Yes / There is a need to understand the nature of aggregation of cyclodextrins (CDs) with guest molecules in increasingly complex formulation systems. To this end an innovative application of Taylor dispersion analysis (TDA) and comparison with dynamic light scattering (DLS) have been carried out to probe the nature of ICT01-2588 (ICT-2588), a novel tumor-targeted vascular disrupting agent, in solvents including a potential buffered formulation containing 10% hydroxypropyl-β-cyclodextrin. The two hydrodynamic sizing techniques give measurement responses are that fundamentally different for aggregated solutions containing the target molecule, and the benefits of using TDA in conjunction with DLS are that systems are characterised through measurement of both mass- and z-average hydrodynamic radii. Whereas DLS measurements primarily resolve the large aggregates of ICT01-2588 in its formulation medium, methodology for TDA is described to determine the size and notably to quantify the proportion of monomers in the presence of large aggregates, and at the same time measure the formulation viscosity. Interestingly TDA and DLS have also distinguished between aggregate profiles formed using HP-β-CD samples from different suppliers. The approach is expected to be widely applicable to this important class of drug formulations where drug solubility is enhanced by cyclodextrin and other excipients.

京都大学 / 新制・論文博士 / 博士(地球環境学) / 乙第13628号 / 論地環博第18号 / 新制||地環||53(附属図書館) / 京都大学大学院地球環境学舎地球環境学専攻 / (主査)教授 勝見 武, 准教授 高井 敦史, 教授 安原 英明, 教授 越後 信哉 / 学位規則第4条第2項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

The present research is concerned with developing analysis methods for analyzing and exploring finite-amplitude elastic wave propagation through periodic media. Periodic arrangements of materials with high acoustic impedance contrasts can be employed to control wave propagation. These systems are often termed phononic crystals or metamaterials, depending on the specific design and purpose. Design of these systems usually relies on computation and analysis of dispersion band structures which contain information about wave propagation speed and direction. The location and influence of complete (and partial) band gaps is a particularly interesting characteristic. Wave propagation is prohibited for frequencies that correspond to band gaps; thus, periodic systems behave as filters, wave guides, and lenses at certain frequencies. Controlling these behaviors has typically been limited to the manufacturing stage or the application of external stimuli to distort material configurations. The inclusion of nonlinear elements in periodic unit cells offers an option for passive tuning of the dispersion band structure through amplitude-dependence. Hence, dispersion analysis methods which may be utilized in the design of nonlinear phononic crystals and metamaterials are required. The approach taken herein utilizes Bloch wave-based perturbation analysis methods for obtaining closed-form expressions for dispersion amplitude-dependence. The influence of material and geometric nonlinearities on the dispersion relationship is investigated. It is shown that dispersion shifts result from both self-action (monochromatic excitation) and wave-interaction (multi-frequency excitation), the latter enabling dynamic anisotropy in periodic media. A particularly novel aspect of this work is the ease with which band structures of discretized systems may be analyzed. This connection enables topology optimization of unit cells with nonlinear elements. Several important periodic systems are considered including monoatomic lattices, multilayer materials, and plane stress matrix-inclusion configurations. The analysis methods are further developed into a procedure which can be implemented numerically with existing finite-element analysis software for analyzing geometrically-complex materials.

No / Biosimilar pharmaceuticals are complex biological molecules that have similar physicochemical properties to the originator therapeutic protein. They are produced by complex multi-stage processes and are not truly equivalent. Therefore, for a biosimilar to be approved for market it is important to demonstrate that the biological product is highly similar to a reference product. This includes its primary and higher order structures and its aggregation behaviour. Representative lots of both the proposed biosimilar and the reference product are analysed to understand the lot-to-lot variability of both drug substances in the manufacturing processes. Whilst it is not easy to characterise every variation of a protein structure at present additional analytical technologies need to be utilised to ensure the safety and efficacy of any potential biosimilar product. We have explored the use of Taylor dispersion analysis (TDA) to analyse such batch to batch variations in the model protein, bovine serum albumin (BSA) and compared the results to that obtained by conventional dynamic light scattering analysis (DLS). Inter and intra batch differences were evident in all grades of BSA analysed. However, the reproducibility of the TDA measurements, enabled the stability and reversibility of BSA aggregates to be more readily monitored. This demonstrates that Taylor dispersion analysis is a very sensitive technique to study higher order protein states and aggregation. The results, here, also indicate a correlation between protein purity and the physical behaviour of the samples after heat shocking. Here, the protein with the highest quoted purity resulted in a reduced increase in the measured hydrodynamic radius after heat stressing, indicating that less unfolding/aggregation had occurred. Whilst DLS was also able to observe the presence of aggregates, its bias towards larger aggregates indicated a much larger increase in hydrodynamic radii and is less sensitive to small changes in hydrodynamic radii. TDA was also able to identify low levels of larger aggregates that were not observed by DLS. Therefore, given the potential for immunogenicity effects that may result from such aggregates it is suggested that TDA may be suitable in the evaluating detailed batch to batch variability and process induced physical changes of biopharmaceuticals and biosimilars.

Optimizing launcher trajectories is essential for effective mission planning, and specialized software like ASTOS provide an initial, precise overview. However, as launcher development progresses, there is a growing need for the creation of an autonomous flight trajectory software that offers greaterflexibility in adjusting simulation parameters and better represents actual, real-life trajectories. Thisreport introduces an initial version of a comprehensive six-degree-of-freedom launcher trajectory calculation software developed using MATLAB and Simulink. The emphasis is on the development strategy, encompassing discussions on dynamics equations, essential features, and crucial models necessary for accurate simulations. Real-world scenarios often deviate from optimized trajectories, and the software addresses these deviations using sensitivity analysis through Monte Carlosimulations, enabling a thorough examination of uncertainties in input parameters and their impact on trajectories. The article delves into the establishment of the dispersion analysis tool and offers suggestions for further enhancements for both the Simulink model and this dispersion analysis tool. / Optimering av flygbanor är avgörande för effektiv uppdragsplanering, och specialiserad programvara som ASTOS ger en initial, exakt översikt. Men när flygbanans utveckling fortskrider finns det ett växande behov av att skapa en autonom flygbana som erbjuder större flexibilitet när det gäller attjustera simuleringsparametrar och bättre representerar faktiska, verkliga banor. Den här rapporten introducerar en initial version av en omfattande beräkningsprogramvara utvecklad med MATLAB och Simulink för sex frihetsgraders lanseringsbana. Tyngdpunkten ligger på utvecklingsstrategin, som omfattar diskussioner om dynamikekvationer, väsentliga funktioner och avgörande modeller som är nödvändiga för exakta simuleringar. Scenarier i verkligheten avviker ofta från optimerade banor, och programvaran adresserar dessa avvikelser med känslighetsanalys genom Monte Carlo-simuleringar,vilket möjliggör en grundlig undersökning av osäkerheter i inmatningsparametrar och deras påverkan på banor. Rapporten går in i skapandet av spridningsanalysverktyget och erbjuder förslag till ytterligare förbättringar för både Simulink-modellen och detta dispersionsanalysverktyg.

Orientador: João Carlos Dourado / Resumo: Técnicas sismológicas como Função do Receptor, Análise de Dispersão de Ondas de Superfície, Correlação de ruídos sísmicos e razão espectral H/V são cada vez mais estudadas e utilizadas para o conhecimento geológico da crosta. Sendo possível determinar a composição crustal média e os principais contatos obtidos por fortes contrastes de impedância tais como limite crosta superior e inferior, assim como, limite crosta inferior e manto superior (descontinuidade de Moho). O conhecimento da velocidade de percurso das ondas de um sismo registrados através de uma estação sismográfica fornecem informações, como: o tempo de percurso, relação Vp/Vs e outros. A região de Pontes e Lacerda/MT está localizada no Sudoeste do Cráton Amazônico e o levantamento dos dados se deram em fases distintas com implantação de sismômetros alinhados em direção perpendicular (NE-SW) às principais estruturas da Faixa Móvel Aguapeí (NNW-SSE). Além da coleta de dados dessas estações temporárias foram compilados dados de sismos para a estação fixa PTLB, esta estação faz parte das estações sismológicas coordenadas pela UNB (Universidade Nacional de Brasília) e pela USP (Universidade de São Paulo). A espessura média encontrada na crosta para a região variou pouco para as diferentes técnicas abordadas, sendo que, para a técnica de Função do Receptor (estação fixa PTLB) foi obtido valor de aproximadamente 44 Km de espessura e, para as estações temporárias (S01 ao S10) valor médio de 42 km. Já a seção sísmica gerad... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Seismic techniques such as receiver function, surface wave dispersion, seismic noise correlation and H / V spectral ratio are increasingly studied and used for geological knowledge of the crust. It is possible to determine the average crustal composition and the main contacts obtained by strong impedance contrasts as upper and lower crust boundary, as well as, lower crust limit and upper mantle (Moho discontinuity). The knowledge of the speed of travel of the waves of an earthquake recorded through a seismographic station provides information, such as: the travel time, Vp / Vs ratio and others. The region of Pontes e Lacerda / MT is located in the Southwest of the Amazonian craton and the data were taken in different phases with the implantation of seismometers aligned in a perpendicular direction (NE-SW direction) to the main structures of the Faixa Móvel Aguapeí (direction NNW- SSE). In addition to collecting data from these temporary stations, earthquake data were collected for the PTLB fixed station. The average thickness found in the crust for the region did not vary much for the different techniques, and for the Receiver Function (PTLB fixed station), a value of approximately 44 Km of thickness was obtained and for the temporary stations (S01 to S10) average value of 42 km. The seismic section generated by the correlation of the signals for all short-time temporary stations brought the signals coherence in 4s, 5s and later coherence ranging from 9.5 to 11 seconds. This ... (Complete abstract click electronic access below) / Doutor

La caractérisation et le monitoring des ressources en eau souterraine et des processus d'écoulement et de transport associés reposent principalement sur la mise en place de forages (piézomètres). Mais la variété des échelles auxquelles se déroulent ces processus et leur variabilité dans l'espace et dans le temps limitent l'interprétation des observations hydrogéologiques. Dans un tel contexte, l'hydrogéophysique fait appel aux méthodes de prospection géophysique afin, notamment, d'améliorer la très faible résolution spatiale des données de forage et de limiter leur caractère destructif. Parmi les outils géophysiques appliqués à l'hydrogéologie, les méthodes sismiques sont régulièrement utilisées à différentes échelles. Mais la réponse sismique dans le contexte de la caractérisation des aquifères reste complexe. L'interprétation des vitesses estimées est souvent délicate à cause de leur variabilité en fonction de la lithologie de l'aquifère (paramètres mécaniques intrinsèques et géométrie des milieux poreux le constituant, influence du degré de saturation, etc). La perméabilité du milieu a également un effet sur la géométrie d'un réservoir hydrologique dont les contours peuvent varier en espace comme en temps, compliquant ainsi l'interprétation des données sismiques.Les géophysiciens cherchent à pallier ces limites, notamment à travers l'étude conjointe des vitesses (Vp et Vs) des ondes compression (P) et de cisaillement (S), dont l'évolution est par définition fortement découplée en présence de fluides. D'un point de vue théorique, cette approche se révèle appropriée à la caractérisation de certains aquifères, en particulier grâce à l'estimation des rapports Vp/Vs ou du coefficient de Poisson. L'évaluation de ces rapports peut être pratiquée de manière systématique grâce à la tomographie sismique en réfraction en utilisant parallèlement ondes P et S. Mais d'un point de vue pratique, la mesure de Vs reste délicate à mettre en oeuvre car les ondes S sont souvent difficiles à générer et à identifier sur les enregistrements sismiques. Une alternative est proposée par l’estimation indirecte de Vs à partir de l’inversion de la dispersion des ondes de surface, réalisée à partir de mesures de la vitesse des ondes de surface contenues dans les enregistrements sismiques classiques. Bien que généralement proposée pour la caractérisation de milieux 1D, la prospection par ondes de surface peut être déployée le long de sections linéaires dans le but de reconstruire un modèle 2D de distribution des Vs du sous-sol.Une méthodologie a été mise au point afin d'exploiter simultanément et de façon optimale les ondes P et les ondes de surface à partir des mêmes enregistrements sismiques. Lors de sa mise en oeuvre sur le terrain, cette acquisition « en ondes P » a été systématiquement suivie d'une acquisition « en ondes SH » afin de comparer les vitesses Vs obtenues par analyse de la dispersion des ondes de surface et par tomographie en ondes SH. L'utilisation de cette méthodologie dans différents contextes géologiques et hydrogéologiques a permis d'estimer les variations latérales et temporelles du rapport Vp/Vs, en bon accord avec les informations géologiques a priori et les données géophysiques et piézométriques existantes. L'utilisation de l'interférométrie laser a également permis de mettre ces techniques de traitement en application sur des modèles physiques parfaitement contrôlés afin d'étudier la propagation des ondes élastiques dans des « analogues » réalistes de milieux poreux partiellement saturés. / Characterisation and monitoring of groundwater resources and associated flow and transport processes mainly rely on the implementation of wells (piezometers). The interpretation of hydrogeological observations is however limited by the variety of scales at which these processes occur and by their variability in space and in time. In such a context, using geophysical methods often improves the very low spatial resolution of borehole data and limits their destructive nature. Among the geophysical tools applied to hydrogeology, seismic methods are commonly used at different scales. However, the seismic response in the context of aquifer characterisation remains complex. The interpretation of the estimated velocities is often difficult because of their variability depending on the aquifer lithology (intrinsic mechanical parameters and geometry of the constituting porous media, influence of the degree of saturation, etc). The permeability of the medium also affects the geometry of a hydrological reservoir whose contours may vary in space and in time, thus complicating the interpretation of seismic data. Geophysicists seek to overcome these limitations, especially through the joint study of compression (P-) and shear (S-) wave velocities (Vp and Vs), whose evolution is by definition highly decoupled in the presence of fluids. From a theoretical point of view, this approach proves suitable for the characterisation of aquifers, especially by estimating Vp/Vs or Poisson's ratio. The evaluation of these ratios can be systematically carried out with seismic refraction tomography using both P- and S-waves. However, retrieving Vs remains practically delicate because S-waves are usually difficult to generate and identify on seismic records. As an alternative, indirect estimation of Vs is commonly achieved thanks to surface-wave dispersion inversion, carried out from measurements of surface waves phase velocities contained in typical seismic records. Although it is usually proposed for the characterisation of 1D media, surface-wave prospecting can be deployed along linear sections in order to build 2D models of Vs distribution in the ground. A specific methodology has been developed for the combined and optimised exploitation of P- and surface waves present on single seismic records. When deployed on the field, this "P-wave" acquisition has been systematically followed by a "SH-wave" acquisition in order to compare Vs models obtained from surface-wave dispersion analysis and SH-wave refraction tomography. The use of this methodology in several geological and hydrogeological contexts allowed for estimating Vp/Vs ratio lateral and temporal variations in good agreement with a priori geological information and existing geophysical and piezometric data. Laser-based ultrasonic techniques were also proposed to put these processing techniques in practice on perfectly controlled physical models and study elastic wave propagation in partially saturated porous media.

Multisymplectic integrators like Preissman and six-point schemes and a semi-explicit symplectic method are applied to the coupled nonlinear Schr&ouml / dinger equations (CNLSE). Energy, momentum and additional conserved quantities are preserved by the multisymplectic integrators, which are shown using modified equations. The multisymplectic schemes are backward stable and non-dissipative. A semi-explicit method which is symplectic in the space variable and based on linear-nonlinear, even-odd splitting in time is derived. These methods are applied to the CNLSE with plane wave and soliton solutions for various combinations of the parameters of the equation. The numerical results confirm the excellent long time behavior of the conserved quantities and preservation of the shape of the soliton solutions in space and time.

Thesis is divided into two parts. The first part is written rather in theoretical way. It deals with general formation of the dispersion mathematically and verbally. It focuses on the chromatic and polarization mode dispersion. Different types of optical fibers for category G.65X are mentioned as well in connection with the ITU-T. Further attention is drawn first to compensation and then the measurement both of the mentioned dispersions. The thesis describes also analyzers and their main features. The second part is devoted to practical measurements of polarization mode dispersion. In the beginning there are described the components used for construction of the optical measurements and topologies. It is followed by an analysis of an each optical link. The results of these measurement methods and their mutual comparisons are at the end of this section. Measurements in temperature chamber is the subject of a further practical part, which from the beginning captures the essential features of the temperature chamber. This is followed by a description of the measurements, analyses and final valuation depending on the amount of polarization mode dispersion versus the temperature.

L’imagerie du sous-sol par équations d’onde est une application de l’ingénierie pétrolière qui mobilise des ressources de calcul très importantes. On dispose aujourd’hui de calculateurs puissants qui rendent accessible l’imagerie de régions complexes mais des progrès sont encore nécessaires pour réduire les coûts de calcul et améliorer la qualité des simulations. Les méthodes utilisées aujourd’hui ne permettent toujours pas d’imager correctement des régions très hétérogènes 3D parce qu’elles sont trop coûteuses et /ou pas assez précises. Les méthodes d’éléments finis sont reconnues pour leur efficacité à produire des simulations de qualité dans des milieux hétérogènes. Dans cette thèse, on a fait le choix d’utiliser une méthode de Galerkine discontinue (DG) d’ordre élevé à flux centrés pour résoudre l’équation des ondes acoustiques et on développe un schéma d’ordre élevé pour l’intégration en temps qui peut se coupler avec la technique de discrétisation en espace, sans générer des coûts de calcul plus élevés qu’avec le schéma d’ordre deux Leap-Frog qui est le plus couramment employé. Le nouveau schéma est comparé au schéma d’ordre élevé ADER qui s’avère plus coûteux car il requiert un plus grand nombre d’opérations pour un niveau de précision fixé. De plus, le schéma ADER utilise plus de mémoire, ce qui joue aussi en faveur du nouveau schéma car la production d’images du sous-sol consomme beaucoup de mémoire et justifie de développer des méthodes numériques qui utilisent la mémoire au minimum. On analyse également la précision des deux schémas intégrés dans un code industriel et appliqués à des cas test réalistes. On met en évidence des phénomènes de pollution numériques liés à la mise en oeuvre d'une source ponctuelle dans le schéma DG et on montre qu'on peut éliminer ces ondes parasites en introduisant un terme de pénalisation non dissipatif dans la formulation DG. On finit cette thèse en discutant les difficultés engendrées par l'utilisation de schémas numériques dans un contexte industriel, et en particulier l'effet des calculs en simple précision. / Oil engineering uses a wide variety of technologies including imaging wave equation which involves very large computing resources. Very powerful computers are now available that make imaging of complex areas possible, but further progress is needed both to reduce the computational cost and improve the simulation accuracy. The current methods still do not allow to image properly heterogeneous 3D regions because they are too expensive and / or not accurate enough. Finite element methods turn out to be efficient for producing good simulations in heterogeneous media. In this thesis, we thus chose to use a high order Discontinuous Galerkin (DG) method based upon centered fluxes to solve the acoustic wave equation and developed a high-order scheme for time integration which can be coupled with the space discretization technique, without generating higher computational cost than the second-order Leap Frog scheme which is the most widely used . The new scheme is compared to the high order ADER scheme which is more expensive because it requires a larger number of computations for a fixed level of accuracy. In addition, the ADER scheme uses more memory, which also works in favor of the new scheme since producing subsurface images consumes lots of memory and justifies the development of low-memory numerical methods. The accuracy of both schemes is then analyzed when they are included in an industrial code and applied to realistic problems. The comparison highlights the phenomena of numerical pollution that occur when injecting a point source in the DG scheme and shows that spurious waves can be eliminated by introducing a non-dissipative penalty term in the DG formulation. This work ends by discussing the difficulties induced by using numerical methods in an industrial framework, and in particular the effect of single precision calculations.