<p>Supersaturating drug delivery systems are an attractive solubility enabling formulation strategy for poorly soluble drugs due to their potential to significantly enhance solubility and hence, bioavailability. Compendial dissolution testing is commonly used a surrogate for assessing the bioavailability of enabling formulations. However, it increasingly fails to accurately predict <i>in vivo</i> performance due its closed-compartment characteristics and the lack of absorptive sink conditions. <i>In vivo</i>, drug is continually removed due to absorption across the gastrointestinal membrane, which impacts the luminal concentration profile, which in turn affects the dissolution kinetics of any undissolved material, as well as crystallization kinetics from supersaturated solutions. Thus, it is critical to develop an improved methodology that better mimics <i>in vivo</i> conditions. An enhanced approach integrates dissolution and absorption measurements. However, currently-used two-compartment absorptive apparatuses, employing a flat-sheet membrane are limited, in particular by the small membrane surface area that restricts the mass transfer, resulting in unrealistic experimental timeframes. This greatly impacts the suitability of such systems as a formulation development tool. The goal of this research is two-fold. First, to develop and test a high surface area, flow-through, absorptive dissolution testing apparatus, designed to provide <i>in vivo</i> relevant information about formulation performance in biologically relevant time frames. Second, to use this apparatus to obtain mechanistic insight into physical phenomenon occurring during formulation dissolution. Herein, the design and construction of a coupled dissolution-absorption apparatus using a hollow fiber membrane module to simulate the absorption process is described. The hollow fiber membrane offers a large membrane surface area, improving the mass transfer rates significantly. Following the development of a robust apparatus, its application as a formulation development tool was evaluated in subsequent studies. The dissolution-absorption studies were carried out for supersaturated solutions generated via anti-solvent addition, pH-shift and by dissolution of amorphous formulations. The research demonstrates the potential of the apparatus to capture subtle differences between formulations, providing insight into the role of physical processes such as supersaturation, crystallization kinetics and liquid-liquid phase separation on the absorption kinetics. The study also explores dissolution-absorption performance of amorphous solid dispersions (ASDs) and the influence of resultant solution phase behavior on the absorption profile. Residual crystalline content in ASDs is a great concern from a physical stability and dissolution performance perspective as it can promote secondary nucleation or seed crystal growth. Therefore, the risk of drug crystallization during dissolution of ASDs containing some residual crystals was assessed using absorptive dissolution measurements and compared to outcomes observed using closed-compartment dissolution testing. Mesoporous silica-based formulations are another type of amorphous formulations that are gaining increased interest due to higher physical stability and rapid release of the amorphous drug. However, their application may be limited by incomplete drug release resulting from the adsorption tendency of the drug onto the silica surface. Thus, the performance of mesoporous silica-based formulations was also evaluated in the absorptive dissolution testing apparatus to determine the impact of physiological conditions such as gastrointestinal pH and simultaneous membrane absorption on the adsorption kinetics during formulation dissolution. Overall, the aim of this research was to demonstrate the potential of the novel <i>in vitro</i> methodology and highlight the significance of a dynamic absorptive dissolution environment to enable better assessment of complex enabling formulations. <i>In vivo</i>, there are multiple physical processes occurring in the gastrointestinal lumen and the kinetics of these processes strongly depend on the absorption kinetics and <i>vice-a-versa</i>. Thus, using this novel tool, the interplay between solution phase behavior and the likely impacts on bioavailability of supersaturating drug delivery systems can be better elucidated. This approach and apparatus is anticipated to be of great utility to the pharmaceutical industry to make informed decisions with respect to formulation optimization.</p>

La principale difficulté lors de l'administration orale d'un ingrédient pharmaceutique actif (API) est de garantir que la dose clinique de l’API sera dissoute dans le volume disponible de liquides gastro-intestinaux. Toutefois, environ 40% des API sur le marché et près de 90% des molécules en cours de développement sont peu solubles dans l’eau et présentent une faible absorption par voie orale, ce qui entraîne une faible biodisponibilité. Les dispersions solides amorphes (ASD) sont considérées comme l’une des stratégies plus efficaces pour résoudre des problèmes de solubilité des principes actifs peu solubles dans l’eau et, ainsi, améliorer leur biodisponibilité orale. En dépit de leur introduction il y a plus de 50 ans comme stratégie pour améliorer l’administration orale des API, la formation et la stabilité physique des ASD font toujours l'objet de recherches approfondies. En effet, plusieurs facteurs peuvent influer sur la stabilité physique des ASD pendant le stockage, parmi lesquels la température de transition vitreuse du mélange binaire API-polymère, la solubilité apparente de l'API dans le polymère, les interactions entre l'API et le polymère et le procédé de fabrication. Cette thèse consistait en deux parties qui avaient pour objectif le développement de nouvelles formulations sous forme d’ASD d'un antirétroviral, l'Efavirenz (EFV), dispersé dans un polymère amphiphile, le Soluplus, en utilisant deux procédés différents, le séchage par atomisation (SD) et l'extrusion à chaud (HME). EFV est l’API BCS de classe II de notre choix car c’est un API qui représente un défi pour les nouvelles formulations. En effet, il a besoin d’ASD plus fortement concentrées, pour lesquelles la stabilité chimique et physique pendant le stockage et la dissolution seront essentielles. Dans le but de développer de manière rationnelle les ASDs EFV- Soluplus à forte concentration, la première partie s'est concentrée sur la construction d'un diagramme de phases EFV-Soluplus en fonction de la composition et de la température. Le diagramme de phases a été construit à partir d'une étude thermique de recristallisation d'un ASD sursaturé (85 %m EFV), générée par séchage par atomisation. À notre connaissance, il s'agit de la première étude à présenter un diagramme de phase pour ce système binaire. Ce diagramme de phases est très utile et démontre que la solubilité de l'EFV dans les solutions varie de 20 %m (25 °C) à 30 %m (40 °C). Les ASD de EFV dans le Soluplus contenant plus de 30 %m d'EFV doivent être surveillées pendant le stockage dans des conditions typiques de température. Ce diagramme de phases peut être considéré comme un outil de pré-formulation pour les chercheurs qui étudient de nouvelles ASD d'EFV dans le Soluplus afin de prédire la stabilité (thermodynamique et cinétique). Les ASD préparées par différentes techniques peuvent afficher des différences dans leurs propriétés physicochimiques. La deuxième partie de cette thèse portait sur la fabrication d’ASD par des procédés HME et SD. Cette étude montre clairement que la formation d’ASD est une stratégie de formulation utile pour améliorer la solubilité dans l'eau et la vitesse de dissolution de l'EFV à partir de mélanges binaires EFV-Soluplus. Les procédés de fabrication (HME et SD) se sont révélés efficaces pour générer des ASD dans une large gamme de compositions en EFV. L'optimisation du ratio EFV-Soluplus peut être utilisée pour adapter la libération cinétique des ASD. Le choix d’une charge EFV élevée dépassant la solubilité thermodynamique de l’EFV dans le Soluplus est possible, mais il convient de prendre en compte sa stabilité cinétique dans le temps. / The main difficulty when an Active Pharmaceutical Ingredient (API) is orally administered is to guarantee that the clinical dose of the API will be dissolved in the available volume of gastrointestinal fluids. However, about 40% of APIs with market approval and nearly 90% of molecules in the discovery pipeline are poorly water-soluble and exhibits a poor oral absorption, which leads to a weak bioavailability. Amorphous solid dispersions (ASD) are considered as one of the most effective strategies to solve solubility limitations of poorly-water soluble compounds and hence, enhance their oral bioavailability. Despite their introduction as technical strategy to enhance oral APIs bioavailability more than 50 years ago, ASD formation and physical stability remains a subject of intense research. Indeed, several factors can influence the physical storage stability of ASD, among them, the glass transition temperature of the API-carrier binary mixture, the apparent solubility of the API in the carrier, interactions between API and carrier, and the manufacturing process. This thesis consisted of two parts that aim on developing new formulations of ASD of an antiretroviral API, Efavirenz (EFV), dispersed in an amphiphilic polymer, Soluplus, by using two different processes, Spray-drying (SD) and Hot-melt extrusion (HME). EFV is the class II BCS API of our choice because it is a challenging API for new formulations. It needs higher-dosed ASDs, for which chemical and physical stability during storage and dissolution will be critical. Aiming a rational development of high-loaded EFV-Soluplus ASDs, the first part focused on the construction of a temperature- composition EFV-Soluplus phase diagram. The phase-diagram was constructed from a thermal study of recrystallization of a supersaturated ASD (85 wt% in EFV), generated by spray drying. To our knowledge, this is the first study reporting a phase-diagram for this binary system. This phase-diagram is very useful and demonstrated that the EFV solubility in Soluplus ranges from 20 wt% (25 °C) to 30 wt% (40 °C). ASD of EFV in Soluplus containing more than 30 wt% of EFV should be monitored over storage under typical temperature conditions. This phase-diagram might be considered as a preformulation tool for researchers studying novel ASD of EFV in Soluplus, to predict (thermodynamic and kinetic) stability. ASD prepared by different techniques can display differences in their physicochemical properties. The second part of this thesis focused on the manufacturing of ASD by HME or SD processes. This study clearly shows that ASD is a useful formulation strategy to improve the aqueous solubility and the dissolution rate of EFV from EFV-Soluplus binary mixtures. HME and SD manufacturing processes demonstrated to be efficient to generate ASDs in a large range of compositions and loads of EFV. The optimization of EFV to Soluplus ratio can be used to tailor the release kinetics from ASD. The choice of a high EFV load exceeding the thermodynamic solid solubility in Soluplus is possible but it needs the consideration of its kinetic stability over time.