Content: ZnO nanoparticles were developed by 1:2 ratios of Zinc sulphate heptahydrate and Sodium hydroxide by using precipitation method. The structure, morphology of ZnO nanoparticles were investigated by using XRay Diffraction, Scanning Electron Microscopy and Transmission electron Microscopy. X-Ray Diffraction confirms the formation and average crystallite size of ZnO nanoparticles. Scanning Electron Microscopy studies shows the ZnO nanoparticles were in spherical in structure. These ZnO nanoparticles were used in different ratios along with conventional finishing formulations and coated on the leather surface. The performance properties such as water fastness, rub fastness and flexing resistance were evaluated. Application of ZnO nanoparticles in leather finishing showed significant improvement in overall performance properties than conventional finishing formulations. XRD confirms the formation of ZnO nanoparticles (wurtzite structure) at 36.67° (101) plane and the particles size was in the range of 43 nm. SEM image shows that the particles are in the spherical structure wheras EDAX investigate the stoichiometry and chemical purity of the samples to confirm the presence of zinc and oxygen. Optimum quantity up to 2-5 g/L of the season of ZnO nanoparticle is desirable for upgrading the value of leathers by improving color fastness to water, rub fastness and flexing resistance (wet & dry) properties significantly in cationic (wet), NC lacquer emulsions and PU top coat dispersions in finishing formulations. Take-Away: Optimum quantity up to 2-5 g/L of the season of ZnO nanoparticle is desirable for upgrading the value of leathers by improving color fastness to water, rub fastness and flexing resistance (wet & dry) properties significantly in cationic (wet), NC lacquer emulsions and PU top coat dispersions in finishing formulations.

Cancer is the second leading cause of death and is responsible for approximately 9.6 million deaths worldwide in 2018. Among all oncological diseases, lung cancer claims the highest mortality (male: 23.5%; female: 22%) and the second most new cases (male: 13%; female: 12%) in the US. Approximately 40% of newly diagnosed lung cancer patients are in the advanced stage IV, for which platinum-based chemotherapy is the first-line treatment, either by itself or in combination with surgery or radiotherapy. Cisplatin, the first-generation platinum-based anticancer chemotherapeutic agent, has the highest potency against lung cancer but carries many severe adverse effects. Cisplatin also induces drug resistance during long-term chemotherapy. Many more platinum complexes have been investigated as better alternatives, which led to the approval of carboplatin and oxaliplatin by Food and Drug Administration (FDA). In addition, miriplatin suspended in iodolipds (lipiodolization) was approved in Japan for the treatment of hepatocellular carcinoma (HCC) in 2009. Miriplatin has the same non-leaving group as oxaliplatin but different leaving groups of two myristate chains, which make it highly lipophilic. Several characteristics of solid tumors in lung cancer constitute a physiochemical barrier to the homogenous distribution and deep penetration of chemotherapy agents. Nanocarriers provide a promising platform to overcome the physiochemical barrier and to reduce the systemic toxicity of anticancer chemotherapy. In this study, miriplatin is formulated with various lipid-based nanocarriers including micelles and solid lipid nanoparticles (SLNs) thanks to its highly lipophilic structure. The goal of this thesis is to develop and evaluate miriplatin-loaded nano formulations against lung cancer. Miriplatin-loaded formulations were prepared by different methods, including thin film hydration and several scale-up methods including chloroform dripping, chloroform injection, chloroform evaporation, co-solvent evaporation, chloroform slow evaporation and co-solvent slow evaporation. Between the two types of nano formulations under this study, micelles were much smaller (~10 nm in diameter) and more homogeneous (PDI < 0.3), while SLNs were bigger (~ 100 nm in diameter) and more heterogeneous (PDI ~0.8). A quantification method of miriplatin was established using inductively coupled plasma-optical emission spectrometry (ICP-OES). The quantification of platinum recovery from different miriplatin-loaded nano formulations was facilitated by digestion with 70% nitric acid and heating. The co-solvent slow evaporation method to prepare miriplatin-loaded nano formulations improved the platinum recovery prominently from 10% to 70%. Thus, co-solvent slow evaporation has been established as a pharmaceutically viable scale-up method to prepare nano formulations of miriplatin. Miriplatin-loaded nano formulations of different compositions were negatively stained with uranyl acetate and then imaged by transmission electron microscopy (TEM), which showed the formulations’ size and morphology that were consistent with the size and PDI data from dynamic light scattering studies by the Malvern Zetasizer. In the TEM studies, micelles showed a morphology of spherical dots at around 10 nm in diameter while SLNs showed both spherical and rod structures with a size distribution from 50 to 150 nm. A three-dimensional multicellular spheroid (3D MCS) model of A549-iRFP cells was used for in vitro evaluation of the nano formulations’ activity against lung cancer. A549-iRFP cells were engineered from the common lung cancer cell line A549 to stably express the near-infrared fluorescent protein (iRFP). The viability of A549-iRFP 3D MCS after exposure to cisplatin or nano formulations was similar to A549 3D MCS. The anticancer activity of miriplatin-loaded nano formulations against 3D MCS was positively associated with the platinum recovery as quantified by ICP-OES. The miriplatin-loaded nano formulations that had been prepared by the co-solvent slow evaporation method showed substantial anticancer activities against A549 3D MCS and A549-iRFP 3D MCS, which were comparable to cisplatin. Taken together, miriplatin-loaded nano formulations were successfully prepared by co-solvent slow evaporation. The formulations were developed to carry favorable physiochemical properties to enhance the activities of platinum drugs against lung cancer.

This work focuses on the effects of formulation and manufacturing as it effects protein structure and physical stability. Using common physical characterization techniques, X-ray photoelectron spectroscopy, and solid-state hydrogen/deuterium exchange with mass spectrometry, correlations are identified between these results and accelerated stability studies.

No description available.

No description available.

<p dir="ltr">Spatial heterogeneity is ubiquitous across life and the universe; the same is true for phase-separating pharmaceutical formulations, cells, and tissues. To interrogate these spatially-varying complicated samples, simple analysis techniques such as fluorescence recovery after photobleaching (FRAP) can provide information on molecular transport. Conventional FRAP approaches localize analysis to small spots, which may not be representative of trends across the full field of view.</p><p dir="ltr">Taking advantage of strategies used for structures illumination, an approach has been developed to use patterned illumination in combination with FRAP for probing large fields of view while representatively sampling. Patterned illumination is used to establish a concentration gradient across a sample by irreversibly photobleaching fluorophores, such as with the simple comb pattern photobleach presented in Chapters 1 and 4. Patterned photobleaching allows spatial Fourier-domain analysis of multiple spatial harmonics simultaneously. In the spatial FT-domain the real-space photobleach signal is integrated into puncta, greatly increasing the signal to noise ratio compared to conventional point-bleach FRAP. The order of the spatial harmonic is directly related to the length-scale of translational diffusion measured, with a series of harmonics accessing diffusion over many length scales in a single experiment. Measurements of diffusion at multiple length scales informs on the diffusion mechanism by sensitively reporting on deviations away from normal diffusion.</p><p dir="ltr">Complementing the physical hardware for inducing patterned illumination, this dissertation introduces novel algorithms for reconstructing spatially-resolved diffusion maps in heterogeneous materials by combining Fourier domain analysis with patterned photobleaching. FT-FRAP is introduced in Chapter 1 for interrogating phase-separating samples using beam-scanning instrumentation for comb-bleach illumination. This analysis allowed disentangling separate contributions to diffusion from normal bulk diffusion and an interfacial exchange mechanism only available due to multi-harmonic analysis. The introduction of a dot-array bleach pattern using widefield microscopy is presented in Chapter 2 for high-throughput detection of mobility in simple binary systems as well as for segmentation in phase-separating pharmaceutical formulations. The analysis becomes more complicated as more components are added to the system such as a surfactant. Introduced in chapter 3, FT-FRAP with dot-array photobleaching was shown to be useful for characterizing diffusion of phase-separating micro-domain smaller than a single pixel of the camera. Supported by simulations, a biexponential fitting model was developed for quantification of diffusion by multiple species simultaneously. Chapter 4 introduces imaging inside of 3D particles comprised of an active pharmaceutical ingredient (API) in microencapsulated agglomerates which exhibited strong interfacial exchange. Multi-photon excited fluorescence enabled imaging a small focal volume within the particles.</p>

Microscopic simulation software use car-following models to capture the interaction of a vehicle and the preceding vehicle traveling in the same lane. In the literature, much research has been carried out in the field of car-following and traffic stream modeling. Microscopic car-following models have been characterized by using the relationship between a vehicle's desired speed and the distance headway (h) between the lead and follower vehicles. On the other hand, macroscopic traffic stream models describe the motion of a traffic stream by approximating for the flow of a continuous compressible fluid. This research work develops and compares three different formulations of car-following models — speed formulation, molecular acceleration, and fluid acceleration formulation. First, four state-of-the-art car-following models namely, Van Aerde, Greenshields, Greenberg and Pipes models, are selected for developing the three aforementioned formulations. Then a comprehensive car-following behavior encompassing steady-state conditions and two constraints — acceleration and collision avoidance — is presented. Specifically, the variable power vehicle dynamics model proposed by Rakha and Lucic (2002) is utilized for the acceleration constraint. Subsequently, the thesis describes the issues associated with car-following formulations. Recognizing that many different traffic flow conditions exist, three distinct scenarios are selected for comparison purposes. The results demonstrate that the speed formulation ensures that vehicles typically revert to steady-state conditions when vehicles experience a perturbation from steady-state conditions. On the other hand, both acceleration formulations are unable to converge to steady-state conditions when the system experiences a perturbation from a steady-state. The thesis also attempts to address the question of capacity drop associated with vehicles accelerating from congested conditions. Specifically, the capacity drop proposition is analyzed for the case of a backward recovery (typical of a signalized intersection) and stationary shockwave (typical of a capacity drop on a freeway). In the case of the backward recovery shockwave, the acceleration constraint results in a temporally and spatially confined capacity drop as vehicles accelerate to their desired steady-state speed. This temporally and spatially confined capacity drop results in what is typically termed the start loss of a signalized phase. Subsequently, vehicles attain steady-state conditions, in the case of the speed and molecular acceleration formulations, at the traffic signal stop bar after the initial five vehicle departures. The analysis also demonstrates that after attaining steady-state conditions the capacity may drop for the initial vehicle departures as a result of traffic stream dispersion. This traffic dispersion capacity drop increases as vehicles travel further downstream. Alternatively, in the case of a stationary bottleneck the aggressiveness of vehicle accelerations plays a major role in defining the capacity drop downstream of a bottleneck. The study demonstrates that any temporal headways that may be lost while vehicles accelerate to steady-state conditions may not be recuperated and thus result in capacity drops downstream of a bottleneck. A typical example of this scenario is the traffic stream flow rate downstream of a stop sign, which is significantly less than the roadway capacity. The reduction in capacity is caused by losses in temporal headways between successive vehicles which are not recuperated. The study also demonstrates that the ability to model such a capacity drop does not require the use of a dual-regime traffic stream model as is proposed in the Highway Capacity Manual (HCM). Instead, the use of a single-regime model captures the observed capacity with the introduction of an acceleration constraint to the car-following system of equations. / Master of Science

Les machines électriques sont modélisées pour prédire leurs performances et optimiser leur rendement. Cette modélisation peut être faite par des simulations avec la méthode des éléments finis. En particulier, les machines asynchrones nécessitent des simulations 3D pour prendre en compte les courants de Foucault et les têtes de bobines. Dans le logiciel Flux®, des formulations 3D basées sur le potentiel scalaire magnétique sont utilisées avec succès depuis de nombreuses années. Néanmoins, des coupures mathématiques artificielles sont nécessaires, lorsque le domaine n'est pas simplement connexe.Afin de se libérer de ces contraintes de connexité, des formulations en potentiel vecteur magnétique ont été étudiées et développées. En 3D, leur mise en œuvre nécessite l'utilisation d'éléments finis d'arêtes afin de respecter la nature des champs. Avec les éléments d'arêtes, les formulations sont généralement résolues avec une condition de jauge pour les solveurs directs comme pour les solveurs itératifs. De nouvelles formulations en potentiel vecteur magnétique auto-jaugées ont été développées permettant la prise en compte des bobines maillées et des bobines non maillées. La prise en compte du mouvement est relativement simple à mettre en œuvre pour les formulations en potentiel scalaire magnétique avec l'interpolation nodale.Avec les éléments d'arête, l'interpolation est plus délicate. C'est pourquoi la méthode des éléments avec joints a été développée pour prendre en compte le mouvement dans un cas général. / Electric machines are modeled in order to predict their performance and to optimize their output. This modeling can be done by simulation with the finite element method. In particular, induction machines require 3D simulation to take into account eddy currents and coils overhangs. In the Flux® software, 3D formulations based on magnetic scalar potential has been used with success for many years. Nevertheless, artificial mathematical cuts are necessary, when the domain is not simply connected.In order to avoid connection constraints, magnetic vector potential formulations have been studied and developed. In 3D, their implementation requires the use of edge elements to respect the nature of fields. With edge elements, formulations are generally solved with a gauge condition for direct solvers as well as for iterative solvers. New auto-gauged magnetic vector potential formulations have been developed to take into account meshed coils and non-meshed coils. Consideration of movement is relatively simple to implement for magnetic scalar potential formulations with nodal interpolation. With edge elements, the interpolation is more delicate. For this reason, the mortar method has been developed to take into account movement in a general case.

Notre thèse s’inscrit dans le cadre des langages contrôlés pour le génie logiciel. Elle a pour but de faciliter l’adoption de l’approche par règles métier (ARM) par les entreprises en créant un langage contrôlé en vue d’aider à la spécification des règles métier par les experts métier. Notre solution va permettre de réduire la distance sémantique entre les experts métier et les experts système afin de répondre non seulement au besoin d’intercompréhension entre ces derniers mais aussi pour réaliser un transfert automatique de la description des règles métier vers les systèmes d’information (SI). Ce langage contrôlé que nous avons créé permettra d’assurer en plus la consistance et la traçabilité de ces règles avec leur implantation / Our thesis focuses on controlled natural languages (CNL) for software engineering. It aims at facilitating the adoption of the business rule approach (BRA) by companies by creating a CNL in order to help business experts in the specification of their business rules. Our solution will allow reducing the semantic gap between business experts and system experts to meet not only the need for mutual understanding between them but also to achieve an automatic transfer of the description of business rules to information systems (IS). The CNL that we have created will also ensure the consistency and the traceability of these rules together with their implementation

High throughput screening techniques that are routinely used in modern drug discovery processes result in a higher prevalence of poorly water-soluble drugs. Such drugs often have poor bioavailability issues due to their poor dissolution and/or permeability to achieve sufficient and consistent systemic exposure, resulting in sub-optimal therapeutic efficacies, particularly via oral administration. Alternative formulations and delivery routes are demanded to improve their bioavailability. Nanoparticulate formulations of poorly water-soluble drugs offer improved dissolution profiles. The physiology of the lung makes it an ideal target for non-invasive local and systemic drug delivery for poorly water-soluble drugs. In Chapter 2, a particle engineering process ultra-rapid freezing (URF) was utilized to produce nanostructured aggregates of itraconazole (ITZ), a BCS class II drug, for pulmonary delivery with approved biocompatible excipients. The obtained formulation, ITZ:mannitol:lecithin (1:0.5:0.2, w/w), i.e. URF-ITZ, was a solid solution with high surface area and ability to achieve high magnitude of supersaturation. An aqueous colloidal dispersion of URF-ITZ was suitable for nebulization, which demonstrated optimal aerodynamic properties for deep lung delivery and high lung and systemic ITZ levels when inhaled by mice. The significantly improved systemic bioavailability of inhaled URF-ITZ was mainly ascribed to the amorphous morphology that raised the drug solubility. The effect of supersaturation of amorphous URF-ITZ relative to nanocrystalline ITZ on bioavailability following inhalation was evaluated in Chapter 3. The nanoparticulate amorphous ITZ composition resulted in a significantly higher systemic bioavailability than for the nanocrystalline ITZ composition, as a result of the higher supersaturation that increased the permeation. In Chapter 4, pharmacokinetics of inhaled nebulized aerosols of solubilized ITZ in solution versus nanoparticulate URF-ITZ colloidal dispersion were investigated, under the hypothesis that solubilized ITZ can be absorbed faster through mucosal membrane than the nanoparticulate ITZ. Despite similar ITZ lung deposition, the inhaled solubilized ITZ demonstrated significantly faster systemic absorption across lung epithelium relative to nanoparticulate ITZ in mice, due in part to the elimination of the phase-to-phase transition of nanoparticulate ITZ. / text