Briser la frontière observationnelle de l’Univers lointain suscite de nombreux axes de recherches dans la cosmologie moderne. Exigeantes par la sensibilité demandée, ces observations constituent aussi bien un défi technologique pour les prochaines générations d’instruments qu’une étape nécessaire à la compréhension des différentes étapes d’évolution de l’Univers. Une des étapes importantes est la réionisation du milieu intergalactique, époque charnière marquant la fin des “Âges Sombres”. Déterminer quand et comment ce processus s’est déroulé et quelles ont été les sources l’ayant déclenché et entretenu sont les principales questions motivant ces recherches. Les travaux présentés dans cette thèse participent à l’effort de la communauté scientifique internationale dans la caractérisation de l’histoire de l’époque de la réionisation en recherchant des galaxies à grand décalage spectral vers le rouge (redshift). Après un panorama complet des contraintes observationnelles actuelles sur l’époque de la réionisation, sont ensuite présentés les deux projets ayant fournis les données constituant la matière première de cette analyse. En utilisant une même technique d’imagerie en bande étroite dans le domaine de longueurs d’onde proche-infrarouge, des observations avec l’instrument WIRCAM (CFHT) et d’autres avec l’instrument HAWK-I (VLT) ont permis d’établir des contraintes robustes sur la fonction deluminosité des Emetteurs Lyman-α au redshift z = 7.7. A l’occasion de la présentation du second projet, la problématique de la stratégie observationnelle est abordée, notamment via l’utilisation des amas de galaxies comme lentilles gravitationnelles amplifiant le flux des sources d’arrière-plan. L’absence de confirmation spectroscopique des Emetteurs Lyman-– sélectionnés durant l’analyse des données WIRCAM et l’absence de candidats dans le sondage HAWK-I suggèrent une évolution de la fonction de luminosité des Emetteurs Lyman-– entre les redshifts z = 6.5, telle quedéterminée dans d’autres études, et z = 7.7. La tendance de cette évolution, en luminosité ou en densité de galaxies, ne peut pas encore être déterminée compte tenu de la variabilité des résultats obtenus à plus bas redshift. Si cette évolutions’effectuait en luminosité, ce pourrait être le signe d’une augmentation de l’opacité du milieu intergalactique au rayonnement Lyman-α causée par une plus importante fraction d’hydrogène neutre, ce qui est une signature attendue de la réionisation. / Breaking through the observational frontier of the distant universe motivates numerous scientific cases in modern cosmology. Demanding by the required sensitivity, high-redshift observations provide both a technological challenge for next generation instruments and a necessary step toward the understanding of cosmic evolution. One critical epoch is the reionization of the intergalactic medium bringing to light the end of the so-called “Dark Ages”. Determine when and how this process took place and what were the sources that started and maintained the reionization are the mainquestions motivating this research. The work presented in this thesis contributes to the effort of the internationalscientific community in characterizing the reionization epoch history by searching for galaxies at high redshift. First, I describe the current observational constraints in a comprehensive chapter. Then the two datasets used in that work are presented. From narrow-band observations in the near-infrared with WIRCAM at the CFHT and HAWK-I at the VLT, I put strong constraints on the luminosity function of Lyman-α Emitters at z = 7.7. The best strategy for this type of survey is discussed, in particular with the use of massive galaxy clusters acting as gravitational lenses that amplify the flux from background sources. The lack of spectroscopic confirmation of candidates found with WIRCAM and the lack of candidates found with HAWK-I suggest an evolution of the luminosity function from z = 6.5. This evolution could be either in luminosity or in number density but somewhat discrepant results at lower redshift prevent any definitive answer to this question. If the evolution was mostly in luminosity, it could be interpreted as an increase in the opacity of the intergalactic medium caused by an increased fraction of neutral hydrogen, which is an expected signature of reionization.

L'objectif de cette thèse est de caractériser les phénomènes d'oxydation de lubrifiants pétroliers et les produits lourds du pétrole. Dans les deux thématiques « lubrifiants » et «lourds pétroliers », une étude de veille stratégique a été effectuée en préalable des études analytiques et chimométriques dans ce cadre le paramètre temps est important. Il nous permet de comprendre les évolutions des domaines, leurs actualités et leur(s) pertinence(s) en précisant si ces domaines sont déjà en phase technologique et utilisation industrielle ou encore en phase de développement. Les huiles lubrifiantes doivent répondre à certaines exigences afin d'optimiser leur performance lors de l'utilisation dans le moteur. Dans ce travail, divers composés soufrés sont testés afin de déterminer le potentiel antioxydant. Deux huiles de base et sept additifs sont testés. Il apparaît que les composés soufrés avec des longues chaînes aliphatiques augmentent la résistance de l'huile, quelle que soit sa nature. Les fiouls lourds utilisés pour les moteurs de bateau peuvent être considérés comme un déchet de raffinage. Néanmoins, la spécification de ces produits est très stricte notamment pour la combustion, la stabilité et la teneur en soufre. Leurs caractérisations nécessitent l'analyse de diverses propriétés, qui sont essentielles pour le contrôle et le développement de technologies de moteurs d'entraînement. L'utilisation d'un support de diffusion permet de s'affranchir des problèmes de nettoyage de cuve couramment rencontrées. / The objective of this thesis is to characterize the phenomena of oxidation of oil lubricants and the heavy products of petroleum. In both themes « lubricating » and « Heavy Fuel Oil », a study of strategic monitoring was performed before analytical and chemometrics studies in this frame the parameter time is important. It helps us to understand changes domains, their news and their relevance and whether these domains are already in industrial use and technological phase or development stage scientific research. Lubricating oils must meet certain requirements in order to optimize their performance when operating in the engine. In this work various types of sulfur compounds are tested to identify the antioxidant potential. Two base oils and seven additives are tested. It appears that sulfur compounds with long aliphatic chains increases resistance of oil, whatever its nature. Heavy fuel oil used for boat motors can be considered as refining waste. Nevertheless the most stringent specification as burning, stability and sulfur content. Their characterizations require the analysis of various properties, which are essential for driving control and the development of engine technologies. The use of a diffusing support allows to free itself from problems of tank cleaning usually met. The aim of this work is to analyze fuel on the boat at the entrance of the engine in order to increase the motor performances and decrease the pollutants by a near infrared miniaturized sensor.

A irradiação de sistemas adesivos com laser tem obtido resultados promissores, no entanto, seu mecanismo de ação, bem como a longevidade da camada híbrida obtida após a irradiação com laser ainda não estão bem estabelecidos na literatura. A presente tese teve como objetivo: avaliar a absorvância do laser de Diodo por diferentes sistemas adesivos por meio de espectroscopia no infravermelho próximo; avaliar a evaporação de água e solventes proporcionada pelo laser por meio da variação da massa analisada em balança de precisão; avaliar a resistência de união por meio de teste de microtração após envelhecimento de 12 meses. Os dados obtidos foram analisados por modelos de ANOVA, seguidos de teste Tukey (p<0,05) e os resultados demonstraram que: a irradiação no infravermelho próximo, área do espectro eletromagnético que compreende o laser de Diodo, não apresenta interação com os sistemas adesivos testados; o laser de Diodo é capaz de proporcionar maior alteração de massa, mesmo após contínua evaporação dos solventes com jatos de ar por 60s; sistemas adesivos simplificados apresentaram valores de resistência de união imediato semelhantes aos valores obtidos após 12 meses de envelhecimento. Os dados obtidos neste estudo sugerem que a irradiação com laser de Diodo pode contribuir favoravelmente para a adesão em dentina com sistemas adesivos simplificados após 1 ano. / The laser irradiation of adhesive systems has obtained promising results, however, its mechanism of action, as well as the longevity of the hybrid layer obtained after laser irradiation are still not yet well established in the literature. This thesis aimed to: assess the diode laser interaction with different adhesive systems by means of near infrared spectroscopy; evaluate the evaporation of solvents and water provided by the laser through the mass variation analyzed at a precision balance; evaluate the bond strength through microtensile bond strength test after 12 months of aging. The data was analyzed through ANOVA models, followed by Tukey test (p<0.05), and the results demonstrated that: in the near-infrared irradiation area, the electromagnetic spectrum comprising the diode laser, shows no interaction with the adhesive systems tested; the diode laser was able to provide greater mass variation, even after continual evaporation of solvents with air jets for 60s; simplified adhesive systems presented immediate bond strength values similar to the ones verified after 12 months of aging. The data obtained in this study suggest that the Diode laser irradiation can contribute favorably for the adhesion between dentin and simplified adhesive systems after 1 year.

Estruturas fotônicas à base de silício têm despertado grande interesse por permitirem uma perfeita integração entre processos ópticos e eletrônicos em um único chip. Além de compatíveis com a atual indústria microeletrônica, acredita-se, que tais estruturas possam aumentar consideravelmente a velocidade de processamento de informações. Uma microcavidade óptica é um exemplo de estrutura fotônica simples. Feita à base de silício, e dopada com íons terra-rara, tal microcavidade pode intensificar a emissão gerada pelo íon e resultar em um dispositivo de importância tecnológica. O projeto-construção deste tipo de microcavidade deve considerar a sua região de funcionamento e os materiais a serem utilizados. Deve contemplar, ainda, algumas condições externas que, eventualmente, possam alterar o seu funcionamento. Uma dessas condições é descrita pelo chamado coeficiente termo-óptico que indica a dependência do índice de refração com a temperatura. Dentro desse contexto a presente Tese de Doutorado foi dedicada ao estudo de microcavidades ópticas com janelas de transmissão em 650 nm e em 1550 nm &ndash; correspondendo às regiões de menores perdas de fibras ópticas de plástico e de sílica. As microcavidades compreenderam espelhos de Bragg [camadas alternadas de silício amorfo (a-Si) e nitreto de silício amorfo (a-SiN)], um filme de a-SiN como espaçador, e foram depositadas sobre substratos de sílica pela técnica de sputtering. As cavidades MC-Er e MC-ErYb tiveram como espaçadores filmes de a-SiN dopados com Er e Er + Yb, respectivamente. Medidas de fotoluminescência da MC-ErYb na região do infravermelho próximo indicaram um aumento de 48 vezes na emissão dos íons Er3+ (em ~1535 nm) comparado a um filme de a-SiN dopado com érbio devido: (1) a presença do itérbio e, (2) às múltiplas reflexões sofridas pela luz nos espelhos de Bragg. As microcavidades cujos espaçadores eram a-SiN puro foram submetidas a medidas de transmissão óptica em função da temperatura de medida. O deslocamento da janela de transmissão devido às variações de temperatura permitiu determinar o valor do TOC do a-SiN como: (6.2&plusmn;0.1)&times;10-5 ºC-1 (em ~ 620 nm) e, (4.7&plusmn;0.1)&times;10-5 ºC -1 (em ~ 1510 nm). Até onde sabemos, o TOC do a-SiN no VIS foi determinado pela primeira vez neste trabalho. / Silicon photonic based structures have attracted great interest for allowing a perfect integration between optical and electronic process in a single chip. Besides being compatible with the actual microelectronic industry, it is believed that such structures can considerably increase the information processing speed. An optical microcavity is an example of a simple photonic structure. Made based on silicon, and doped with rare-earth ions, such microcavity may enhance the emission generated by the ion and become a device of technological importance. The project-construction of this kind of microcavity has to consider the operation region and the materials used. It still has to take into account external conditions that may, eventually, change its operation. One of these conditions is described by the thermo-optic coefficient (TOC) that shows the dependence of the refractive index with the temperature. Within this context the present PhD thesis was dedicated to the study of optical microcavities with transmission windows at 650 nm and at 1550 nm &ndash; corresponding to the low losses regions of the plastic and silica optical fibers. The microcavities comprised Bragg mirrors [alternated layers of amorphous silicon (a-Si) and amorphous silicon nitride (a-SiN)], one film of a-SiN as spacer, and were deposited on silica substrates by the sputtering technique. The MC-Er and MC-ErYb cavities had Er and Er+Yb-doped a-SiN films as spacers, respectively. Photoluminescence measurements of the MC-ErYb in the near infrared showed an enhancement of 48 times in the emission of the Er3+ ions (at ~ 1535 nm) compared with an Er-doped a-SiN film owing to: (1) the presence of ytterbium and, (2) the multiple reflections experienced by the light at the Bragg mirrors. The microcavities whose spacers were pure a-SiN were submitted to optical transmission measurements as a function of the measurement temperature. The shift of the transmission window due to variations in the temperature allowed determining the a-SiN TOC: (6.2&plusmn;0.1)&times;10-5 ºC-1 (at ~ 620 nm) and, (4.7&plusmn;0.1)&times;10-5 ºC -1 (at ~ 1510 nm). To the best of our knowledge, the a-SiN TOC in the visible was determined for the first time in this work.

As Boas Práticas de Fabricação de Medicamentos (BPFM) enfatizam que a indústria farmacêutica deve dirigir seus esforços no sentido de compreender a variação do processo, incluindo as fontes, o grau de variação e o impacto dessa variação nas características de qualidade do produto. O processo de fabricação de medicamentos tem apresentado significativas mudanças, em especial no que se refere à introdução de tecnologias analíticas que permitem o controle do processo em tempo real. A abordagem baseada na análise de risco e no novo Sistema de Qualidade Farmacêutica constitui ponto central das BPFM para o século XXI. Os órgãos regulatórios têm exigido da indústria farmacêutica sua adesão na melhoria contínua relativa ao desempenho de seus processos e, por consequência, na qualidade do produto. O objetivo do presente trabalho foi o desenvolvimento e validação de método analítico empregando espectroscopia no infravermelho próximo, assim como a avaliação do processo de fabricação de comprimidos de Captopril 25 mg, empregando abordagem racional-científica. Com referência à avaliação do processo, foram adotadas as seguintes ferramentas: análise de modos e efeitos de falhas (FMEA); gráficos de controle; índices de capacidade e análise de variância (ANOVA). A espectroscopia por infravermelho próximo (NIR) foi selecionada por apresentar maior rapidez na obtenção dos resultados, maior simplicidade na preparação das amostras, multiplicidade das análises a partir de uma única leitura e por apresentar característica não invasiva. Os resultados comprovaram a adequação dessa tecnologia na avaliação quantitativa do Captopril nas etapas de mistura de pós e de compressão. Os desvios padrão relativos na determinação da uniformidade de Captopril na mistura de pós e nos comprimidos empregando método no NIR foram, respectivamente 3,15 e 0,18%. No que se refere à avaliação da estabilidade e da capacidade do processo, as ferramentas adotadas permitiram a compreensão das fontes de variabilidade, assim como a determinação de seu grau, nas diferentes etapas do processo. Os índices de capacidade (CpK) relativos à uniformidade de Captopril (% p/v) na mistura de pós, ao peso médio do comprimido, à uniformidade de conteúdo e à % (p/v) dissolvida de Captopril, no ensaio de dissolução, foram 0,70, 1,94, 1,80 e 2,19, respectivamente. / The Good Manufacturing Practices (GMP) for Medicinal Products point out that the pharmaceutical industry must direct efforts to understand the variation of the processes, including the sources, the level of variation and the variation impact on the process in characteristics of the product. The manufacturing process has shown meaningful changes, especially in the introduction of new analytical technologies that allow the process control in real time. The approach based on risk analyses and on the new Pharmaceutical Quality System is a central key for the GMP for the XXI century. The Regulatory Agencies have demanded the pharmaceutical industry to adhere the continuous improvement related to the performance of its processes and, consequently, the product quality. Thus, the present paper aimed the development and validation of the analytical method employing NIR spectroscopy as the assessment of manufacturing process of Captopril 25 mg tablets, using rational scientific approach. Regarding the process assessment, the following tools were adopted: analysis of failure modes and effects analysis (FMEA), control charts, capability indexes, as well as analysis of variance (ANOVA). The near-infrared spectroscopy was selected due to its greater speed in getting the results, simplicity in sample preparation, and multiplicity of analysis from a single reading and provide non-invasive feature. The results confirmed the suitability of this technology in quantitative assessment of Captopril on the steps of mixing powders and compression. The relative standard deviations for the determination of Captopril uniformity in the post mixtures and in the tablets employing NIR were 3,15 e 0,18%, respectively. In reference to the stability assessment and process capacity, the tools adopted permitted the understanding of the sources of variability, as well as the determination of their level in different phases of the process. The capacity indexes relating to Captopril uniformity (% p/v) in the powder mixture, the average weight of the tablet, the content uniformity and the % (p/v) dissolved Captopril, in the dissolution assay were 0,70, 1,94, 1,80 and 2,19, respectively.

Sprachverstehen erfordert ein Zusammenspiel verschiedener mentaler Prozesse. Zuerst muss der kontinuierliche akustische Sprachstrom in einzelne Einheiten (z.B. Wörter) unterteilt werden. Segmentale und suprasegmentale linguistische Information unterstützt den Segmentierungsprozess. Wissen über die neuronalen Mechanismen dieser Prozesse ist wesentlich um Sprachverarbeitungs- und Sprachentwicklungsprozesse zu verstehen. Ziel der Dissertation ist die Charakterisierung neuronale Korrelate der Verarbeitung sprachrelevanter akustischer Information bei Erwachsenen und Säuglingen mittels kombinierter Nahinfrarot-Spektroskopie- und Elektroenzephalographie-Messungen. Studie I untersucht zeitliche und topographische Aspekte der phonotaktischen Verarbeitung bei Erwachsenen. Die Ergebnisse zeigen, dass phonotaktische Information links-hemisphärisch verarbeitet wird. Ob diese Lateralisierung auf die linguistischen oder akustischen Eigenschaften der Reize zurückzuführen ist bleibt unklar. Erwachsenen-Studien zeigen, dass die lateralisierte Verarbeitung von Sprache aus der Spezialisierung des auditorischen Kortex für bestimmte zeitliche akustische Variationen im Sprachsignal resultiert. Studie II und III untersuchen, ob diese Asymmetrie bereits bei Säuglingen vorliegt. Dafür werden zeitlich variierte nicht-sprachliche akustische Reize präsentiert. Die zeitlichen Variationen entsprechen kritischen Modulationen im Sprachsignal. Studie II zeigt, dass bei Neugeborenen die zeitlichen Modulationen zu differenzierten und lateralisierten Verarbeitungsmustern führen, die über die ersten Lebensmonate konstant bleiben (Studie III). Die Ergebnisse unterstützen die Annahme, dass die lateralisierte Verarbeitung von Sprache mit einer Spezialisierung des auditorischen Kortex für bestimmte zeitliche Frequenzen zusammenhängt. Das Gehirn ist von Geburt auf die Wahrnehmung zeitlicher akustischen Variationen spezialisiert, die für die Entschlüsselung des Sprachsignals relevant sind. / The comprehension of spoken language requires the segmentation of the continuous acoustic speech stream into smaller units (e.g., words). Segmental and suprasegmental linguistic information guide the segmentation process. Investigating the underlying neuronal mechanisms is crucial for understanding the general nature of language perception, and language acquisition in infancy. This dissertation aimed to determine neuronal mechanisms underlying the perception of basic auditory cues relevant for the segmentation of speech in adults and infants using concurrent recordings of near-infrared spectroscopy and electroencephalography. Study I assessed temporal and topographic characteristics of phonotactic processing in adults, thus forming the basis for future studies in infants. The results show that phonotactic processing recruits a left hemispheric network. Whether these asymmetries are a function of linguistic attributes or of basic temporal signal properties is under debate. Studies in adults link hemispheric specialization for speech perception to an asymmetry in cortical tuning and reveal that the auditory cortices are differentially sensitive to temporal features of speech. Whether this asymmetry is already established in infancy is addressed by study II and III. These studies used acoustic non-linguistic sounds that vary in their temporal structure, thus sharing critical temporal features with language. Study II reveals that newborns process temporally varying stimuli in a differential and lateralized fashion. Study III indicates that this lateralization pattern remains constant over the first months of life. The findings support the notion that the lateralization of language functions might result from a specialization for different acoustic properties. The data provide further evidence that language acquisition is linked to basic capacities in auditory processing, and reveal that from birth the brain is tuned to critical temporal properties of linguistic signals.

Die Arbeit stellt die optische Methode der Nahinfraotspektroskopie (NIRS) in der Anwendung zur Messung von Oxygenierungsänderungen am Kopf des Erwachsenen dar. Dabei werden zunächst methodische Aspekte behandelt. Dies schließt (i) die Frage ein ob Änderungen des Redox-Status der Cytochromoxidase mit der NIRS bestimmt werden können; (ii) diskutiert die Ergebnisse zur Darstellbarkeit schneller optischer Signale, wie sie in invasiven Studien als Korrelat der elektrophysiologisch messbaren neuronalen Prozesse bekannt sind und (iii) richtet sich auf die bessere Definition des Messvolumens, sowohl im Sinne einer zweidimensionalen Bildgebung der Oxygenierungs-änderungen an der Hirnoberfläche als auch die Möglichkeiten zu einer Tiefenauflösung. Bezüglich der grundlegenden physiologischen Fragestellungen thematisiert die Arbeit im zweiten Teil Fragestellungen der neuro-vaskulären Kopplung. Dies ist die Frage, wie sich die neuronale, elektrophysiologisch meßbare Aktivität von Neuronen in eine hämodynamische Antwort übersetzt. Hier sind die Einordnung der NIRS-Befunde in ein Modell der vaskulären Antwort aber auch gleichzeitige Messungen mit elektrophysiologischen Methoden und weiteren vaskulär-basierten Methoden, insbesondere der funktionellen Kernspintomographie, Fokus. Schließlich stellt die Arbeit die klinischen Perspektiven in der Neurologie dar, wie sie sich besonders für die vaskulären Erkrankungen des Gehirns aber auch für Fragestellungen bei Epilepsie und Migräne ergeben. / We here present a optical method, near-infrared spectroscopy (NIRS), and its application for non-invasive measurement of oxygenation changes in the adult head. The first part deals with methodological aspects of NIRS. This includes (i) the question whether changes of cytochrome-oxidase redox state can be monitored by NIRS; (ii) the discussion of study results investigating the non-invasive detectability of fast optical signals , known to reflect electrophysiological changes in invasive animal preparations; (iii) and finally the issue how the sampling volume can be better defined, and with respect to a two-dimensional imaging approach of cortical oxygenation changes and the methodological options to achieve a depth resolution. In a second chapter we then focus on the underlying physiological issues mainly raising questions concerning neuro-vascular coupling. Neuro-vascular coupling means the translation of neuronal activity, as can be measured by electrophysiological methods, into the haemodynamic response. Here the focus is on how the results of functional NIRS studies can be interpreted in the light of a model of the vascular response. Also the simultaneous assessment of electrophysiological parameters or the parameters of other methods based on the vascular response, especially fMRI, are dealt with in this chapter. Finally the here presented work gives perspectives of potential clinical applications of the method. This primarily means the application in stroke and other vascularly diseases in neurology, but also includes questions in the clinical fields of epilepsy and migraine.

In this thesis the optical method of Near-Infrared-Spectroscopy (NIRS) is evaluated with regards to its capability of non-invasive detection of Leão´s cortical spreading depression (CSD) and spontaneous peri-infarct-depolarizations (PID). With the NIR-spectrometer NIRO 500 (Hamamatsu, Japan) regional cerebral oxy-genation (rCBO) changes were measured during CSD in 9, and during PID in 10 barbiturate anesthatized rats. The method if NIRS that relies on oxygen-dependent absorption changes of hemo-globin and cytochrome oxydase as well as the high penetrability of biologic tissues for light in the range between 700 and 1000 nm proved suitable to detect and to distinguish both CSD and PID experimentally. This distinction relies on the robust decrease of deoxy- and increase of oxyhemo-globin concentrations (i.e. a relative hyperoxemia) during CSD while PID is cha-racterized by an initial increase of deoxy- and decrease of oxyhemoglobin (relative hypooxemia). Despite the profound anatomical differences between gyrencephalic humans and lyssencephalic rats, the observed patterns of rCBO changes may guide the inter-pretation of future NIRS measurements in patients with migraines with aura (CSD) or stroke (PID). However, for concentration changes of oxydized cytochrome aa3 with its low con-centration compared to the hemoglobins, the pathophysiological interpretation of the data obtained with NIRO 500 is confounded by the limits of attenuation mea-surements at only four wavelengths. A validation of the cytochrome oxydase signal and an improved quantification of all concentration changes is highly desirable and may be achieved by employment of a continuous-wavelength device measuring the full spectral range of the near infrared. It would also allow to measure the mean optical pathlength in the highly scattering tissue and to correct for its physiologically occuring changes e.g. by measurements at the water absorption peak. Similar improvements would enhance the value of the method for further physiolo-gical and pathophysiological studies because NIRS provides the unique opportu-nity to obtain simultaneous data on blood oxygenation as well as the redox state of the mitochondrial cytochrome oxydase.

L’objectif de cette thèse est de démontrer le potentiel de la spectroscopie proche infrarouge multipoints pour suivre en ligne des milieux diffusants et absorbants dont les propriétés physique et chimique varient au cours du temps. Des travaux ont tout d’abord porté sur l’étude d’un milieu où seule la diffusion varie au cours du temps. Le suivi de la réaction de précipitation de la silice a été choisi pour illustrer un tel milieu. Dans un premier temps, des spectres en transmission collimatée ont été mesurés sur des échantillons prélevés au cours du procédé. Grâce à l’application de la loi de Beer-Lambert, il a été possible d'obtenir les coefficients de diffusion de chaque échantillon et ainsi retrouver les différentes étapes de la réaction. Une analyse en composante principale de ces coefficients a montré la présence de deux régimes de diffusion dans le milieu réactionnel. Dans un second temps, une sonde de mesures multipoints, a été immergée dans un réacteur de fabrication. Des spectres ont été mesurés à des angles de 30°, 90°, 150°, 170° et 180° par rapport à la source, tout au long de la précipitation. Une analyse univariée, aux différents angles, a montré des différences et des similitudes entre les positions, en lien avec les interactions lumière matière. Puis une analyse multivariée multi tableaux ACCPS (Analyses en Composantes Communes et Poids Spécifiques) a été appliquée. Elle permet de combiner les informations issues des différents angles et de montrer les informations communes et spécifiques. Cela a permis de valider l’utilisation de la mesure multipoints pour le contrôle du procédé. Grâce à l’analyse des scores globaux, différents types de diffusion et la spécificité de certains angles dans la détection de modifications physiques, ont été identifiés. L’analyse des loadings individuels, a confirmé les différentes étapes réactionnelles identifiées et a révélé des phénomènes relatifs à la diffusion de la lumière comme l’allongement du trajet optique. La même démarche, analyses en laboratoire puis en ligne, a été appliquée à un milieu où la diffusion et l’absorption varient. Le suivi des produits issus des procédés pour l’amélioration de l’extraction du pétrole a été choisi pour illustrer un tel milieu. Dans un premier temps, des microémulsions (eau, huile et tensio-actif) ont été fabriquées de sorte à ce que les propriétés chimiques et physiques soient différentes. Puis chaque phase a été analysée séparément. Une analyse en composantes principales a permis de caractériser les systèmes grâce à l’identification des phases. Elle a également montré que les différences entre elles étaient liées, à la fois à l’absorption et à la diffusion. Pour séparer ces deux phénomènes, une résolution multivariée de courbes par régression alternée a été appliquée. Cela a permis d’expliquer plus en détail les différences entre les phases et d’obtenir des suivis semi-quantitatifs. Enfin dans la dernière partie, les mêmes échantillons ont été analysés en circulation avec une sonde multipoints. Une ACCPS a de nouveau été appliquée et a montré que des phénomènes de diffusion différents avaient lieu entre les classes. De plus elle a mis en lumière une hétérogénéité dans la composition des phases, qui ne pouvait pas être détectée avec des mesures en statique. / The aim of this thesis is to demonstrate the potential of multipoint near infrared spectroscopy to monitor online scattering and absorbing environments, where physical and chemical properties change over time. The work was first based on the study of an environment where scattering was the only parameter varying over time. Monitoring of the silica precipitation reaction has been chosen to illustrate that environment. First of all, spectra in collimated transmittance mode were acquired from samples collected during the process. Thanks to the Beer-Lambert law, scattering coefficients of each sample were obtained and from them the different steps of the reaction were found. A principal component analysis of those coefficients showed the existence of two scattering modes into the reaction environment. In the second phase, a multipoint probe was submerged in an industrial reactor. Spectra were measured during the precipitation with angle of 30°, 90°, 150°, 170° and 180° to the source. A univariate analyse at those different angles showed differences and similarities between the positions, linked to the interaction of light and matter. Then, a multiblock and multivariate analysis, CCSWA (Common Component and Specific Weight Analysis), was applied. It allows the combination of information from different angles and also shows common and specific information, in order to validate the use of multipoint measurement to monitor the process. Thanks to the analysis of global scores, different kind of scattering and the specificity of some angle, in the detection of physical modifications were identified. The analysis of individual loadings confirmed the identification of the different steps of reaction and has revealed some phenomena related to light scattering, such as the extension of the optical path. The same approach, analysis in the laboratory then online, was applied on an environment where scattering and absorption vary. Monitoring of products from the process to improve oil extraction, has been chosen to illustrate that environment. First of all, micro emulsions (water, oil and surfactant) were made so that physical and chemical properties would be different between samples. Then, each phase was analysed separately. A principal component analysis was used to characterize the system by phase identification. It also showed the differences between the phases were linked, both to absorption and scattering. In order to separate those two phenomena, a multivariate resolution by alternate regression has been applied. It has permitted to explain in more details the differences between the phases and to obtain semi-quantitative monitoring. Finally, in the last part, the same samples were analysed in circulation with a multipoint probe. A CCSWA has been applied again and showed that different scattering phenomenon occurred between the categories. Moreover, it highlighted a heterogeneity in the phases' composition that couldn’t be detected in static measurement.

This project utilised a novel solvent-free continuous cocrystallisation (SFCC) method to manufacture pharmaceutical co-crystals. The objectives were to optimize the process towards achieving high co-crystal yields and to understand the behaviour of co-crystals under different conditions. Particular attention was paid to the development of near infrared (NIR) spectroscopy as a process analytical technology (PAT). Twin screw, hot melt extrusion was the base technique of the SFCC process. Changing parameters such as temperature, screw speed and screw geometry was important for improving the co-crystal yield. The level of mixing and shear was directly influenced by the screw geometry, whilst the screw speed was an important parameter for controlling the residence time of the material during hot melt extrusion. Ibuprofen – nicotinamide 1:1 cocrystals and carbamazepine – nicotinamide 1:1 co-crystals were successfully manufactured using the SFCC method. Characterisation techniques were important for this project, and NIR spectroscopy proved to be a convenient, accurate analytical technique for identifying the formation of co-crystals along the extruder barrel. Separate thermal and model shear deformation studies were also carried out to determine the effect of temperature and shear on co-crystal formation for several different pharmaceutical co-crystal pairs. Finally, NIR spectroscopy was used to create two partial least squares regression models, for predicting the 1:1 co-crystal yield of ibuprofen – nicotinamide and carbamazepine – nicotinamide, when in a powder mixture with the respective pure API. It is believed that the prediction models created in this project can be used to facilitate future in-line PAT studies of pharmaceutical co-crystals during different manufacturing processes.