Résumé confidentiel / Résumé confidentiel

Le Lebanese Atomic Energy Commission (LAEC) poursuit un programme de développement des techniques analytiques pour compléter l’analyse par faisceau d’ions (IBA). Il a décidé de s’équiper d’un spectromètre de masse couplée à l’imagerie 2D puis récemment 3D avec l’acquisition d’un spectromètre de masse IONTOF V™ équipé de deux colonnes ioniques délivrant des faisceaux d’agrégats de bismuth et d’argon. Dans ce cadre, mon sujet de thèse a porté sur l'optimisation de l’instrument nouvellement acquis pour l’analyse d’échantillons contenant des composés organiques. Les premiers sujets de recherche sont la mise au point du protocole d’analyse quantitative de médicaments en utilisant la technique « cluster-SIMS-imaging » et l’analyse de la météorite Paris pour localiser la matière organique et déterminer sa composition. Dans les deux cas une approche multi-technique a été utilisée : IBA au LAEC, µ-Raman et µ-IR autour des équipements de Soleil et µPIXE réalisée auprès de l’accélérateur AGLAE (Centre de recherche et de restauration des musées de France, C2RMF).L’analyse de médicaments a été initiée au Liban en collaboration avec un fabricant local de produits pharmaceutiques (Mediphar Laboratories) dans le but d’établir de nouveaux procédés de contrôle qualité de produits finis. Mon étude a montré la complexité du dosage de médicament due à la présence de plusieurs molécules actives (Principe Actif, PA) et de substances organiques et minérales inactives (excipients) mélangées dans des conditions secrètes. Les effets de matrice sont dominants et modifient l’émission ionique conduisant à des erreurs systématiques importantes. Cette complexité a été analysée avec l’étude du Fludinium™ possédant deux PAs. Les résultats de cette étude ont permis d’obtenir la première courbe d’étalonnage du rapport des deux PAs et de quantifier ceux-ci dans les conditions du médicament commercial. Le protocole pour effectuer cette courbe d’étalonnage et les contrôles « qualité » ont été déterminés. Ceux-ci incorporeront une analyse en profil pour contrôler l’homogénéité des échantillons et l’obtention d’étalons produits par le fabricant en suivant ses processus de fabrication. En effet, les expériences ont montré que la réalisation du médicament en laboratoire à partir de ses éléments (PAs et excipients) ne donnait pas la même réponse ionique que le médicament commercial. L’analyse de la météorite Paris a été initiée par une collaboration avec une équipe de l’Institut d’Astrophysique Spatial d’Orsay impliquée dans l’exobiologie et la recherche des premières molécules pré-biotiques dans des échantillons extraterrestres. Le but des recherches est de caractériser la matière organique représentant quelques pourcents en poids dans une matrice minérale complexe, sans utiliser des méthodes chimiques pouvant induire une modification de ces molécules. Cette étude a démontré l’intérêt de l’approche multi-technique centrée autour de la spectrométrie de masse couplée à l’imagerie ionique pour déterminer les éléments principaux de la matrice minérale et organique. L’analyse par µPIXE avec une cartographie micrométrique a permis d’attribuer les distributions d’ions moléculaires et agrégats des spectres de masse aux différents composés minéraux. Ces attributions se poursuivent avec la constitution d’une base de données de spectres de référence. La composante organique a été extraite et les premières hypothèses de composition ont été envisagées autour des HAPs (Hydrocarbure Aromatique Polycyclique), MOI (Matière Organique Insoluble) et analogues de carbone amorphe produits par irradiation UV de glaces dont les compositions en gaz représentent différentes hypothèses pour les nuages interstellaires. Les protocoles d’analyses multi-techniques établis (incorporant un suivi de l’échantillon par spectrométrie de masse et imagerie ionique) permettent le démarrage d’analyse d’autres échantillons extra-terrestres collectés sur terre ou dans l’espace. / The Lebanese Atomic Energy Commission (LAEC) is incorporated in a development program of the analytical techniques in order to complete the Ion Beam Analysis (IBA). It was decided to get a mass spectrometer coupled to 2D and recently to 3D imaging, by acquiring an ION TOFVTM system equipped with two ionic columns delivering bismuth and argon cluster beams.In this context, my thesis is focused on the optimization of the instrument, recently purchased, for the analysis of samples containing organic compounds. The first subjects of research are the development of a protocol for quantitative analysis of drugs using the « cluster-SIMS-imaging » technique and the Paris meteorite analysis to determine its composition and to localize the organic matter. In the last case a multi-techniques approach was used : IBA in LAEC, µ-Raman et µ-IR around the Soleil synchrotron equipments and µPIXE carried with the AGLAE accelerator (Centre de recherche et de restauration des musées de France, C2RMF).The drug analysis was initiated in Lebanon in collaboration with a local pharmaceutical manufacturer (Mediphar Laboratories) in order to establish new processes for quality control of the final products. My study showed the complexity of the drug quantification which is due to the presence of several active ingredients (AI) and inactive organic and minerals components (excipients) mixed in secret conditions. Matrix effects are dominant and modify the ionic emission leading to significant systematic errors. This complexity has been analyzed with the study of FludiniumTM with two active ingredients. The results of this study allowed to obtain the first calibration curves of the ratio between the two AIs and to quantify them in the commercial drug. The protocol to perform the calibration curve and the « quality» controls were determined. These incorporate a profile analysis to control the homogeneity of the samples and the obtaining standards produced by the pharmaceutical manufacturer following the same process used for the commercial drug. Indeed, the experiments have shown that the preparation of the drug in the laboratory from its elements (AIs and excipients) doesn’t give the same ionic emission as for the commercial drug.The Paris meteorite analysis was initiated by a collaboration with the Institut d’Astrophysique Spatiale d’Orsay team involved in the exobiology and the research of the first prebiotic molecules in the extraterrestrial samples. The work objective is to characterize the organic matter representing few percents in mass in a complex mineral matrix, without any chemical extraction that can induce a modification of these molecules. This study has demonstrated the interest of the multi-techniques approach centered on the mass spectrometry coupled to the ionic imaging for the determination of the main mineral and organic elements of the matrix. µPIXE analysis coupled to the micrometric mapping permits to attribute the distribution of molecular ions and clusters of the mass spectra with different mineral compounds. These attributions continue with the creation of the data base of standard spectra. The organic component was determined and the first hypotheses were considered concerning PAHs (Polycyclic Aromatic Hydrocarbon), IOM (Insoluble Organic Matter) and analogues of amorphous carbon produced par UV irradiation of ices with a gas composition representing different hypotheses for the interstellar clouds. The establish protocols for multi-techniques (incorporating a follow of the sample by mass spectrometry and ion imaging) permits to start the analysis of other extra terrestrial samples collected on earth or in space.

The mechanochemical polycondensation between a diamine and a dialdehyde constitutes a sustainable alternative to classical solvent-based polymerization reactions. This process not only allows for a higher conversion and a shorter reaction time as compared to standard solvent-based syntheses of this conjugated polymer, but the reaction can also be adjusted by the energy introduced via the ball mill.

The thesis deals with research of pulse compression of the acoustic signal in terms of applications in civil engineering. Based on the study and analysis of these methods, automated measuring equipment for non-destructive testing with pseudorandom sequence of maximum length and automated signal analysis, have been designed and implemented. In a single test cycle are obtained three parameters that characterize the linear and nonlinear behavior of the sample. A nonlinear parameter, Time of Flight of ultrasonic wave in the sample is further in the work compared with the conventional pulse measuring, and spectral analysis is compared with the method impact-echo. Functionality and optimization of the testing method was performed on a total of three sets of test pieces made of various building materials. The experiments proved simple result interpretation, and high sensitivity to structural damage associated with temperature loading. The results were correlated with conventional nondestructive methods and by destructive testing was measured change in compressive strength and flexural strength. This work also includes continual measurement of fundamental frequency influenced by moisture on a mortar sample. Use of pulse compression signal is in the civil engineering quite unusual. Only in recent years this topic is discussed in scientific articles with increasing frequency. Great potential lies in the association of three test methods into a single. Beneficial is high test speed and measurement reproducibility, but also theoretical possibility of testing massive test elements.

The research presented in this dissertation is focused on the construction of complex molecular structures on planar gold and silicon dioxide surfaces using a variety of surface modification techniques, along with thorough surface characterization at each modification step. The dissertation is structured into six separate chapters. In Chapter 1, an introduction to the importance and implications of molecular level surface modification, commonly employed surface modification methods, and available surface characterization techniques is presented. Chapter 2 shows applications of novel methodologies for the functionalization of gold surfaces using alkane dithiol self-assembled monolayers and thiol-ene click chemistry. The resulting functionalized gold substrates demonstrate higher chemical stability than alkanethiol self-assembled monolayers alone and allow spatially controlled functionalization of gold surfaces with light. In Chapter 3, work on tunable hydrophobic surfaces is presented. These surfaces are prepared using a combination of organosilane chemistry, layer-by-layer polyelectrolyte deposition, and thiol-ene chemistry. These hydrophobic surfaces demonstrate high mechanical and chemical stability, even at low pH (1.68). The pinning of water droplets could be tuned on them by the extent of their thermal treatment. Comprehensive surface characterization using X-ray photoelectron spectroscopy (XPS), time-of-flight secondary ion mass spectrometry (ToF-SIMS), spectroscopic ellipsometry, atomic force microscopy, and water contact angles was carried out on the molecular assemblies prepared on gold and silicon dioxide surfaces. Chapters 4 and 5 are focused on the application, data interpretation, and enhancement in sensitivity of different surface characterization methods. In Chapter 4, XPS, ToF-SIMS, and principal components analysis are used to probe a real world corrosion-type problem. This systemic study showed the destruction of a protective coating composed of a nitrilotris(methylene)triphosphonic acid by a low-intensity fluorine plasma. In Chapter 5, enhancement in ToF-SIMS signals is shown via bismuth metal deposition. These surfaces are also probed by spectroscopic ellipsometry using the interference enhancement method. Finally, Chapter 6 concludes this dissertation by describing possible future work.

Anthropogenic emissions into the troposphere can impact air quality, leading to poorer health outcomes in the affected areas. Volatile organic compounds (VOCs) are a group of chemical compounds, including some which are toxic, that are precursors in the formation of ground-level ozone and secondary organic aerosols. VOCs have a variety of sources, and the distribution of atmospheric VOCs differs significantly over time and space. Historically, the large number of chemical species present at low concentrations (parts-per-trillion to parts-per-billion by volume) have made VOCs difficult to measure in ambient air. However, with improvements in analytical instrumentation, these measurements are becoming more common place. Direct mass spectrometry (MS), such as membrane introduction mass spectrometry (MIMS) and proton-transfer reaction time-of-flight mass spectrometry (PTR-ToF-MS) facilitate real-time, continuous measurements of VOCs in air, with full scan mass spectral data capturing changes in chemical composition with high temporal resolution. Operated on-road, mobilized direct MS has been used for quantitative mapping of VOCs at the neighborhood scale, but identifying VOC sources based on the observed mixture of molecules in the full scan MS dataset has yet to be explored. This dissertation describes the use of chemometric techniques to interrogate full scan MS data, and the progression from discriminating VOC samples of known chemical composition based on full scan MIMS data through to the apportionment of VOC sources measured continuously with a PTR-ToF-MS system operating in a moving vehicle. Lab‐constructed VOC samples of known chemical composition and concentration demonstrated the use of principal component analysis (PCA) to discriminate, and k-nearest neighbours to classify, samples based on normalized full scan MIMS data. Furthermore, multivariate curve resolution-alternating least squares (MCR-ALS) was used to resolve mixtures into molecular component contributions. PCA was also used to discriminate ‘real-world’ VOC mixtures (e.g., woodsmoke VOCs, headspace above aqueous hydrocarbon samples) of unknown chemical composition measured by MIMS. Using vehicle mounted MIMS and PTR-ToF-MS systems, full scan MS data of ambient atmospheric VOCs were collected and PCA was applied to the normalized full scan MS data. A supervised analysis performed PCA on samples collected near known VOC sources, while an unsupervised analysis using PCA followed by cluster analysis was used to identify groups in a continuous, time series PTR-ToF-MS dataset measured between Nanaimo and Crofton, British Columbia (BC). In both the supervised and unsupervised analysis, samples impacted by emissions from different sources (e.g., internal combustion engines, sawmills, composting facilities, pulp mills) were discriminated. With PCA, samples were discriminated based on differences in the observed full scan MS data, however real-world samples are often impacted by multiple VOC sources. MCR-weighted ALS (MCR-WALS) was applied to the continuous, time series PTR-ToF-MS data from three field campaigns on Vancouver Island, BC for source apportionment. Variable selection based on signal-to-noise ratios was used to reduce the mass list while retaining the observed m/z that capture changes in the mixture of VOCs measured, improving model results, and reducing computation time. Both point (e.g., anthropogenic hydrocarbon emissions, pulp mill emissions) and diffuse (e.g., VOCs from forest fire smoke) VOC sources were identified in the data, and were apportioned to determine their contributions to the measured samples. The data analyzed captured fine scale changes in the ambient VOCs present in the air, and geospatial maps of each individual source, and of the source apportionment were used to visualize the distribution of VOC sources across the sampling area. This work represents the first use of MCR-WALS to identify and apportion ambient VOC sources based on continuous PTR-ToF-MS data measured from a moving vehicle. The methods described can be applied to larger scale field campaigns for the source apportionment of VOCs across multiple days to capture diurnal and seasonal variations. Identifying spatial and temporal trends in the sources of VOCs at the regional scale can help to identify pollution ‘hot spots’ and inform evidence-based public policy for improving air quality. / Graduate / 2022-08-17

Die Systematische Toxikologische Analyse (STA) stellt auf Grund der großen Vielfalt und der ständigen Zunahme an toxikologisch relevanten Substanzen eine der größten Herausforderungen in der chemischen Analyse dar. In der vorliegenden Arbeit wurde daher die Eignung der Flüssigchromatographie in Kombination mit der Hybrid-Quadrupol-Flugzeitmassenspektrometrie (LC-QTOF-MS) für diesen Zweck untersucht. Dazu wurden eine Datenbank mit über 7360 und eine CID-Spektrenbibliothek mit mehr als 2720 toxikologisch relevanten Substanzen erstellt und geeignete Probenvorbereitungsmethoden entwickelt. Die Erprobung der Methoden erfolgte an dotierten Blut- und Haarproben. Hierbei zeigte sich, dass die Analyse im Auto-MS/MS-Modus (Messzyklen von MS- und MS/MS-Spektren) eine Identifizierung basischer Substanzen mittels CID-Spektren zwischen 0,5 und 2 ng/ml im Blut ermöglichte. Die Nachweisgrenzen der für 24 Wirkstoffe validierten Methode in Haaren lagen bei 3 bis 15 pg/mg. Die Eignung der LC-QTOF-MS zur STA von Haarproben wurde an 30 Drogentodesfällen und 60 Todesfällen mit bekannter chronischer Medikamenteneinnahme zu Lebzeiten sowie an 77 Blutproben nachgewiesen. Für die Suche nach Metaboliten wurde ein Metaboliten-Tool entwickelt. In der praktischen Anwendung auf Datenfiles von Blut- und Haarproben erwies sich das Tool als wertvolles Hilfsmittel zur Identifizierung unbekannter Peaks und zur Bestätigung von Suchergebnissen in der Datenbank. Zur automatischen Konzentrationsabschätzung identifizierter Substanzen wurde ein Tool „Estimate Concentration“ geschaffen. Die Überprüfung des Verfahrens an realen Blut- und Haarproben durch Vergleich mit HPLC-DAD- und GC-MS-Ergebnissen wies eine gute Übereinstimmung der Konzentrationen auf. Insgesamt zeigten die Untersuchungen, dass die LC-QTOF-MS zurzeit die am besten geeignete Methode für die STA darstellt. Auch bei einem erst später aufkommenden Verdacht kann eine gezielte Suche in dem bereits gemessenen Datenfile durchgeführt werden. / Due to the large variety and the steady increase of toxicologically relevant substances, systematic toxicological analysis (STA) is one of the most difficult tasks in analytical chemistry and, therefore, a steady topic of research and methodical improvement. For this reason, the suitability of liquid chromatography in combination with hybrid quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) for STA was investigated. For this purpose, a database of more than 7360 and a CID spectra library of more than 2720 toxicologically relevant substances and suitable methods for sample preparation were developed. The application was evaluated at spiked blood and hair samples. It was found that the analysis in Auto-MS/MS mode (alternating measurement cycles of MS and MS/MS spectra) allowed substance identification in blood using CID spectra between 0.5 and 2 ng/ml for basic substances. The detection limits of the validated method in hair ranged from 3 to 15 pg/mg for 24 drugs. The suitability of LC-QTOF-MS for STA was tested for hair samples from 30 drug-related death cases and from 60 death cases with known chronic medication as well as for 77 blood samples. For the search of metabolites, a metabolite tool was developed. In the practical application to data files from blood and hair samples, the tool proved to be very helpful for identification of unknown peaks and for confirmation of results obtained only from the database without CID spectra. A tool "Estimate Concentration" was created for automatic estimation of concentrations of identified substances. The application to real blood and hair samples and the comparison of the concentrations with results from HPLC-DAD and GC-MS showed good agreement. Overall, these investigations showed that LC-QTOF-MS is currently the most favorable method for STA. Because of the comprehensive registration of all substances in a sample, the data files can be checked for the presence of certain poisons even later without new measurements.

In the last 10-15 years there has been a renewed interest in amorphous Se (a-Se) and its alloys due to their application as photoconductor materials in the new fully digital direct conversion flat panel x-ray medical image detectors. For a number of reasons, the a-Se photoconductor layer in such x-ray detectors has to be operated at very high electric fields (up to 10 Volts per micron) and one of the most difficult problems related to such applications of a Se is the problem of the dark current (the current in the absence of any radiation) minimization in the photoconductor layer. <p>This PhD work has been devoted to researching the possibilities for dark current minimization in a-Se x-ray photoconductors devices through a systematic study of the charge transport (carrier mobility and carrier lifetimes) and dark currents in single and multilayered a-Se devices as a function of alloying, doping, deposition condition and other fabrication factors. The results of the studies are extensively discussed in the thesis. We have proposed a new technological method for dark current reduction in single and multilayered a-Se based photoconductor for x-ray detector applications. The new technology is based on original experimental findings which demonstrate that both hole transport and the dark currents in a-Se films are a very strong function of the substrate temperature (Tsubstrate) during the film deposition process. We have shown that the new technique reduces the dark currents to approximately the same levels as achievable with the previously existing methods for dark current reduction. However, the new method is simpler to implement, and offers some potential advantages, especially in cases when a very high image resolution (20 cycles/mm) and/or fast pixel readout (more than 30 times per second) are needed. <p>Using the new technology we have fabricated simple single and double (ni-like) photoconductor layers on prototype x-ray image detectors with CCD (Charge Coupled Device) readout circuits. Dark currents in the a-Se photoconductor layer were not a problem for detector operation at all tested electric fields. Compared to the currently available commercial systems for mammography, the prototype detectors have demonstrated an excellent imaging performance, in particular superior spatial resolution (20 cycles/mm). Thus, the newly proposed technology for dark current reduction has shown a potential for commercialization.

In the last 10-15 years there has been a renewed interest in amorphous Se (a-Se) and its alloys due to their application as photoconductor materials in the new fully digital direct conversion flat panel x-ray medical image detectors. For a number of reasons, the a-Se photoconductor layer in such x-ray detectors has to be operated at very high electric fields (up to 10 Volts per micron) and one of the most difficult problems related to such applications of a Se is the problem of the dark current (the current in the absence of any radiation) minimization in the photoconductor layer. <p>This PhD work has been devoted to researching the possibilities for dark current minimization in a-Se x-ray photoconductors devices through a systematic study of the charge transport (carrier mobility and carrier lifetimes) and dark currents in single and multilayered a-Se devices as a function of alloying, doping, deposition condition and other fabrication factors. The results of the studies are extensively discussed in the thesis. We have proposed a new technological method for dark current reduction in single and multilayered a-Se based photoconductor for x-ray detector applications. The new technology is based on original experimental findings which demonstrate that both hole transport and the dark currents in a-Se films are a very strong function of the substrate temperature (Tsubstrate) during the film deposition process. We have shown that the new technique reduces the dark currents to approximately the same levels as achievable with the previously existing methods for dark current reduction. However, the new method is simpler to implement, and offers some potential advantages, especially in cases when a very high image resolution (20 cycles/mm) and/or fast pixel readout (more than 30 times per second) are needed. <p>Using the new technology we have fabricated simple single and double (ni-like) photoconductor layers on prototype x-ray image detectors with CCD (Charge Coupled Device) readout circuits. Dark currents in the a-Se photoconductor layer were not a problem for detector operation at all tested electric fields. Compared to the currently available commercial systems for mammography, the prototype detectors have demonstrated an excellent imaging performance, in particular superior spatial resolution (20 cycles/mm). Thus, the newly proposed technology for dark current reduction has shown a potential for commercialization.

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