Heikki Räikkönen

Controlling granule size by granulation liquid feed pulsing

The effects of inlet air humidity, granulation liquid feed rate and granulation liquid feed pulsing on the particle-size distribution of final granules were studied in a laboratory scale fluid-bed granulator using a central composite study design. The factors examined were modelled using three different particle-size measurement techniques (sieve analysis, laser light diffraction and the spatial filtering technique). Best goodness of fit (R2=0.94) and goodness of prediction (Q2=0.90) values were obtained using particle-size results of the spatial filtering technique. Increasing inlet air humidity and granulation liquid feed rate resulted in greater median granule size, as expected. When pulsing (interruption of granulation liquid feed in predetermined sequences) was used, the median granule size decreased clearly. This effect was strong, especially with high inlet air humidity and rapid liquid feed rate processes. Granulation liquid feed pulsing is an effective way to modify the particle size of final granules. Pulsing can be used as a controlling tool to compensate for excessive moisture content in the granulation process.

Gaining fluid bed process understanding by in-line particle size analysis.

Different process phenomena and process failure modes could be monitored using the in-line particle size data measured by spatial filtering technique (SFT). In addition to the real-time granule growth monitoring, other events, such as the blocking of filter bags and the distributor plate, could be observed. SFT was used off-line, at-line and in-line in 14 differently manufactured granulation batches. No significant fouling occurred during the manufacturing due to the appropriate positioning of the probe. The off-line SFT results correlated well (R(2) = 0.97) with the sieve analysis results. It was also found that size segregation influenced both the in-line and at-line particle size results during the fluidization: in-line method underestimated and at-line method overestimated the final particle size.

Improving flow properties of ibuprofen by fluidized bed particle thin-coating.

The surfaces of ibuprofen particles (d(50) 42 microm) were modified by coating the particles with diluted aqueous hydroxypropyl methylcellulose (HPMC) solution in an instrumentated top-spray fluid bed granulator. The objective was to evaluate whether an extremely thin polymer coating could be an alternative to granulation in enhancing powder flow and processing properties. The studied variables were inlet air temperature and spray rate. The treated powders showed a clear improvement in flow rate as measured with a flow meter designed for powders with poor flow properties. The particle size was determined using optical microscopy and image analysis. The particle size, size distribution and circularity of the treated and untreated ibuprofen batches showed no difference from each other. Consequently, the improvement in flow properties can be attributed to the trace amounts of hydroxypropyl methylcellulose applied onto the particle surfaces. In conclusion, fluidized bed particle thin-coating (PTC) alters the surface of ibuprofen powder particles and improves the flow properties of ibuprofen powder with changes in neither particle size, size distribution nor morphology.

Rapid Particle Size Measurement Using 3D Surface Imaging

The present study introduces a new three-dimensional (3D) surface image analysis technique in which white light illumination from different incident angles is used to create 3D surfaces with a photometric approach. The three-dimensional features of the surface images created are then used in the characterization of particle size distributions of granules. This surface image analysis method is compared to sieve analysis and a particle sizing method based on spatial filtering technique with nearly 30 granule batches. The aim is also to evaluate the technique in flowability screening of granular materials. Overall, the new 3D imaging approach allows a rapid analysis of large amounts of sample and gives valuable visual information on the granule surfaces in terms of surface roughness and particle shape.

Granule size control and targeting in pulsed spray fluid bed granulation

The primary aim of the study was to investigate the effects of pulsed liquid feed on granule size. The secondary aim was to increase knowledge of this technique in granule size targeting. Pulsed liquid feed refers to the pump changing between on- and off-positions in sequences, called duty cycles. One duty cycle consists of one on- and off-period. The study was performed with a laboratory-scale top-spray fluid bed granulator with duty cycle length and atomization pressure as studied variables. The liquid feed rate, amount and inlet air temperature were constant. The granules were small, indicating that the powder has only undergone ordered mixing, nucleation and early growth. The effect of atomizing pressure on granule size depends on inlet air relative humidity, with premature binder evaporation as a reason. The duty cycle length was of critical importance to the end product attributes, by defining the extent of intermittent drying and rewetting. By varying only the duty cycle length, it was possible to control granule nucleation and growth, with a wider granule size target range in increased relative humidity. The present study confirms that pulsed liquid feed in fluid bed granulation is a useful tool in end product particle size targeting.

Granule size distribution of tablets

The purpose of this study was to determine the variation in the granule size distribution in a die of an eccentric tableting machine. Theophylline anhydrate and alpha-lactose monohydrate were granulated with an aqueous solution of polyvinylpyrrolidone, using an instrumented fluid bed granulator. The granules were tabletted, using an instrumented eccentric tableting machine. Punch forces were recorded and tablets were collected in order during the tableting process. Powder samples, which had the same mass as the tablets, were also collected from the die for particle size determination. The particle size distribution was measured, using a spatial filtering technique. In addition, the segregation of microcrystalline cellulose pellets during tableting was analyzed. The particle size distribution changed dramatically during the tableting process, due to a segregation phenomenon.

Effect of fluidisation activity on end-point detection of a fluid bed drying process

The influence of inlet air humidity variations on fluid bed drying end-point detection was the primary focus here. Various drying end-point criteria based on temperature and humidity measurements were compared. Seasonally changing inlet air humidity affects the moisture content of the finished granules, as long as the drying process remains unchanged. However, a specific moisture content of the finished granules is commonly desired after fluid bed drying. When experimental batches of varying inlet air humidity were compared at the beginning of the drying phase, the temperature of the granules increased linearly as the humidity of the inlet air increased. This effect causes variation in moisture contents of the final granules of different batches when the fixed temperature of the mass is used as an end-point criterion. With varying inlet air humidity, the often used DeltaT temperature difference method resulted in more precise estimation of the drying end-point than the constant temperature criterion. In this study new insights were found into the correlation between moisture content and temperature of the fluidising mass. Fluidisation activity greatly affected detection of drying end-point. Use of the DeltaT criterion requires proper fluidisation throughout the process.

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.

In situ droplet size and speed determination in a fluid-bed granulator.

The droplet size affects the final product in fluid-bed granulation and coating. In the present study, spray characteristics of aqueous granulation liquid (purified water) were determined in situ in a fluid-bed granulator. Droplets were produced by a pneumatic nozzle. Diode laser stroboscopy (DLS) was used for droplet detection and particle tracking velocimetry (PTV) was used for determination of droplet size and speed. Increased atomization pressure decreased the droplet size and the effect was most strongly visible in the 90% size fractile. The droplets seemed to undergo coalescence after which only slight evaporation occurred. Furthermore, the droplets were subjected to a strong turbulence at the event of atomization, after which the turbulence reached a minimum value in the lower halve of the chamber. The turbulence increased as speed and droplet size decreased due to the effects of the fluidizing air. The DLS and PTV system used was found to be a useful and rapid tool in determining spray characteristics and in monitoring and predicting nozzle performance.

New insights into segregation during tabletting

The aim of this study was to evaluate how different granule size distributions affect the tablet compression process. The emphasis was on developing new analytic methods for compression data for entire batch. In all, 18 batches of granules containing theophylline and lactose were tabletted, using an instrumented eccentric tabletting machine. During tablet compression, upper and lower punch forces were recorded. Mathematical methods were developed for analysing the compression data during tabletting. The results suggested two types of undulation in the tabletting data: (1) short-time scale variation or tablet-to-tablet changes in force data and (2) long-time scale undulation describing the changes occurring throughout the tabletting process, such as segregation. These undulation phenomena were analysed, using various mathematical methods. In addition the results suggest that smaller particles have better tabletting properties, to a certain limit. However particle size alone cannot explain the tabletability of granules.