIR. The R ² values for predicted moisture content by NIR versus KF and predicted moisture values by NIR versus LOD were 0.94 (p < 0.00001) and 0.85 (p < 0.0002), respectively. The adjusted R ² for KF versus LOD correlation was 0.85 (p < 0.0001). Analysis of the response surface design data showed that inlet air temperature over a range of 35–55°C had a significant linear impact on granule moisture content as measured by predicted NIR (adjusted R ² = 0.84, p < 0.02), KF (adjusted R ² = 0.91, p < 0.0001), and LOD (adjusted R ² = 0.85, p < 0.0006). The inlet air dew point range of 10–20°C did not have a significant impact on any of the moisture measurements.     

Low moisture availability reduces the positive effect of increased soil temperature on biomass production of white birch (Betula papyrifera) seedlings in ambient and elevated carbon dioxide concentration

White birch (Betula papyrifera Marsh.) seedlings were grown under two carbon dioxide concentrations ([CO₂]) (360 vs 720 μmol mol^?1), three soil temperatures (T_soil) (5, 15, 25°C initially, increased to 7, 17, 27°C, respectively, one month later), and three moisture regimes (low: 30–40%, intermediate: 45–55%, high: 60–70% field water capacity) for four months in environment‐controlled greenhouses. The dry mass of stem, leaves, and roots was measured after 2 and 4 months of treatment. Low T_soil decreased stem, leaf and total biomass in both measurements, however, the decrease was significantly greater in the elevated than ambient [CO₂] after 4 months. Intermediate T_soil increased root biomass in both measurements. Low moisture reduced stem, leaf, root and total biomass after both 2 and 4 months of treatment. There was a significant T_soil‐moisture interactive effect on leaf, root, and total biomass after 4 months of treatment, suggesting that the magnitude of biomass enhancement in warmer T_soil was dependent on the moisture regime. For instance, the increase in total biomass from the low to high T_soil was 22, 50, and 47% under the low, intermediate and high moisture regimes, respectively. In contrast, the T_soil×moisture effect on stem biomass was significant after 2 months, but not after 4 months of treatment. High T_soil increased leaf mass ratio (LMR) after 4 months of treatment, but decreased both root mass ratio (RMR) after both 2 and 4 months, and root:shoot ratio (RSR) after 4 months of treatment. The low moisture regime decreased LMR after 2 and 4 months of treatment, but increased RSR after 4 months of treatment. There were no significant [CO₂] effects on biomass allocation or [CO₂]×T_soil×moisture interactions on biomass production/allocation.     

Relationship between leaf water spin-lattice relaxation time and water relation parameters in three wheat cultivars

Pot culture studies were conducted using two drought-tolerant and one susceptible cultivar of wheat (Triticum aestivum L.) under three different moisture regimes. Proton spin-lattice relaxation time, T₁, leaf water content, LWC, leaf water potential, Ψ, solute potential, Ψ_s and turgor potential, Ψ_p were measured from 45 to 75 d after sowing at weekly intervals. The three cultivars did not differ significantly in their values of LWC, leaf water potential, and their components in the stressed and unstressed plants; but they did differ significantly in their T₁ values both under stressed and unstressed conditions on all days of measurement, with the drought tolerant cultivars having a higher T₁ compared to the susceptible cultivar. This suggests that leaf water T₁ is a better parameter for describing plant water status than the traditional water relation indices. The relation between Ψ and T₁ was logarithmic, indicating the similarity between T₁ and water activity of the cellular water.