La luzerne est une plante fourragère, de la famille des Fabacées, largement cultivée en France du fait de sa richesse en protéines. Industriellement, cette plante est pressée, puis séchée sur tambour rotatif. L’étape de pressage conduit à l’obtention de grandes quantités de jus, lui aussi riche en protéines. L’objectif de cette thèse a été de développer un procédé de bioraffinerie de la luzerne, applicable aux autres plantes fourragères, permettant la valorisation des toutes les fractions de la plante. La première étape consiste en un fractionnement thermo-mécanique de la luzerne entière par extrusion bi-vis. Deux fractions sont obtenues : un résidu fibreux solide en partie déshydraté, pouvant être utilisé dans la filière agro-matériaux, et un filtrat vert, riche en protéines. L’extrusion bi-vis est une alternative intéressante aux procédés classiques de déshydratation, car l’étude de l’optimisation des paramètres d’extrusion a permis de montrer qu’il est possible de récupérer la grande majorité des protéines de la plante dans le filtrat. Ce filtrat subit par la suite une séparation liquide/solide par centrifugation, permettant la récupération d’un culot vert, dont on peut extraire la chlorophylle. Le jus clarifié est ultrafiltré, puis traité par chromatographie hydrophobe, avec l’huile de tournesol comme solvant extracteur, de manière à séparer différentes protéines. L’étude plus fondamentale de la fixation des protéines sur résine a permis de modéliser le fractionnement des protéines par interactions hydrophobes. / Alfalfa is a common Legume, cultivated as a forage crop, thanks to its high protein content. In the green crop industry, alfalfa is pressed and dried on a rotative cylinder. The pressing step leads to the production of large amounts of green juice, rich in proteins. The aim of this work was to develop a biorefinery process for alfalfa, which could be adapted to other green crops, allowing the valorization of each fraction. The first step is the whole plant thermo-mechanical fractionation in the twin-screw extruder. Two fractions are obtained: a solid fibrous residue, partly dehydrated which could be valorized as an agro-material, and a green filtrate, rich in proteins. Twin-screw extrusion is an interesting alternative to usual industrial dehydration processes. Indeed, the study of the extruder parameters optimization showed that most of the alfalfa proteins can be recovered in the filtrate. This green extract is then centrifuged, in order to separate the solid particles. Chlorophyll can be extracted from the centrifugation pellet. The clarified juice is treated by ultrafiltration, and lastly fractionated thanks to hydrophobic chromatography, with sunflower oil as the solvent, in order to separate the proteins. The more fundamental study of proteins fixation on resins allowed us to modelize proteins fractionation using hydrophobic interactions.

Melt granulation is a versatile process that is underutilized in the pharmaceutical industry. Most pharmaceutical wet granulation and twin-screw extruders can be adapted for melt granulation. Twin-screw melt granulation (TSMG) is of interest since is a continuous process and allows for flexible process design and a high degree of control. TSMG can be used to produce formulations for oral immediate or sustained release. This research focuses on the use of TSMG to taste-mask APIs. Many APIs are bitter or unpleasant tasting. Taste-masking may be required, particularly for products intended for pediatric patients. Taste-masking has been achieved with many different techniques, but a simple, cost-effective method that can be applied to many different APIs is not currently available. A matrix encapsulation approach using continuous twin-screw melt granulation was attempted with three different APIs. The resulting granule properties, particularly particle size, are related to the granulation process parameters. Prediction of taste-masking based on in vitro assessments is challenging and generally clinical evaluation is required. A small-volume dissolution method was developed as a screening test the melt granules. It is not clear if this technique is predictive of clinical taste-masking performance, but it is expected to be an improvement over discrete sampling or typical quality control dissolution methods. The dissolution rate was estimated using the Noyes-Whitney equation and correlated to the mean granule particle size. From this, a simple model for time to a taste threshold could be used to define a design space around the granulation process. / Pharmaceutical Sciences

No / Mechanochemistry provides a method to reduce or eliminate the use of solvents by carrying out reactions through the grinding of neat reagents. Until recently a significant drawback of this form of synthesis has been the limited ability to scale up. However, it has been shown that twin screw extrusion (TSE) may overcome this problem as demonstrated in the continuous synthesis of co-crystals, Metal Organic Frameworks (MOFs) and Deep Eutectic Solvents (DES), in multi kg h−1 quantities. TSE has provided a means to carry out mechanochemical synthesis in a continuous, large scale and efficient fashion, which is adaptable to a manufacturing process. Herein, we highlight the potential of this technique for organic synthesis by reporting four condensation reactions, the Knoevenagel condensation, imine formation, aldol reaction and the Michael addition, to produce analytically pure products, most of which did not require any post synthetic purification or isolation. Each reaction was carried out in the absence of solvents and the water byproduct was conveniently removed as water vapour during the extrusion process due to the elevated temperatures used. Furthermore, the Knoevenagel condensation has been studied in detail to gain insight into the mechanism by which these mechanochemical reactions proceed. The results point to effective wetting of one reactant by another as being critical for these reactions to occur under these reaction conditions. / EPSRC EP/L019655/1

Ce projet vise à développer un nouveau procédé de fabrication de nanofibrilles de cellulose (NFC) à fort taux de matière sèche et en consommant peu d’énergie. L’extrusion bi-vis, technique industrielle, efficace énergétiquement et facilement adaptable fut ainsi utilisée pour produire des NFC à 20%. En diminuant considérablement la teneur en eau, cette nouvelle stratégie permet de diminuer le coût du transport, d’améliorer le stockage et d’élargir leur domaine d’application. Ce travail a consisté (i) à développer de nouveaux prétraitements chimiques des fibres de celluloses, respectueux de l’environnement pour faciliter la fibrillation de la cellulose et produire des NFC fonctionnelles de qualité, (ii) à optimiser les conditions d’extrusion ainsi que le profil de vis et (iii) à préparer des matériaux à partir de cette nouvelle matière. Quatre prétraitements chimiques ont été identifiés comme facilement industrialisables et ensuite optimisés. La nanofibrillation par extrusion a été ensuite simulée par un logiciel pour obtenir des conditions d’extrusion optimisées. La production de NFC de qualité à l’échelle semi-industrielle a été validée. Différentes applications ont été envisagées pour ces nouvelles NFC à fort taux de matière sèche. / This project aims at developing a new process to produce high solid content cellulose nanofibrils (CNF) decreasing the energy consumption and preserving the high quality compared to classic processes. Twin screw extrusion (TSE), industrially well-known, energy efficient and highly adaptable technique, was optimized to produce CNF at 20 wt% solid content. By decreasing considerably the water content, this new strategy improves the transport cost, the storage and widening the field of application and formulation. The objectives were to (i) develop new green pretreatments of cellulose fibers to facilitate the fibrillation and produce high quality functionalized CNF, (ii) optimize TSE screw profile and conditions to produce CNF and (iii) prepare new materials made of this new type of CNF. Four chemical pretreatments of cellulose fibers have been identified as industrially feasible, leading to high quality functionalized CNF and were widely studied and optimized. The nanofibrillation by TSE was simulated using a simulation software and TSE conditions were then successfully optimized. This cost-effective approach was validated at semi-industrial scale. Finally, different new applications with this new grade of CNF were considered.

Co-rotating twin-screw extruders are unique and versatile machines that are used widely in the plastics and food processing industries. Due to the large number of operating variables and design parameters available for manipulation and the complex interactions between them, it cannot be claimed that these extruders are currently being optimally utilised. The most significant improvement to the field of twin-screw extrusion would be through the provision of a generally applicable dynamic process model that is both computationally inexpensive and accurate. This would enable product design, process optimisation and process controller design to be performed cheaply and more thoroughly on a computer than can currently be achieved through experimental trials. This thesis is divided into three parts: dynamic modelling, measurement and control. The first part outlines the development of a dynamic model of the extrusion process which satisfies the above mentioned criteria. The dynamic model predicts quasi-3D spatial profiles of the degree of fill, pressure, temperature, specific mechanical energy input and concentrations of inert and reacting species in the extruder. The individual material transport models which constitute the dynamic model are examined closely for their accuracy and computational efficiency by comparing candidate models amongst themselves and against full 3D finite volume flow models. Several new modelling approaches are proposed in the course of this investigation. The dynamic model achieves a high degree of simplicity and flexibility by assuming a slight compressibility in the process material, allowing the pressure to be calculated directly from the degree of over-fill in each model element using an equation of state. Comparison of the model predictions with dynamic temperature, pressure and residence time distribution data from an extrusion cooking process indicates a good predictive capability. The model can perform dynamic step-change calculations for typical screw configurations in approximately 30 seconds on a 600 MHz Pentium 3 personal computer. The second part of this thesis relates to the measurement of product quality attributes of extruded materials. A digital image processing technique for measuring the bubble size distribution in extruded foams from cross sectional images is presented. It is recognised that this is an important product quality attribute, though difficult to measure accurately with existing techniques. The present technique is demonstrated on several different products. A simulation study of the formation mechanism of polymer foams is also performed. The measurement of product quality attributes such as bulk density and hardness in a manner suitable for automatic control is also addressed. This is achieved through the development of an acoustic sensor for inferring product attributes using the sounds emanating from the product as it leaves the extruder. This method is found to have good prediction ability on unseen data. The third and final part of this thesis relates to the automatic control of product quality attributes using multivariable model predictive controllers based on both direct and indirect control strategies. In the given case study, indirect control strategies, which seek to regulate the product quality attributes through the control of secondary process indicators such as temperature and pressure, are found to cause greater deviations in product quality than taking no corrective control action at all. Conversely, direct control strategies are shown to give tight control over the product quality attributes, provided that appropriate product quality sensors or inferential estimation techniques are available.

Co-rotating twin-screw extruders are unique and versatile machines that are used widely in the plastics and food processing industries. Due to the large number of operating variables and design parameters available for manipulation and the complex interactions between them, it cannot be claimed that these extruders are currently being optimally utilised. The most significant improvement to the field of twin-screw extrusion would be through the provision of a generally applicable dynamic process model that is both computationally inexpensive and accurate. This would enable product design, process optimisation and process controller design to be performed cheaply and more thoroughly on a computer than can currently be achieved through experimental trials. This thesis is divided into three parts: dynamic modelling, measurement and control. The first part outlines the development of a dynamic model of the extrusion process which satisfies the above mentioned criteria. The dynamic model predicts quasi-3D spatial profiles of the degree of fill, pressure, temperature, specific mechanical energy input and concentrations of inert and reacting species in the extruder. The individual material transport models which constitute the dynamic model are examined closely for their accuracy and computational efficiency by comparing candidate models amongst themselves and against full 3D finite volume flow models. Several new modelling approaches are proposed in the course of this investigation. The dynamic model achieves a high degree of simplicity and flexibility by assuming a slight compressibility in the process material, allowing the pressure to be calculated directly from the degree of over-fill in each model element using an equation of state. Comparison of the model predictions with dynamic temperature, pressure and residence time distribution data from an extrusion cooking process indicates a good predictive capability. The model can perform dynamic step-change calculations for typical screw configurations in approximately 30 seconds on a 600 MHz Pentium 3 personal computer. The second part of this thesis relates to the measurement of product quality attributes of extruded materials. A digital image processing technique for measuring the bubble size distribution in extruded foams from cross sectional images is presented. It is recognised that this is an important product quality attribute, though difficult to measure accurately with existing techniques. The present technique is demonstrated on several different products. A simulation study of the formation mechanism of polymer foams is also performed. The measurement of product quality attributes such as bulk density and hardness in a manner suitable for automatic control is also addressed. This is achieved through the development of an acoustic sensor for inferring product attributes using the sounds emanating from the product as it leaves the extruder. This method is found to have good prediction ability on unseen data. The third and final part of this thesis relates to the automatic control of product quality attributes using multivariable model predictive controllers based on both direct and indirect control strategies. In the given case study, indirect control strategies, which seek to regulate the product quality attributes through the control of secondary process indicators such as temperature and pressure, are found to cause greater deviations in product quality than taking no corrective control action at all. Conversely, direct control strategies are shown to give tight control over the product quality attributes, provided that appropriate product quality sensors or inferential estimation techniques are available.

Yes / Chemical manufacturing typically requires more than one step, involving multiple batch processes, which makes synthesis at scale laborious and wasteful. Herein, we demonstrate that several reactions can be telescoped into a single continuous process and/or be carried out as a continuous multi-component reaction (MCR), by twin screw extrusion (TSE), in the complete absence of solvent. / EPSRC (EP/L019655/1).

No / Mechanochemical synthesis has been applied to the rapid synthesis of Deep Eutectic Solvents (DESs), including Reline 200 (choline chloride : urea, 1 : 2), in a continuous flow methodology by Twin Screw Extrusion (TSE). This gave products in higher purity and with Space Time Yields (STYs), four orders of magnitude greater than for batch methods

No / The oligomerisation of L-amino acids by papain was studied in a mixer ball mill and in a planetary ball mill. The biocatalyst proved stable under the ball milling conditions providing the corresponding oligopeptides in good to excellent yields and with a variable degree of polymerisation. Both parameters were found to be dependent on the reaction conditions and on the nature of the amino acid (specifically on its side-chain size and hydrophobicity). In addition, the chemoenzymatic oligomerisation was demonstrated by utilising twin-screw extrusion technology, which allowed for a scalable continuous process. Finally, the synthesised oligo(L-Leu) 2b proved to be active as a catalyst in the Juliá–Colonna enantioselective epoxidation of chalcone derivatives. / We acknowledge RWTH Aachen University for support by the Distinguished Professorship Program funded by the Excellence Initiative of the German federal and state governments. We kindly acknowledge Marcus Frings and Plamena Staleva for the HPLC analysis of products 4a–c (RWTH Aachen University) and ASEP for the TGA analysis (Queen’s University Belfast). D. E. C. and S. L. J. acknowledge the agency EPSRC, grant no. EP/R019655/1. Part of this work was performed at the Center for Chemical Polymer Technology (CPT) unit of DWI, which was supported by the EU and the federal state of North Rhine-Westphalia (grant EFRE 30 00 883 02).

Yes / The continuous and scalable synthesis of a porous organic cage (CC3), obtained through a 10-component imine polycondensation between triformylbenzene and a vicinal diamine, was achieved using twin screw extrusion (TSE). Compared to both batch and flow syntheses, the use of TSE enabled the large scale synthesis of CC3 using minimal solvent and in short reaction times, with liquid-assisted grinding (LAG) also promoting window-to-window crystal packing to form a 3-D diamondoid pore network in the solid state. A new kinetically trapped [3+5] product was also observed alongside the formation of the targeted [4+6] cage species. Post-synthetic purification by Soxhlet extraction of the as-extruded ‘technical grade’ mixture of CC3 and [3+5] species rendered the material porous. / Engineering and Physical Sciences Research Council (EPSRC) under the Grants EP/R005710/1 (AIC) and EP/R005540/1 (SLJ), and for an EPSRC Summer Vacation Bursary at the University of Liverpool (FG, RLG). We also thank the European Research Council under FP7, RobOT, ERC Grant Agreement No. 321156 (AIC), for financial support. RLG thanks the Royal Society for a University Research Fellowship.