Master of Science / Food Science Institute / David L. Wetzel / Grain processing and handling requires quality determinations to ensure wholesome products that meet or surpass legal standards and specifications required by the end consumer. Near infrared spectroscopy has proven to be a useful and versatile tool to enable grain processers to make adjustments as needed. Near infrared chemical imaging also provides spatial information within the image and relative composition of chemically distinct components within the product. The potential use of chemical imaging to determine extraneous material in bread baking quality flour was addressed. A specimen preparation technique was developed. Insect fragment spiked specimens were imaged to determine their imaging effectiveness for application near the allowable limit of insect fragment concentration. Imaging was achieved using indium antimonide array detection of diffusely reflected radiation. The detector array of 81,920 pixels collected radiation from an area of 30.72 mm by 38.4 mm with a pixel size of 120 µm². Spectra were collected simultaneously from each pixel without moving parts by scanning with a liquid crystal tunable filter. Partial least squares analysis of each pixel within the sample allowed a summation of the insect quantity. The chemical structural distinction of chitin in the high protein matrix of the insect residue was in contrast to the non-digested carbohydrate residue in the lesser protein matrix of the flour. The method developed provided a linear response for a concentration range from approximately half the allowable limit to twice the limit for two insects that commonly contaminate flour. For the two insects studied the slopes are comparable with a slight off-set over a practical working range, so that insect concentration can be determined independently of species recognition.

The widely available charge coupled device (CCD) and lately CMOS imaging devices have created many applications on a mass scale. However these devices are limited to wavelengths shorter than about 1 μm. Hybrid photon upconversion devices have been developed recently. The end goal is to achieve an alternative technology for imaging in the 1.5-μm region. The hybrid upconversion idea relies on the integration of a photodetector and an organic light emitting diode (OLED). Under a forward bias for the OLED, the detected signal in the Photodetector is sent to the OLED, resulting in an increase in emission at a shorter wavelength and therefore achieving optical up conversion. An OLED device can simply consists of a stack of anode, a hole transport layer (HTL), a light-emitting layer, an electron transport layer (ETL), a cathode layer, and it typically emits visible light. As each organic molecule is a topologically perfect structure, the growth of each organic layer does not require “lattice matching”, which has been the fundamental limit for inorganic semiconductor monolithic devices. Thus, integration of an OLED with a III–V compound semiconductor is a highly feasible and desirable approach for making low-cost, large-area, potentially high efficiency devices. This thesis addresses the physics, fabrication and characterization of hybrid near infrared optical upconverters and their imaging application. Firstly, one novel hybrid optical upconverter structure is presented, which substantially improves the upconversion efficiency by embedding a metal mirror. Efficient carrier injection from the inorganic photodetector to the OLED is achieved by the insertion of a thin Au metal embedded mirror at the inorganic-organic interface. The upconversion efficiency was improved by more than 100%. Secondly, the overall upconversion efficiency can be increased significantly, by introducing a gain mechanism into the Photodetector section of the upconverter. A promising option to implement gain is a heterojunction phototransistor (HPT). An InGaAs-InP HPT was integrated with an OLED, which converts 1.5-μm Infrared light to visible light with a built-in electrical gain (~94). The overall upconversion efficiency was improved to be 1.55 W/W. Thirdly, this upconversion approach can also be used to realize a pixelless imaging device. A pixelless hybrid upconversion device consists of a large-area single-mesa device, where the OLED output is spatially correlated with the input 1.5-µm scene. Only the parts receiving incoming photons will emit output photons. To achieve this functionality, photon-generated carriers must flow mainly along the layer-growth direction when injected from the InGaAs light absorption layer into OLED light emission layer. A prototype of pixelless imaging device based on an i-In0.53Ga0.47As/C60 heterojunction was demonstrated, which minimized lateral current spreading. This thesis presents experimental results of the first organic/inorganic hybrid optical amplifer and the first hybrid near infrared imaging device.

The widely available charge coupled device (CCD) and lately CMOS imaging devices have created many applications on a mass scale. However these devices are limited to wavelengths shorter than about 1 μm. Hybrid photon upconversion devices have been developed recently. The end goal is to achieve an alternative technology for imaging in the 1.5-μm region. The hybrid upconversion idea relies on the integration of a photodetector and an organic light emitting diode (OLED). Under a forward bias for the OLED, the detected signal in the Photodetector is sent to the OLED, resulting in an increase in emission at a shorter wavelength and therefore achieving optical up conversion. An OLED device can simply consists of a stack of anode, a hole transport layer (HTL), a light-emitting layer, an electron transport layer (ETL), a cathode layer, and it typically emits visible light. As each organic molecule is a topologically perfect structure, the growth of each organic layer does not require “lattice matching”, which has been the fundamental limit for inorganic semiconductor monolithic devices. Thus, integration of an OLED with a III–V compound semiconductor is a highly feasible and desirable approach for making low-cost, large-area, potentially high efficiency devices. This thesis addresses the physics, fabrication and characterization of hybrid near infrared optical upconverters and their imaging application. Firstly, one novel hybrid optical upconverter structure is presented, which substantially improves the upconversion efficiency by embedding a metal mirror. Efficient carrier injection from the inorganic photodetector to the OLED is achieved by the insertion of a thin Au metal embedded mirror at the inorganic-organic interface. The upconversion efficiency was improved by more than 100%. Secondly, the overall upconversion efficiency can be increased significantly, by introducing a gain mechanism into the Photodetector section of the upconverter. A promising option to implement gain is a heterojunction phototransistor (HPT). An InGaAs-InP HPT was integrated with an OLED, which converts 1.5-μm Infrared light to visible light with a built-in electrical gain (~94). The overall upconversion efficiency was improved to be 1.55 W/W. Thirdly, this upconversion approach can also be used to realize a pixelless imaging device. A pixelless hybrid upconversion device consists of a large-area single-mesa device, where the OLED output is spatially correlated with the input 1.5-µm scene. Only the parts receiving incoming photons will emit output photons. To achieve this functionality, photon-generated carriers must flow mainly along the layer-growth direction when injected from the InGaAs light absorption layer into OLED light emission layer. A prototype of pixelless imaging device based on an i-In0.53Ga0.47As/C60 heterojunction was demonstrated, which minimized lateral current spreading. This thesis presents experimental results of the first organic/inorganic hybrid optical amplifer and the first hybrid near infrared imaging device.

Emerging technologies in the healthcare industry encompass revolutionary devices or drugs that have the potential to change how healthcare will be practiced in the future. While there are several emerging healthcare technologies in the pipeline, a few key innovations are slated to be implemented clinically sooner based on their mass appeal and potential for healthcare breakthroughs. This thesis will focus on specific topics in the emerging technological fields of nanotechnology for photothermal cancer therapy, 3D printing for irreversible electroporation applications, and imageable biomaterials. While these general areas are receiving significant attention, we highlight the potential opportunities and limitations presented by our select efforts in these fields. First, in the realm of nanomedicine, we discuss the optimization and characterization of sodium thiosulfate facilitated gold nanoparticle synthesis. While many nanoparticles have been examined as agents for photothermal cancer therapy, we closely examine the structure and composition of these specific nanomaterials and discuss key findings that not only impact their future clinical use, but elucidate the importance of characterization prior to preclinical testing. Next, we examine the potential use of 3D printing to generate unprecedented multimodal medical devices for local pancreatic cancer therapy. This additive manufacturing technique offers exquisite design detail control, facilitating tools that would otherwise be difficult to fabricate by any other means. Lastly, in the field of imageable biomaterials, we demonstrate the development of composite catheters that can be visualized with near infrared imaging. This new biomaterial allows visualization with near infrared imaging, offering potentially new medical device opportunities that alleviate the use of ionizing radiation. This collective work emphasizes the need to thoroughly optimize and characterize emerging technologies prior to preclinical testing in order to facilitate rapid translation. / Master of Science

<p>There is a critical need to target tumor hypoxia as patients with hypoxic tumors have worse prognosis due to aggressive phenotypes and resistance to radiotherapy and chemotherapy. The overall goal of this work is to improve response to conventional cancer therapies by targeting tumor hypoxia. This has been carried out and evaluated through the use of polymersome-encapsulated myoglobin (PEMs) with the hypothesis that O2-releasing PEMs will increase tumor oxygenation, and thereby improve response to radiotherapy. Mb was chosen as an O2 carrying protein to deliver to tumors because it has a strong association to O2, providing a mechanism to deliver O2 only within the hypoxic regions of the tumor. Mb was loaded within nanoscale polymeric vesicles that were expected to accumulate within solid tumors due to the enhanced permeability and retention (EPR) effect. This hypothesis has been tested through the following aims:</p><p>1. Develop NIR imaging techniques for studying the biodistribution and pharmacokinetics of polymersomes</p><p>2. Establish the effects of Mb-containing polymersomes on tumor physiology</p><p>3. Modify tumor growth through delivery of Mb polymersomes in combination with a cytotoxic therapy specific to aerobic tumors</p><p>These aims have been evaluated through numerous in vivo studies. First, polymersomes of various polymer formulations and diameters ranging from 110-550 nm were prepared with a near-infrared (NIR) -emissive fluorophore. Using live animal fluorescence imaging, I was able to study the biodistribution of the polymersomes following i.v. administration, demonstrating significant polymersome accumulation in orthotopic 4T1 mammary carcinomas. In addition, a novel method for measuring pharmacokinetics was developed, using serial small volume blood draws from individual mice. The plasma fluorescence in microcapillary tubes was used to quantify polymersome concentrations, demonstrating long circulation half-lives that varied from 6-23 h. Toxicity of various polymersome formulations were also studied in vitro and in vivo, revealing negligible toxicities.</p><p>For the second aim, PEMs were administered i.v. in tumor-bearing mice. Unexpectedly, we observed a dramatic gross tumor effect within hours of treatment in both orthotopic 4T1 tumors and flank Renca renal cell carcinomas. Histological analysis revealed endothelial cell apoptosis as early as 1 h following treatment, with scattered tumor cell death throughout the tumor by 4 h. Hematoxylin and eosin staining showed significant necrosis 24 h following PEM treatment. Vascular effects and polymersome distribution were studied in 4T1 window chamber tumors. Following i.v. treatment with PEMs, intravital microscopy was used to image polymersome fluorescence, brightfield transmission was imaged for vessel morphology and blood flow, and a tunable filter was used for determining hemoglobin (Hb) oxygen saturation. Tumor hemorrhaging was observed within hours of PEM treatment, which was not seen with empty polymersomes. This was consistent with the gross tumor effects observed initially. Hb saturation decreased in both the PEM and empty polymersome groups, but not in saline-treated mice. While we expected to observe an increase in tumor oxygenation by using Mb as an oxygen carrier, we actually observed hemorrhage, decreased oxygenation, and central tumor necrosis. In vitro studies using human endothelial cells demonstrated dramatic changes in cell morphology and increased permeability due to Mb and PEM treatments, which appear to be enhanced in an oxidative environment. These in vitro and in vivo observations are similar to what is seen with tumor vascular disrupting agents.</p><p>For the third aim, I combined radiotherapy (RT) and PEM treatment with a new hypothesis. I originally expected the PEMs to increase tumor oxygenation, thus making the tumor more susceptible to RT. However, considering the results from the second aim, this hypothesis was modified: the PEMs would result in necrosis of the tumor core, while RT would target the more oxygenated rim of the tumor, thus leading to improved tumor growth delay compared with PEM or RT alone. This hypothesis was tested in both orthotopic, syngeneic 4T1 tumors as well as flank FaDu xenografts. 4T1 tumor cells were surgically implanted within the dorsal mammary fat pad of mice and grown until ~200 mm3. A CT microirradiator with a square collimator was used in order to locate and specifically irradiate the tumor. Within 1 h following RT, the PEMs were administered i.v.. Mice receiving PEMs with no RT showed a significant decrease in tumor growth compared with saline-treated mice (p = 0.0001 for time to 3x original tumor volume). In addition, the combination of RT plus PEMs reduced tumor growth compared with RT alone (p = 0.0144 for time to 3x original tumor volume). However, this effect was not seen with FaDu tumors. This may have been due to excessive radiation dose or other compounding factors: the timing between RT and PEM treatment was not optimized, and the number of mice per group was small (3-4). </p><p>Thus, the conclusions for each aim are as follows:</p><p>1. Develop NIR imaging techniques for studying the biodistribution and pharmacokinetics of polymersomes</p><p>NIR imaging techniques were optimized for studying polymersomes, demonstrating long plasma circulation times and accumulation within tumors.</p><p>2. Establish the effects of Mb-containing polymersomes on tumor physiology</p><p>While the hypothesis was that PEMs would accumulate within hypoxic tumors and subsequently increase O2 tension, we observed a rapid decrease in tumor oxygenation followed by a dramatic hemorrhagic effect of Mb polymersomes, which appear to be due to both endothelial cell apoptosis and morphological changes, resulting in central tumor necrosis.</p><p>3. Modify tumor growth through delivery of Mb polymersomes in combination with a cytotoxic therapy specific to aerobic tumors</p><p>Combination therapy of PEMs with RT results in enhanced tumor growth delay in aggressive 4T1 mammary carcinomas compared with RT or PEMs alone.</p><p>These studies have led to a proposed mechanism for the PEM anti-tumor effect in combination with RT. Prior to PEM administration, RT is administered, resulting in tumor cell kill of the well-oxygenated tumor periphery. Mb polymersomes are then injected i.v. and begin to accumulate within tumors due to the EPR effect. As shown in Aim 1, this accumulation occurs over a short time scale. Within 30 min of PEM treatment, the Mb is believed to act on tumor vessels, resulting in morphological changes and apoptosis of endothelial cells. These effects are expected to increase permeability of the vessels and expose the basement membrane, which leads to clotting and decreased blood flow. Both decreased perfusion and increased permeability are believed to have a catastrophic effect on interior tumor vessels. Hemorrhage results as the endothelial cells die, resulting in tumor core necrosis. Therefore, the result is tumor cell kill at the periphery due to RT and central tumor necrosis due to PEM treatment.</p><p>PEMs have potential in cancer therapy as a new class of VDAs. While the mechanism requires further investigation, this work has demonstrated that PEM treatment results in tumor vessel destruction and central necrosis. PEMs accumulate within tumors, thus minimizing the systemic toxicity of treatment commonly seen with VDAs. By combining PEMs with a therapy that kills the better perfused tumor periphery, PEMs show promise in improving tumor response. Future mechanistic studies will be needed in order to maximize vessel damage and optimize combination dosing schedules to improve outcome.</p> / Dissertation

Thesis (Msc Food Sc (Food Science))--University of Stellenbosch, 2009. / The use of near infrared (NIR) hyperspectral imaging and hyperspectral image analysis for distinguishing between whole maize kernels of varying degrees of hardness and fungal infected and non-infected kernels have been investigated. Near infrared hyperspectral images of whole maize kernels of varying degrees of hardness were acquired using a Spectral Dimensions MatrixNIR camera with a spectral range of 960-1662 nm as well as a sisuChema SWIR (short wave infrared) hyperspectral pushbroom imaging system with a spectral range of 1000-2498 nm. Exploratory principal component analysis (PCA) on absorbance images was used to remove background, bad pixels and shading. On the cleaned images, PCA could be used effectively to find histological classes including glassy (hard) and floury (soft) endosperm. PCA illustrated a distinct difference between floury and glassy endosperm along principal component (PC) three. Interpreting the PC loading line plots important absorbance peaks responsible for the variation were 1215, 1395 and 1450 nm, associated with starch and moisture for both MatrixNIR images (12 and 24 kernels). The loading line plots for the sisuChema (24 kernels) illustrated peaks of importance at the aforementioned wavelengths as well as 1695, 1900 and 1940 nm, also associated with starch and moisture. Partial least squares-discriminant analysis (PLS-DA) was applied as a means to predict whether the different endosperm types observed, were glassy or floury. For the MatrixNIR image (12 kernels), the PLS-DA model exhibited a classification rate of up to 99% for the discrimination of both floury and glassy endosperm. The PLS-DA model for the second MatrixNIR image (24 kernels) yielded a classification rate of 82% for the discrimination of glassy and 73% for floury endosperm. The sisuChema image (24 kernels) yielded a classification rate of 95% for the discrimination of floury and 92% for glassy endosperm. The fungal infected and sound whole maize kernels were imaged using the same instruments. Background, bad pixels and shading were removed by applying PCA on absorbance images. On the cleaned images, PCA could be used effectively to find the infected regions, pedicle as well as non-infected regions. A distinct difference between infected and sound kernels was illustrated along PC1. Interpreting the PC loading line plots showed important absorbance peaks responsible for the variation and predominantly associated with starch and moisture: 1215, 1450, 1480, 1690, 1940 and 2136 nm for both MatrixNIR images (15 and 21 kernels). The MatrixNIR image (15 kernels) exhibited a PLS-DA classification rate of up to 96.1% for the discrimination of infected kernels and the sisuChema had a classification rate of 99% for the same region of interest. The The iv sisuChema image (21-kernels) had a classification rate for infected kernels of 97.6% without pre-processing, 97.7% with multiplicative scatter correction (MSC) and 97.4% with standard normal variate (SNV). Near infrared hyperspectral imaging is a promising technique, capable of distinguishing between maize kernels of varying hardness and between fungal infected and sound kernels. While there are still limitations with hardware and software, these results provide the platform which would greatly assist with the determination of maize kernel hardness in breeding programmes without having to destroy the kernel. Further, NIR hyperspectral imaging could serve as an objective, rapid tool for identification of fungal infected kernels.

La thérapie photodynamique (PDT) est une méthode de lutte contre le cancer basée sur l’utilisation de la lumière et d’un composé sensible à la lumière, appelé photosensibilisateur (PS). Le PS absorbe la lumière et, en présence d’oxygène, engendre la production des dérivés réactifs de l'oxygène (DRO), lesquels sont toxiques et provoquent la régression de la tumeur. La limitation principale des PSs utilisés dans les tests cliniques est leur faible sélectivité envers les tissus cancéreux. Le but principal de ce projet est de créer des agents multifonctionnels combinant sur une même molécule l’activité PDT, la vectorisation et l’imagerie optique proche infrarouge. Dans cette région du spectre optique, les cellules possèdent une faible autofluorescence, et la lumière proche infrarouge pénètre plus profondément dans les tissus biologiques que la lumière visible. Nous proposons ici de modifier une structure dendrimérique de type poly(amidoamine) de génération 3, en tant que plateforme polyvalente. En effet, ce dernier possède trente-deux groupes terminaux qui peuvent être facilement substitués par des PSs. De plus, cette macromolécule peut complexer dans ses cavités jusqu’à 8 cations lanthanides émettant dans le proche infrarouge. Quatre nouveaux ligands dendrimère ont été synthétisés avec différents PSs tels que des dérivés de naphtalimide, d’anthraquinone et de tétraphénylporphyrine. De plus, le naphtalimide a été couplé avec des groupes dérivés de l’acide folique pour assurer la vectorisation envers les tissus cancéreux. Les complexes de lanthanide émettant dans le proche infrarouge ont été préparés pour chaque dendrimère. La caractérisation des performances des différents complexes a été réalisée. La production de DRO et la présence de complexes d’Yb(III) a été démontrée dans les cellules HL60. Les dendrimères modifiés par les groupes anthraquinone et tétraphénylporphyrine en tant que PS, ont montré, dans les cellules vivantes, une émission proche infrarouge lorsqu’ils sont sous la forme de complexe d’Yb(III). Les résultats obtenus montrent que les complexes de lanthanides formés avec des ligands dendrimères peuvent servir comme des agents de PDT et des rapporteurs luminescents proche infrarouge in cellulo. / PDT is a cancer treatment that uses the combination of a nontoxic photoactivated molecule (photosensitizer), an appropriate source of light excitation and molecular oxygen to generate reactive oxygen species (ROS) leading to the decrease of size or to the destruction of tumors. However, the PDT efficiency of currently used drugs is limited by the selectivity for the cancer tissue. The main goal of this work is to develop a multifunctional agent which combines a PDT activity, a tumor targeting and near-infrared (NIR) optical imaging. The use of reporters that absorb at low energy is justified by low tissue autofluorescence and high tissue penetration depth in the NIR spectrum window. For this purpose, we have chosen the generation-3 poly(amidoamine) dendrimers as a versatile platform. Such macromolecules can incorporate eight NIR emitting lanthanide ions inside their branches forming species with thirty-two end groups at the periphery that can be substituted by suitable photosensitizers. Four new dendrimer ligands were synthesized with different photosensitizers, such as derivatives of naphthalimide, anthraquinone, and porphyrin. In addition the naphthalimide photosensitizer was functionalized with a targeting molecule, based on folic acid, to induce selectivity of the molecule towards cancer tissues. The corresponding NIR emitting lanthanide complexes were prepared for each dendrimer. Four Yb(III)-dendrimer complexes were characterized for their photophysical and ROS production properties. All complexes demonstrated a ROS production. The dendrimer functionalized with anthraquinone and tetraphenylporphyrin photosensitizers show strong NIR emission in living cells. These new multifunctional Yb(III)-dendrimer complexes have been designed to broaden the current scope of PDT agents and of NIR optical imaging agents.

Résumé : À partir de 2002, grâce à l’introduction du concept de la Qualité par la Conception (en anglais Quality by Design : QbD) par l’agence américaine des produits alimentaires et médicamenteux, l’industrie pharmaceutique a intensifié les efforts et les investissements pour permettre une libération en temps réel des lots commerciaux. Le QbD propose que la qualité soit construite dès la conception initiale du médicament plutôt que d'être évaluée à la fin de sa fabrication. Ainsi, avec l’initiative QbD, les tests de contrôle de la qualité des médicaments, réalisés après la fabrication des comprimés, peuvent être éliminés si les paramètres qui les influencent sont contrôlés. En effet, ces tests de contrôle qualité dits traditionnels requièrent en général plusieurs heures pour leurs préparations et leurs réalisations. Tel est le cas du test de dissolution. Ce test est très consommateur de ressources matérielles et humaines. La réalisation de stratégies de contrôle pour les tests de dissolution basée sur une approche QbD pourrait être bénéfique pour l'industrie pharmaceutique. À travers ce travail, nous avons pu : • proposer différentes stratégies novatrices de contrôle du test de dissolution de comprimés pharmaceutiques sur la base des principes du QbD, • apporter un nouvel éclairage sur la compréhension des phénomènes impliqués dans la dissolution de comprimés pharmaceutiques. Les résultats de ce projet de recherche ont permis 1) la mise en évidence des paramètres critiques influençant le test de dissolution, 2) l’élaboration et l’évaluation de modèles statistiques pour les combinaisons de variation de paramètres selon un plan d’expérience préalablement conçu, 3) la corrélation du test de dissolution à des paramètres critiques de procédés de fabrication et d’attributs de matériaux grâce aux technologies d’analyse de procédés. // Abstract : With the introduction in 2002 of the concept of Quality by Design (QbD) by the Food and Drug Administration, the pharmaceutical industry intensified efforts and investments to reach real time release of commercial batches, reducing time between manufacturing and availability to the patient. QbD proposes that quality should be built in the initial design of a product rather than being assessed at the end of the tablet manufacturing. Thus, with the QbD initiative, quality control tests of tablets like dissolution testing performed after manufacturing could be removed if the parameters impacting them are controlled. Indeed, quality control tests such as traditional dissolution tests generally require several hours for their preparation and their realizations. Dissolution tests are time consuming, require large amounts of material and human resources. The elimination of these tests through a QbD approach could be beneficial for the pharmaceutical industry. Thanks to this work, it was possible to :  propose different innovative strategies to control the dissolution test of pharmaceutical tablets based on the principles of Quality by Design,  have a better understanding of this quality control test. The main results relies on 1) the identification of critical parameters influencing the dissolution test, 2) the development and evaluation of statistical models for the combination of variation of parameters according to an experimental design, 3) the correlation of dissolution test to critical manufacturing process parameters and attributes of materials through process analysis technology.

Hand-held optical imagers are developed towards clinical breast cancer imaging. Herein, a Gen-2 hand-held optical imager has been developed with unique features: (i) image curved breast tissues with ~86% surface contact, and (ii) perform reflectance and transillumination imaging using the novel forked probe heads. Extensive phantom studies were performed using 1% Liposyn solution (background, ~ 300 ml and 1000 ml volumes) and 0.45 cc India Ink (absorption) targets, under different target:background contrast ratios and target depths. Two-dimensional surface images detected target(s) up to 2.5 cm deep via reflectance imaging, and up to 5 cm deep via transillumination imaging. Preliminary studies on gel-based breast phantoms (~700 ml) detected targets via reflectance and transillumination imaging. Preliminary in-vivo reflectance studies on normal and cancerous breast tissues also detected targets, although with artifacts. In future, the portable Gen-2 imager has potential for clinical breast imaging via reflectance and transillumination approach after extensive in-vivo studies.

A partir de 2002, grâce à l'introduction du concept de la Qualité par la Conception (en anglais Quality by Design : QbD) par l'agence américaine des produits alimentaires et médicamenteux, l'industrie pharmaceutique a intensifié les efforts et les investissements pour permettre une libération en temps réel des lots commerciaux. Le QbD propose que la qualité soit construite dès la conception initiale du médicament plutôt que d'être évaluée à la fin de sa fabrication. Ainsi, avec l'initiative QbD, les tests de contrôle de la qualité de médicaments, réalisés après la fabrication des comprimés, peuvent être éliminés si les paramètres qui les influencent sont contrôlés.En effet, ces tests de contrôle qualité dits traditionnels requièrent en général plusieurs heures pour leurs préparations et leurs réalisations. Tel est le cas du test de dissolution. Ce test est très consommateur de ressources matérielles et humaines. La réalisation de stratégies de contrôle pour les tests de dissolution basée sur une approche QbD pourrait être bénéfique pour l'industrie pharmaceutique.À travers ce travail, nous avons pu :• proposer différentes stratégies novatrices de contrôle du test de dissolution de comprimés pharmaceutiques sur la base des principes du QbD,• apporter un nouvel éclairage sur la compréhension des phénomènes impliqués dans la dissolution de comprimés pharmaceutiques.Les résultats de ce projet de recherche ont permis 1) la mise en évidence des paramètres critiques influençant le test de dissolution, 2) l'élaboration et l'évaluation de modèles statistiques pour les combinaisons de variation de paramètres selon un plan d'expérience préalablement conçu, 3) la corrélation du test de dissolution à des paramètres critiques de procédés de fabrication et d'attributs de matériaux grâce aux technologies d'analyse de procédés. / With the introduction in 2002 of the concept of Quality by Design (QbD) by the Food and Drug Administration, the pharmaceutical industry intensified efforts and investments to reach real time release of commercial batches, reducing time between manufacturing and availability to the patient. QbD proposes that quality should be built in the initial design of a product rather than being assessed at the end of the tablet manufacturing. Thus, with the QbD initiative, quality control tests of tablets like dissolution testing performed after tablets manufacturing could be removed if the parameters impacting them are controlled.Indeed, quality control tests such as traditional dissolution tests generally require several hours for their preparation and their realizations. Dissolution tests are very consuming of time, material, equipment and human resources. The elimination of these tests through a QbD approach could be beneficial for the pharmaceutical industry.Thanks to this work, it was possible to :• propose different innovative strategies to control the dissolution test of pharmaceutical tablets based on the principles of Quality by Design,• have a better understanding of this quality control test.The main results relies on 1) the identification of critical parameters influencing the dissolution test, 2) the development and evaluation of statistical models for the combination of variation of parameters according to an experimental design, 3) the correlation of dissolution test to critical manufacturing process parameters and attributes of materials through process analysis technology.