Orally disintegrating tablets: formulation development, novel engineering solutions and fixed dose combinations

Orally disintegrating tablets (ODTs) are an attractive solid dosage form for patients who suffer from dysphagia, a difficulty in swallowing, which is particularly prevalent in paediatric and geriatric populations. ODTs and fixed dose combination (FDC) formulations are popular as they improve patient compliance and combination of the two has not previously been explored. The requirement for ODTs to disintegrate rapidly whilst also being mechanically robust means that high drug loading is a significant challenge. An ODT formulation for the betalactam antibiotic flucloxacillin was developed at doses of 250 and 125 mg. ODTs were mechanically robust, however this limited disintegration to within 3 mins, with mannitol fragmentation being a major limitation. Polymeric film coating was devised as a potential technique to enhance ODT mechanical properties. Due to high attrition during fluidisation a novel stationary coating technique was developed as a proof of concept. ODTs coated in this way, coupled with a postcoating curing step, demonstrated an increase in hardness of almost double and essentially zero friability. This novel coating technique could prove hugely beneficial in the formulation of high dose or poorly compactable drugs. The application of ODTs for FDCs was tested with four model drugs: amlodipine (5 mg), atorvastatin (10 mg), isoniazid (50 mg) and rifampicin (75 mg). ODT formulations for single and FDCs showed rapid disintegration and good mechanical properties. Comparison of single and FDC dissolution profiles was performed using FDA recommended f1 and f2 testing. Bioavailability from ODTs was assessed using in vitro Caco-2 permeability and dissolution data and in silico physiologically based pharmacokinetic modelling. Bioequivalence was demonstrated between single and FDC for each drug in both fed and fasted states, whilst atorvastatin showed a positive food effect (enhanced peak plasma concentration and area under the curve), due to reduced metabolism by CYP3A4

Robust and efficient meshfree solid thermo-mechanics simulation of friction stir welding

Friction stir welding, FSW, is a solid-state joining method that is ideally suited for welding aluminum alloys. Welding of the aluminum is accomplished by way of a hardened steel tool that rotates and is pushed with great force into the work pieces. Friction between the tool and the aluminum causes heat to be generated, which softens the aluminum, rendering it easy to deform plastically. In recent years, the FSW process has steadily gained interest in various fabrication industries. However, wide spread acceptance has not yet been attained. Some of the main reasons for this are due to the complexity of the process and the capital cost to procure the required welding equipment and infrastructure. To date, little attention has been paid towards finding optimal process parameters that will increase the economic viability of the FSW process, thus offsetting the high initial investment most. In this research project, a robust and efficient numerical simulation code called SPHriction-3D is developed that can be used to find optimal FSW process parameters. The numerical method is meshfree, allowing for all of the phases of the FSW process to be simulated with a phenomenological approach. The dissertation starts with a focus on the current state of art. Next an in-depth development of the proposed meshfree formulation is presented. Then, the emphasis turns towards the presentation of various test cases along with experimental validation (the focus is on temperature, defects, and tool forces). The remainder of the thesis is dedicated to the development of a robust approach to find the optimal weld quality, and the associated tool rpm and advancing speed. The presented results are of engineering precision and are obtained with low calculation times (hours as opposed to days or weeks). This is possible, since the meshfree code is developed to run in parallel entirely on the GPU. The overall outcome is a cutting edge simulation approach for the entire FSW process. Le soudage par friction malaxage, SFM, est une méthode idéale pour relier ensemble des pièces en aluminium. Lors du procédé, un outil en acier très dur tourne à haute vitesse et est presser dans les plaques avec beaucoup de force. L’outil frotte sur les plaques et génère la chaleur, ce qui ramollie l’aluminium, ceci le rendant plus facile à déformé mécaniquement. Récemment, le SFM a connu une croissance de reconnaissance important, par contre, l’industrie ne l’as pas encore adopté unilatéralement. Il existe encore beaucoup de terrain à défricher avant de bien comprendre comment les paramètres du procédé font effet sur la qualité de la soudure. Dans ce travail, on présente une approche de simulation numérique sans maillage pour le SFM. Le code développé est capable de prendre en considération des grandes déformations plastiques, le ramollissement de l’aluminium avec la température, et la condition de frottement complexe. Cette méthode permet de simulé tous les phases du procédé SFM dans une seule modèle. La thèse commence avec un mis en contexte de l’état actuel de la simulation numérique du SFM. Une fois la méthodologie de simulation sans maillage présenté, la thèse concentre sur différents cas de vérification et validation. Finalement, un travail d’optimisation des paramètres du procédé est réalisé avec le code numérique. La méthode de simulation présentée s’agit d’une approche efficace et robuste, ce qui le rend un outil de conception valable pour les ingénieurs qui travaille dans le domaine de SFM