Yes / The design of a melt synthesis of the first air-stable formulation of the metastable form III of paracetamol is derived from thermo-spectroscopic and thermo-diffraction experiments. Melt crystallisation in the presence of β-1,4-saccharides produces form III selectively and the excipients appear to act as stabilising ‘active’ templates of the metastable polymorph. / This article is part of themed collection: Pharmaceutical Solids.

No / Determining bioequivalence for solution pressurized metered dose inhalers (pMDI) is difficult because the critical characteristics of such products are poorly defined. The aim of this study was to elucidate the non-aerodynamic properties of the emitted aerosol particles from two solution pMDI products that determine their biopharmaceutical differences after deposition. Novel particle capture and analysis techniques were employed to characterize the physicochemical and biopharmaceutical properties of two beclomethasone dipropionate (BDP) products: QVAR and Sanasthmax. The BDP particles emitted from the Sanasthmax inhaler were discernibly different those emitted from QVAR in terms of size (50% larger, less porous), solid state (less crystalline) and dissolution (20-fold slower). When deposited onto the surface of respiratory epithelial cell layers, QVAR delivered ∼50% more BDP across the cell layer in 60 min than Sanasthmax. Biopharmaceutical performance was not attributable to individual particle properties as these were manifold with summative and/or competing effects. The cell culture dissolution− absorption model revealed the net effect of the particle formed on drug disposition and was predictive of human systemic absorption of BDP delivered by the test inhalers. This illustrates the potential of the technique to detect the effect of formulation on the performance of aerosolized particles and contribute to assessment of bioequivalence. / This work was in part funded by a grant from the Safety and Environmental Assurance Centre, Unilever Colworth, U.K. Particle sizing was performed by Steve Ingham, Institute of Pharmaceutical Science, King’s College London.

Yes / Multidrug resistance (MDR) limits the beneficial outcomes of conventional breast cancer chemotherapy. Ras-related nuclear protein (Ran-GTP) plays a key role in these resistance mechanisms, assisting cancer cells to repair damage to DNA. Herein, we investigate the co-delivery of Ran-RCC1 inhibitory peptide (RAN-IP) and doxorubicin (DOX) to breast cancer cells using liposomal nanocarriers. A liposomal delivery system, co-encapsulating DOX, and RAN-IP, was prepared using a thin-film rehydration technique. Dual-loaded liposomes were optimized by systematic modification of formulation variables. Real-Time-Polymerase Chain Reaction was used to determine Ran-GTP mRNA expression. In vitro cell lines were used to evaluate the effect of loaded liposomes on the viability of breast and lung cancer cell lines. In vivo testing was performed on a murine Solid Ehrlich Carcinoma model. RAN-IP reversed the Ran-expression-mediated MDR by inhibiting the Ran DNA damage repair function. Co-administration of RAN-IP enhanced sensitivity of DOX in breast cancer cell lines. Finally, liposome-mediated co-delivery with RAN-IP improved the anti-tumor effect of DOX in tumor-bearing mice when compared to single therapy. This study is the first to show the simultaneous delivery of RAN-IP and DOX using liposomes can be synergistic with DOX and lead to tumor regression in vitro and in vivo.

Introduction: Integrating 3-dimensional (3D) printing with lipid-based formulation (LBF) is impacting pediatric pharmaceutical manufacturing by enabling personalized oral dosage forms tailored to children's specific needs. Serious challenges are created by manipulating conventional adult dosages to produce suitable dosages for the pediatric population. The study explores an emulsion gel with two model lipophilic drugs, Aprepitant and Irbesartan, using semi-solid extrusion (SSE) as a 3D printing method to produce patient-centered dosages. Method: The solubility of the two model drugs in the studied LBF type IIIA – MC was determined using the shake-flask method combined with High-Performance Liquid Chromatography with Ultraviolet Detection (HPLC-UV) analysis. Once determined, LBF was loaded with 90% of the soluble drug amount to later produce the emulsion by mixing the drug-loaded LBF with Milli-Q water. The emulsion gel was produced as the next step by adding three different polymers to the emulsion. The three polymers were Methylcellulose Methocel (A4C), Methylcellulose Methocel (A4M), and Sodium Crosscarmellose (AcDiSol). Lastly, tablets were 3D-printed using a BIO X 3D printer with a pneumatic printhead. The tablets were vacuum-dried and analyzed for mass and content uniformity, and disintegration time.  Results: The thermodynamic solubility of Aprepitant in LBF IIIA – MC was determined to be 11.30 mg/g while the solubility of Irbesartan was 4.08 mg/g. The produced tablets contained lower concentrations of the drugs compared to the traditional dosages available on the market. The 3D-printed tablets passed the European Pharmacopeia requirements for mass and content uniformity, and disintegration time.  Conclusion: The study showed justified results indicating the emulsion gel can be used to produce tablets loaded with different poorly water-soluble drugs. All characterization studies done on the 3D-printed tablets carried out according to the European Pharmacopeia guidelines showed correct mass and content uniformity together with reasonable disintegration time. This suggests that the emulsion gel has the potential to be used to produce tablets loaded with any other lipophilic drug, potentially multiple drugs loaded at the same time.

This work presents a comprehensive investigation into optimizing cathode formulations for lithium-ion batteries (LIBs), focusing on advancing energy density, C-rate capability, and cost efficiency. A special focus was on the measurement and assessment of the electronic conductivity of cathodes. Electrode slurries with varying formulations were prepared and coated, examining the effects of cathode active materials (CAMs), binders, and conductive additives (CAs). Variations in electrode loading and density were done to provide a holistic perspective on electrode production parameters. Electrochemical performance was evaluated through half-coin cells (HCC), electronic resistance meas-urement (ERM), and electrochemical impedance spectroscopy (EIS) using three-electrode cells. Experimental data were used to develop semi-empirical models and behavioral schemes, offering new insights into cathode design. The first key outcome highlights a holistic understanding of cathode development. Comparisons of CAMs such as Lithium-Nickel-Cobalt-Manganese oxide (NCM) and Lith-ium-Manganese-Iron phosphate (LMFP) emphasized the impact of crystal density, press density and specific capacity on the reachable volumetric energy density. Electrode de-sign parameters like electrode loading, press density and porosity were assessed for their impact on C-rate capability, cost and volumetric energy density. Temperature and state-of-charge (SoC) effects on resistance types were characterized, revealing essential impacts on electrode kinetics. Secondly, the thesis focuses on characterizing electronic resistance at the electrode compound and electrode/current collector interface and its correlation with typically used performance indicators such as half coin cells. Using a newly commercially availa-ble electronic resistance measurement device (HIOKI RM2610), electronic resistances were measured, and important impact factors were identified. A total electronic re-sistance (TER) threshold of 0.25 Ω∙cm² was established, below which further perfor-mance gains were not measurable in half coin cells. These findings can enable predic-tions of cathode performance based on electronic resistance measurement (ERM) re-sults, a major contribution to the field of cathode development. Lastly, the gained insights were applied to develop a more efficient cathode optimiza-tion strategy. The integration of electronic resistance measurement (ERM) can signifi-cantly reduce the need for extensive electrochemical testing and can therefore help to make electrode development more time and cost efficient.:1 TABLE OF CONTENTS Danksagung I Abstract II 1 Table of contents 3 2 Symbols and Abbreviations 6 2.1 Formula Symbols and Constants 6 2.2 Abbreviations 7 3 Introduction 9 3.1 Motivation and Aims of the Thesis 9 3.2 Structure of This Thesis 11 4 Fundamentals and State of the Art 13 4.1 Function Principle and Components of a LIB 13 4.1.1 Cathode 15 4.1.2 Anode 15 4.1.3 Electrolyte 15 4.1.4 Separator and Current Collector 16 4.2 Thermodynamics 17 4.2.1 Energy Storage Principle of a LIB 17 4.2.2 Electrical Potential of a LIB 20 4.2.3 Li-Capacity 23 4.3 LIB Cell Kinetics 25 4.3.1 Electronic Resistances in the Cell 29 4.3.2 Electrolyte Resistance 30 4.3.3 Charge-Transfer Resistance 36 4.3.4 Solid State Diffusion Resistance 38 4.4 Cathode Development in LIB 39 4.4.1 Cathode Active Materials (CAM) 39 4.4.2 Conductive Additives (CA) and Binder 41 4.4.3 Cathode Electrode Development 43 4.5 LIB in Automotive Use 44 4.6 Definitions and Relevant Quantities 47 4.6.1 C-rate 47 4.6.2 SoC 47 4.6.3 Cycle Life and State of Health (SoH) 47 4.6.4 Area Types 47 4.6.5 Resistance Normalization 48 4.6.6 Calculation Boundaries 48 5 Materials and Methods 50 5.1 Materials and Electrode Production 50 5.1.1 Active Materials 50 5.1.2 Inactive Materials 50 5.1.3 Electrode Preparation 51 5.2 Cells and Test Methods 52 5.2.1 Thickness Measurement, Press Density and Porosity Calculation 52 5.2.2 Electrode Peel Test 53 5.2.3 Electronic Resistance Measurement (ERM) 53 5.2.4 HCC – C-rate (and OCV) Testing 55 5.2.5 Sandwich Pouch (SWP) – and Testing 55 5.2.6 3-Electrode Cells and EIS Measurements 56 6 Cathode Design Influence Factors 58 6.1 Qualitative Understanding of Cathode Design Influence Factors 58 6.2 Quantifying Influence of Loading, Porosity and C-rate 67 6.3 Quantifying Temperature and SoC Dependencies of Resistance Types 73 6.4 Cathode Design Schematics 85 7 Electronic Resistances in Cathodes 89 7.1 ERM Methods and Their Advantages and Disadvantages 89 7.2 Utilizing and Understanding Dry Multi-point Measurements 97 7.3 Correlation of ERM With HCC Performance 104 7.4 CAs Specific Strengths and Weaknesses 109 7.5 Synergy Effects of CA-mixtures and its Predictability 111 8 Tailored Cathode Designs with Help of ERM 117 8.1 On the Relevance and Need for Binder in a Cathode 117 8.2 Impact of Binder and CA Reduction on Cycle Life 121 8.3 Cathode Optimization Calculations 124 9 Summary and Outlook 131 10 References 135 11 Table of Figures 141 12 Table of Tables 148 13 List of scientific Contributions 149 Appendix 150 Appendix A: Capacities Influenced by CAM Cracking and Diffusion at High Degree of Lithiation 150 Appendix B: Different Operating Windows of LMFP 152 Appendix C: Additional Results for Electronic Resistance in Cathode Measurements 153 Appendix D: Price Assumptions and Calculations 155 Appendix E: Use of Writing Tools for this Work 156 Appendix F: Curriculum vitae 157

La modélisation des problèmes d'interactions sol-structure et fluide-structure couvre plusieurs domaines de recherche très actifs qui traitent une multitude d'aspects tels que la géométrie non bornée du sol et dans certains cas du fluide stocké, les effets dissipatifs visqueux et radiatifs, l'application du chargement sismique, le choix des variables de base, les propriétés algébriques des systèmes d'équations résultant du couplage,... etc. Dans le présent travail, différents modèles numériques de couplage sol-structure et fluide-structure ont été examinés. Les limites de troncature géométrique du sol et du fluide on été traitées avec des éléments infinis dont les performances ont été comparées à celles des conditions de radiations. Le problème de vibrations libres couplées des systèmes fluide-structure a été résolu en introduisant de nouvelles techniques de symétrisation efficaces. De plus, une nouvelle formulation symétrique en éléments de frontière a été proposée. Cette formulation permet de produire une matrice symétrique définie positive et aboutit ainsi à un système algébrique similaire à celui qui découle de la discrétisation en éléments finis. La matrice bâtie dite "raideur équivalente" peut facilement être assemblée ou couplée avec les matrices de la formulation en éléments finis. Toutes les applications qui ont servi soit à comparer des modèles soit à valider les programmes développés, ont été effectué es dans le cas des barrages poids en béton. Ce cas constitue un problème de couplage fluide-sol-structure typique / Modeling fluid-structure and soil-structure interaction problems covers several research fields dealing with multiple aspects such as : unbounded geometry of soil media and in some cases of retained fluid, viscous and radiation dissipative effects, application of seismic loading, choice of the basic variables, algebraic properties of the resulting coupled system, ... etc. In this work, different numerical models of soil-structure and fluid-structure coupling have been studied. The truncation boundaries of the soil and of the fluid domains have been considered by using infinite elements whose performances were compared to those of radiation conditions. The problem of the free coupled vibrations of the fluid-structure systems has been solved by introducing efficient symmetrization techniques. In addition, a new symmetric boundary element formulation is proposed. It allows to produce a positive definite and symmetric matrix and therefore to conduct to an algebraic system similar to the one obtained from finite element discretization. The produced matrix called "equivalent stiffness matrix" can easily be assembled or coupled to finite element matrices. All of the applications which have been done in order to compare models or to validate the developed programs were built in the case of concrete gravity dams, which constitute typical coupled fluid- soil-structure problems

Cette thèse aborde la reformulation dans des discussions entre jeunes Libanais francophones. Après une approche lexicologique de formuler/reformuler/reformulation qui vise à faire émerger leurs spécificités par rapport à dire/redire, énoncer/réénoncer, etc., et une tentative de trouver une unité à l’objet discursif qu’est la reformulation, une double approche des reformulations du corpus est engagée. La première, linguistique, dresse une typologie de ce phénomène dans le corpus. Se voulant globale, elle prend en compte des critères linguistiques (phonologique, sémantique, lexical, morphosyntaxiques) et d’autres qui relèvent de la dimension interactive dans laquelle s’inscrivent les reformulations (instances, initiation et rôle de la reformulation dans le discours). Le principal apport de cette approche qualitative et quantitative est d’avoir montré l’aspect central de la morphosyntaxe dans le marquage des reformulations nuançant ainsi les approches du phénomène à travers les marqueurs lexicaux et les connecteurs. La deuxième approche se centre sur les locuteurs et sur leur statut de non-natifs en s’interrogeant sur le potentiel des reformulations à nous renseigner sur leur compétence de communication. De plus, le travail se penche sur des phénomènes de contacts de langues dans le cadre de l’activité reformulatoire des locuteurs dans le corpus. Cette thèse se consacre enfin, dans le cadre théorique de la grammaticalisation/pragmaticalisation, à l’étude d’un marqueur discursif du dialecte libanais «jæʕne» qui fait irruption dans le discours des locuteurs et témoigne, entre autres emplois, de celui de marqueur de reformulation. Les emplois de jæʕne sont considérés aussi comme des phénomènes de contacts de langue d’une part dans le cadre d’alternance codique et d’autre part, à travers des calques opérés par les locuteurs sur c’est-à-dire. / This PhD thesis approaches reformulation in conversations between young francophone Lebanese. It starts with a lexicological approach of the words formulate/reformulate/reformulation in order to emphasize their differences with say/say again, utter/utter again and goes on with a deep analysis of reformulation as a discursive object, followed by a two-fold approach of the occurrences in the corpus. The first approach is a linguistic one and also deals with the interactional dimension of reformulations. Quantitative and qualitative analyses emphasize the role of morphosyntax in marking reformulations, completing the approaches based on discourse markers and connectives. The second approach, focusing on the speakers, takes into account their non-native speaker status. We are questioning here the way in which reformulations can provide information about their communicative competence. Reformulation is seen as a communicative strategy they use in order to solve communication problems. Our work ends with the analysis of a Lebanese French discourse marker, jæʕne, used by the speakers to indicate reformulation (among other things). The first part of the analysis draws a typology of all its uses within the grammaticalization/pragmaticalization framework while the second one studies it as a language contact phenomenon.

L'Interaction Fluide-Structure (IFS) décrit une classe très générale de problème physique, ce qui explique la nécessité de développer une méthode numérique capable de simuler le problème FSI. Pour cette raison, un solveur IFS est développé qui peut traiter un écoulement de fluide incompressible en interaction avec des structures différente: élastique ou rigide. Dans cet aspect, le solveur peut couvrir une large gamme d'applications.La méthode proposée est développée dans le cadre d'une formulation monolithique dans un contexte Eulérien. Cette méthode consiste à considérer un seul maillage et résoudre un seul système d'équations avec des propriétés matérielles différentes. La fonction distance permet de définir la position et l'interface de tous les objets à l'intérieur du domaine et de fournir les propriétés physiques pour chaque sous-domaine. L'adaptation de maillage anisotrope basé sur la variation de la fonction distance est ensuite appliquée pour assurer une capture précise des discontinuités à l'interface fluide-solide.La formulation monolithique est assurée par l'ajout d'un tenseur supplémentaire dans les équations de Navier-Stokes. Ce tenseur provient de la présence de la structure dans le fluide. Le système est résolu en utilisant une méthode élément fini et stabilisé suivant la formulation variationnelle multiéchelle. Cette formulation consiste à décomposer les champs de vitesse et pression en grande et petite échelles. La particularité de l'approche proposée réside dans l'enrichissement du tenseur de l'extra contraint.La première application est la simulation IFS avec un corps rigide. Le corps rigide est décrit en imposant une valeur nul du tenseur des déformations, et le mouvement est obtenu par la résolution du mouvement de corps rigide. Nous évaluons le comportement et la précision de la formulation proposée dans la simulation des exemples 2D et 3D. Les résultats sont comparés avec la littérature et montrent que la méthode développée est stable et précise.La seconde application est la simulation IFS avec un corps élastique. Dans ce cas, une équation supplémentaire est ajoutée au système précédent qui permet de résoudre le champ de déplacement. Et la contrainte de rigidité est remplacée par la loi de comportement du corps élastique. La déformation et le mouvement du corps élastique sont réalisés en résolvant l'équation de convection de la Level-Set. Nous illustrons la flexibilité de la formulation proposée par des exemples 2D. / Numerical simulations of fluid-structure interaction (FSI) are of first interest in numerous industrial problems: aeronautics, heat treatments, aerodynamic, bioengineering... Because of the high complexity of such problems, analytical study is in general not sufficient to understand and solve them. FSI simulations are then nowadays the focus of numerous investigations, and various approaches are proposed to treat them. We propose in this thesis a novel monolithic approach to deal with the interaction between an incompressible fluid flow and rigid/ elastic material. This method consists in considering a single grid and solving one set of equations with different material properties. A distance function enables to define the position and the interface of any objects with complex shapes inside the volume and to provide heterogeneous physical properties for each subdomain. Different anisotropic mesh adaptation algorithms based on the variations of the distance function or on using error estimators are used to ensure an accurate capture of the discontinuities at the fluid-solid interface. The monolithic formulation is insured by adding an extra-stress tensor in the Navier-Stokes equations coming from the presence of the structure in the fluid. The system is then solved using a finite element Variational MultiScale (VMS) method, which consists of decomposition, for both the velocity and the pressure fields, into coarse/resolved scales and fine/unresolved scales. The distinctive feature of the proposed approach resides in the efficient enrichment of the extra constraint. In the first part of the thesis, we use the proposed approach to assess its accuracy and ability to deal with fluid-rigid interaction. The rigid body is prescribed under the constraint of imposing the nullity of the strain tensor, and its movement is achieved by solving the rigid body motion. Several test case, in 2D and 3D with simple and complex geometries are presented. Results are compared with existing ones in the literature showing good stability and accuracy on unstructured and adapted meshes. In the second, we present different routes and an extension of the approach to deal with elastic body. In this case, an additional equation is added to the previous system to solve the displacement field. And the rigidity constraint is replaced with a corresponding behaviour law of the material. The elastic deformation and motion are captured using a convected level-set method. We present several 2D numerical tests, which is considered as classical benchmarks in the literature, and discuss their results.

Dans cette thèse, nous nous intéressons à un problème de fiabilité dans les réseaux multicouches IP-sur-WDM. Etant donné un ensemble de demandes pour lesquelles on connaît une topologie fiable dans la couche IP, le problème consiste à sécuriser la couche optique WDM en y cherchant une topologie fiable. Nous montrons que le problème est NP-complet même dans le cas d'une seule demande. Ensuite, nous proposons quatre formulations en termes de programmes linéaires en nombres entiers pour le problème. La première est basée sur les contraintes de coupes. Nous considérons le polyèdre associé. Nous identifions de nouvelles familles de contraintes valides et étudions leur aspect facial. Nous proposons également des algorithmes de séparation pour ces contraintes. En utilisant ces résultats, nous développons un algorithme de coupes et branchements pour le problème et présentons une étude expérimentale. La deuxième formulation utilise comme variables des chemins entre des terminaux dans le graphe sous-jacent. Un algorithme de branchements et génération de colonnes est proposé pour cette formulation. Par la suite, nous discutons d'une formulation dite naturelle utilisant uniquement les variables de design. Enfin, nous présentons une formulation étendue compacte qui, en plus des variables naturelles, utilise des variables de routage. Nous montrons que cette formulation fournit une meilleure borne inférieure. / This thesis deals with a problem related to survivability issues in multilayer IP-over-WDM networks. Given a set of traffic demands for which we know a survivable logical routing in the IP layer, the aim is determine the corresponding survivable topology in the WDM layer. We show that the problem is NP-hard even for a single demand. Moreover, we propose four integer linear programming formulations for the problem. The first one is based on the so-called cut inequalities. We consider the polyhedron associated with the formulation. We identify several families of valid inequalities and discuss their facial aspect. We also develop separation routines. Using this, we devise a Branch-and-Cut algorithm and present experimental results. The second formulation uses paths between terminals of the underlying graph as variables. We devise a Branch-and-Price algorithm based on that formulation. In addition, we investigate a natural formulation for the problem which uses only the design variables.  Finally, we propose an extended compact formulation which, in addition to the design variables, uses routing variables. We show that this formulation provides a tighter bound for the problem.

Ce travail a été effectué dans le cadre du projet Rem3D® dans lequel participent plusieurs entreprises avec l'objectif de développer un logiciel d'injection en 3D par éléments finis. L'objectif est de développer une méthode numérique pour modéliser le comportement viscoélastique des polymères de l'état solide à l'état liquide à travers une approche multiphasique qui est largement utilisé pour traiter le problème de l'interaction fluide-structure (IFS). La philosophie est d'utiliser une formulation mixte de trois champs (u, v, p) (déplacement, vitesse, pression), où u et v représentent les principales variables de déformation et de vitesse de déformation. Nous sommes amenés au problème de Navier-Stokes compressibles avec l'extra-contrainte, qui est résolu en utilisant la méthode des éléments finis mixte. Le présent travail contribue aussi certains éléments de stabilisation pour la simulation numérique des problèmes multiphasiques par l'approche monolithique.Comparaison entre la littérature et l'expérience est accompli par la validation du cas élastique et cas modèle viscoélastique de Kelvin-Voigt dans le lagrangien approche ainsi qu'eulérien approche. L'extension de la méthodologie au modèle visco-hyper-élastique est débuté par la modélisation et la validation au point matériel, puis l'implémentation dans la bibliothèque des éléments finis CimLib®. Enfin, un schéma stabilisation de résolution du type EVSS est adopté pour le modèle viscoélastique de Kelvin-Voigt, le modèle visco-hyper-élastique de Néo-Hookean, et aussi le modèle visco-hyper-élastique qui propose une prometteuse porte ouverte dans la simulation et modélisation, non seulement pour la viscoélasticité, mais aussi pour les applications dynamique complexes. / This work concerns the simulation of viscoelastic behavior of polymer at different states. Viscoelastic modeling of polymer was performed from the solid state to the liquid state via a multiphase approach which is largely used to deal with the fluid structure interaction. To ensure the appreciation of the FSI, viscoelasticity is considered in two parts: an elastic one and viscous other where the main idea is to use a mixed formulation in three fields (u, v, p) (displacement, velocity, pressure), with u and v, represented the primary variables of a strain and a strain rate formulation. We are led to the Navier-Stokes compressible problem with extra-stress, which is solved by using the Mixed Finite Element. The present work contributes some stabilization elements to the numerical simulation of multiphase problem by the monolithic approach.Comparison between the literature and experiments was performed through the validation of an elastic case and the viscoelastic Kelvin-Voigt model in the context of Lagrangian framework as well as Eulerian framework. The extension of the methodology to a visco-hyper-elastic is given through the modeling and validation on material point on the finite elements library CimLib®. Finally, a stabilization scheme of the EVSS type is adopted for viscoelastic Kelvin-Voigt model, hyper-elastic Neo-Hookean model, and also visco-hyper-elastic model which proposed an open door in computational modeling, not only with viscoelasticity but also complex dynamic application.