No / Results of a study on the influence of process parameters such as impeller speed, granulation time and binder viscosity on granule strength and properties are reported. A high shear granulator (Cyclomix manufactured by Hosokawa Micron B.V., The Netherlands) has been used to produce granules. Calcium carbonate (Durcal) was used as feed powder and aqueous polyethylene glycol (PEG) as the binder. The dried granules have been analysed for their strength, density and size distribution. The results show that increasing the granulation time has a great affect on granules strength, until an optimum time has been reached. The underlying cause is an increase in granule density. Granules are consolidated more at higher impeller speeds. Moreover, the granule size distribution seems not to be affected significantly by an increase in impeller speed. Granules produced with high binder viscosity have a considerably lower strength, wide strength distribution due to poor dispersion of binder on the powder bed. Binder addition methods have showed no considerable effect on granule strength or on granule size distribution.

No / A novel method for manufacturing granules with a large particle at their core, referred to as seeded granules, is presented. As an example, calcium carbonate powders (Durcal) of different grades are used as primary particles and polyethylene glycol (PEG) as liquid binder in high shear granulators of different scales (Cyclomix, manufactured by Hosokawa Micron B.V., The Netherlands). The conditions giving rise to seeded granulations are specified in the form of an operational regime map. It is found that the seeded structure is strongly dependent on the impeller speed and the primary particles size distribution. It is shown that a Stokes number of around 0.1 represents the optimal dynamic conditions in the given example for producing seeded granules, regardless of the scale of the granulator.

No / The effect of the operating conditions of three continuous high shear granulators on the internal structure and strength of granules has been investigated and the possibility of seeded granulation has been explored. In a recently concluded programme of research on the scale-up of a high shear granulator, Cyclomix (manufactured by Hosokawa Micron B.V., The Netherlands), a novel method of granulation called seeded granulation was introduced, where each granule contained, at its core, a large particle from the upper tail end of the feed particle size distribution. Seeded granulation is particularly useful for process control of continuous granulators as there is the potential to control granulation by the flow rate of the seed particles. Hence, the performance of three different types of continuous granulators in terms of granule strength and structure has been evaluated here; these are Extrudomix, Modulomix (manufactured by Hosokawa Micron, UK and The Netherlands, respectively) and the Nica M6 Turbine continuous granulator (manufactured by GEA, UK). Calcium carbonate (Durcal 65) powder was granulated using an aqueous solution of polyethylene glycol (PEG) as binder in the same ratio as used previously in our batch granulation, to allow comparison between the continuous and batch processes. The crushing strength was characterised by quasi-static side crushing between two platens using a mechanical testing machine. The internal structure and morphology were evaluated by scanning electron microscopy and the extent of seeding quantified. Granules produced in all the three continuous granulators were significantly weaker than those of the batch granulator tested previously. Among the continuous granulators only the Modulomix granulator produced some seeded granules. It is considered that longer residence time is necessary to produce seeded granules.

Twin screw wet granulation (TSG) has been studied as a continuous manufacturing alternative to batch granulation for nearly twenty years. One of the main differences between batch granulation and TSG lies in the exiting granules being presented as a bimodal particle size distribution (PSD) in the latter case. Current process analytical technologies (PAT) can monitor a monomodal distribution well but there have been no techniques disclosed in the public domain so far that can accurately monitor this unusually shaped PSD. Acoustic emissions (AE) has been identified as a PAT of interest due to its ease of use (lack of calibration), low cost, and non-invasive design relative to other PATs used for monitoring PSDs. Hence the goal of this thesis was to develop AE as a process analytical technology (PAT) capable of estimating the full distribution of produced granules by TSG in real time. The first research study of this thesis focused on the development of the new technology. The AE PAT consisted of an acoustic sensor, an impact plate, and software to convert the time-domain signal of particle collisions into a time-averaged frequency-domain spectrum to be subsequently used to estimate a weight-averaged particle size distribution. A novel and much required addition to the PAT was inclusion of a digital filter based on particle mechanics parameters to overcome auditory masking which hindered accurately converting the cumulative sounds of impact into a PSD. The PAT was tested in this study with granulated lactose monohydrate and with the new digital filter, obtaining a maximum error of 1 wt% across all particle sizes tested. In the second research study, as more formulations commonly used in the industry were tested, the filter proved unable by itself to account for the differences in impact mechanics and therefore needed to be modified to incorporate the more inelastic behaviour now being seen. Two micromechanical models were explored, and the Walton-and-Braun model was found to be the most suitable for the AE PAT – reducing its error from 8 wt% down to 2.75 wt% across four formulations producing coefficients of restitution from 0.79 to 0.24. In the last research study in this thesis, the now-functional inline PAT was used to reveal mechanistic details related to the transition state in granulation as a TSG starts up, to improve the field’s understanding of the granulation mechanism. The technique was able to estimate the PSD over much shorter periods of material collection compared to sieving, allowing the evolution of the PSD as a function of time to be examined for varying degrees of fill (DF) and liquid-to-solids ratios. It was determined that the time to steady state, at both DF tested, occurred at approximately 5 times the mean residence time of the process by both PAT and sieving analyses. Particle sizes between 102-2230 μm were then tracked as a function of time below 120 s and variations of granule growth were seen for each degree of fill which added to the understanding of the granulation mechanism. This PAT shows great promise as a monitoring tool to implement quality by design principles for TSG in pharmaceutical manufacturing. / Thesis / Doctor of Philosophy (PhD)

Yes / Twin-screw granulation has emerged as a key process in powder processing industries and in the pharmaceutical sector to produce granules with controlled properties. This comprehensive review provides an overview of the simulation techniques and approaches that have been employed in the study of twin-screw granulation processes. This review discusses the major aspects of the twin-screw granulation process which include the fundamental principles of twin-screw granulation, equipment design, process parameters, and simulation methodologies. It highlights the importance of operating conditions and formulation designs in powder flow dynamics, mixing behaviour, and particle interactions within the twin-screw granulator for enhancing product quality and process efficiency. Simulation techniques such as the population balance model (PBM), computational fluid dynamics (CFD), the discrete element method (DEM), process modelling software (PMS), and other coupled techniques are critically discussed with a focus on simulating twin-screw granulation processes. This paper examines the challenges and limitations associated with each simulation approach and provides insights into future research directions. Overall, this article serves as a valuable resource for researchers who intend to develop their understanding of twin-screw granulation and provides insights into the various techniques and approaches available for simulating the twin-screw granulation process.

La fabrication de comprimés pharmaceutiques par granulation humide a typiquement recours aux lits fluidisés pour le séchage des particules. Encouragée par les agences réglementaires, l'industrie a entamé une migration vers la production continue et automatisée, mais les procédés discontinus (batch) opérés sans rétroaction, excepté un contrôle qualité en fin de cycle, demeurent largement majoritaires dans le secteur. Dans le cas des séchoirs à lit fluidisé, cette approche occasionne plusieurs complications comme le sous-séchage, le surséchage et la surchauffe des granules thermosensibles, qui peuvent conduire au rejet du lot. Toutefois, la commande avancée et la production en continu peuvent réduire les problèmes d'opération. Ce projet de recherche concerne donc l'automatisation du séchage par lit fluidisé ou, plus spécifiquement, sa modélisation, sa commande et son observation. La conception et la comparaison de diverses stratégies d'estimation et de contrôle nécessitent d'abord un modèle mathématique représentatif du procédé. Pour y parvenir, une identification « boite grise » estime les paramètres empiriques d'une description phénoménologique à deux phases du lit fluidisé à partir de données expérimentales et un second lot de données valide les simulations qui en résultent. Cet ouvrage évalue ensuite la commande prédictive linéaire, non linéaire et économique sur le simulateur calibré. L'étude explore aussi les filtres de Kalman standard et non parfumé, ainsi que l'estimateur à fenêtre glissante, comme capteur virtuel de teneur en eau des particules, le principal indicateur de qualité au séchage. La première partie de cette thèse se concentre sur les séchoirs verticaux discontinus, et la deuxième, sur un nouveau prototype de réacteur horizontal entièrement continu. Les résultats de cette recherche confirment les avantages indéniables de ces technologies, soit un contrôle serré de la qualité du produit, et une diminution des coûts et de l'empreinte environnementale des opérations. / Manufacturing pharmaceutical tablets through wet granulation typically relies on fluidized bed drying for the particles. Advocated by regulatory agencies, the industry initiated a paradigm shift towards fully continuous and automated production, but batch processes operated without feedback, except a quality control at the end of the cycle, still prevail in the sector. For the case of fluidized bed dryers, this approach results in several issues like under drying, over drying, overheating of thermosensitive granules, that can lead to the rejection of the batch. However, advanced control and continuous processing can reduce the operational hurdles. This research project investigates the automation of fluidized bed drying or, more specifically, its modeling, control and observation. The design and comparison of various estimation and feedback strategies first require a representative mathematical model of the process. For this, a grey-box identification estimates the empirical parameters of a two-phase fluidized bed description from experimental data, and a second dataset validates the resulting simulations. This work then investigates linear, nonlinear, and economic model predictive control on the calibrated simulator. The study also explores the standard and unscented Kalman filter, and the moving-horizon estimator, as soft sensors for the particle moisture content, a critical quality attribute at drying. The first part of this thesis focuses on vertical batch dryers, and the second one, on a new prototype of a fully continuous horizontal reactor. The results of this research confirm the undeniable advantages of those technologies, namely a tight control of the product quality, and reductions in the costs and the environmental footprint of the operations.

No description available.

Im Rahmen der vorliegenden Arbeit wird die Kompaktier-Granulierung von Kalisalzen zur Herstellung von Düngemittelgranulat experimentell untersucht und ein Modellansatz zur Beschreibung von derartigen Kreisläufen abgeleitet. Bei der Kompaktier-Granulierung wird fein-disperses Kalisalz mit Hilfe von Walzenpressen zu sogenannten Schülpen verpresst. Diese werden durch nachfolgende Zerkleinerung und Klassierung zu Düngemittelgranulat (enge Partikelgrößenklasse, wie beispielsweise 2 – 4 mm) verarbeitet. Basierend auf halb-industriellen Kreisläufen werden im vorliegenden Beitrag wesentliche Prozesswechselwirkungen zwischen Kompaktierung, Zerkleinerung und Klassierung ausgearbeitet. Detailuntersuchungen zeigen, dass sich insbesondere die Schülpenfestigkeiten wie auch die schüttgutmechanischen Eigenschaften des Pressenaufgabegutes im Kreislaufbetrieb ändern. Darauf aufbauend wird ein Modellansatz abgeleitet der die Abschätzung des Kreislaufbetriebs erlaubt.

L'objet du projet CALAS est l'étude de la supergranulation solaire, structure à grande échelle de la photosphère. L'origine de la supergranulation est encore controversée et nécessite des observations à très haute résolution spatiale sur un grand champ de vue. Le projet CALAS répond à ces exigences en proposant de concevoir une caméra rapide combinant grand champ et haute résolution, installée à la Lunette Jean Rösch, réfracteur de 50 cm de diamètre situé au Pic du Midi. Cette caméra utilise des capteurs CMOS (Complementary Metal Oxide Semi-conductor) dont les avantages sont notamment la rapidité de lecture, le coût réduit et de grands formats disponibles.<br />Nous avons conçu une chaîne d'acquisition complète, comprenant la caméra et son électronique de commande, une électronique de lecture couplée à un logiciel de prise de vues, et un système de stockage des données.<br />Le projet a également consisté à concevoir un banc optique sur deux voies permettant l'observation de la surface solaire en mode imagerie mais aussi en mode Doppler et magnétographie, par l'utilisation d'un filtre magnéto-optique. Le travail a également nécessité d'étudier l'intégration de CALAS au sein de la Lunette Jean Rösch, en participant à la jouvence de cet instrument.<br />Enfin, au cours de ce projet, outre de nombreuses missions d'observation à la Lunette Jean Rösch, j'ai également été amené à participer à une campagne internationale d'observations coordonnées consacrée à l'étude des mouvements de la photosphère dans l'environnement de filaments. A l'issue de cette thèse, les premières observations à grand champ et haute résolution de la photosphère solaire ont été réalisées à la LJR, et leur excellente qualité se révèle déjà tout à fait prometteuse pour la suite de l'exploitation scientifique.

In this thesis, a thorough study of the batch top-spray fluidized bed granulation was carried out including experimental study, population balance model (PBM), computational fluid dynamic (CFD) study and control strategy development. For the experimental study, the influence variables of pulsed frequency, binder spray rate and atomization pressure of a batch top-spray fluidized bed granulation process were studied using the Box-Behnken experimental design method. Different mathematical models were developed to predict the mean size of granules, yield, relative width of granule distribution, Hausner ratio and final granule moisture content. Validation experiments have shown the reliability and effectiveness of using the Box-Behnken experimental design method to study a fluidized bed granulation process. The one-dimensional population balance models (ODPBMs) have been developed to model a pulsed top-spray fluidized bed granulation, linking the operating factors of the pulsed frequency, the binder spray rate, and atomization air pressure with the granule properties to predict granule growth behavior at different operating conditions. A multi-stage open optimal control strategy based on the developed ODPBMs was proposed to reduce the model and process mismatch through adjusting the trajectory of the evolution of the granule size distribution at predefined sample intervals. The effectiveness of the proposed modeling and multi-stage open optimal control strategy has been validated by experimental and simulation tests. In addition, an Eulerian-Eulerian two-fluid model (EETFM) was developed to describe the gas-particle two-phase flow in the fluidized bed granulator. By computational fluid dynamic analysis, it has been proven that the fluidized bed granulation system is not homogeneous, based on which a two-compartmental population balance model (TCPBM) was developed to describe the particle growth in the fluidized bed granulation. Validation experiments have shown the effectiveness and superior accuracy of the TCPBM comparing with the ODPBM in predicting the final particle size distribution.