Excipients are used in pharmaceutical formulations as fillers and drug carriers. Their successful function is inextricably linked to their physicochemical properties and, in turn, these properties are directly related to their structure. This thesis is concerned with the structural and spectroscopic characterisation of a selection of excipients by powder and single crystal X-ray diffraction, Raman and IR spectroscopy and MASNMR and an investigation of their stability as a function of temperature, humidity and particle size. As well as being a well-known excipient used in the pharmaceutical industry, lactose is also a common food additive. The diverse usage of lactose has led to a wealth of contradictory information relating to both structure and properties of this material. The first part of experimental work in this thesis identifies the four real lactose polymorphs; the naturally occurring a-lactose monohydrate; the anhydrous stable form of a-lactose; the hygroscopic unstable form of a-lactose; and the anomeric equivalent, p-lactose using powder X-ray diffraction. The work shows that anhydrous lactose formed by solvent dehydration often termed aM is simply the anhydrous stable form of a-lactose formed via a different route. Simple methods for discerning between the polymorphs using standard laboratory equipment are suggested. IlC MASNMR data were collected on all four forms of lactose for the first time and illustrate key differences between the four structures. Single crystal data were successfully collected on the a-lactose monohydrate and refinement carried at low temperature to determine the hydrogen bonded arrangement for the first time. Rietveld refmement of the hygroscopic unstable form of a-lactose using in-situ temperature resolved X-ray diffraction has shown that the hygroscopic form can be produced as a single phase. Refinement of Plactose using the Rietveld method has shown that powder diffraction data were comparable with single crystal data, with respect to structure refinement but attempts at both crystallisation and refinement of the stable anhydrous a-lactose polymorph were unsuccessful due to the complexity of the structure. Powder X-ray diffraction analysis was shown to be an effective tool in the quantification of mixed phase lactose samples with respect to both mixed phase stable anhydrous a-lactose and a-lactose monohydrate; and mixed p-Iactose and a-lactose monohydrate samples. The accuracy of the technique was determined to be at least 5%. Quantification was carried out using relative intensities of a well resolved unique reflection for each phase within the system. Dehydration techniques applied to lactose were applied to other hydrated pharmaceutical sugars; trehalose dihydrate and raffmose pentabydrate. Solid state techniques; powder X-ray diffraction, Raman and IR spectroscopy; showed that discrimination of other sugar hydrates became more complex with increasing levels of hydration.

L’augmentation de la demande en lait infantile génère une forte croissance de la production mondiale de lactose. En raison d’exigences accrues sur la qualité du produit, le mottage, ou prise en masse spontanée de la poudre, est une non-conformité pouvant s’avérer très coûteuse. En utilisant une approche procédé – produit, ce projet vise à identifier les paramètres critiques et comprendre les mécanismes de mottage du lactose, pour donner les moyens aux industriels de prévenir le mottage. Les résultats obtenus sur des poudres produites à l’échelle pilote montrent le rôle déterminant des impuretés (i.e. composés autres que le lactose) et de la granulométrie. En effet, les impuretés renforcent l’hygroscopicité et le mottage. De plus, en augmentant la teneur en impuretés, la surface spécifique et le nombre de points de contact, une diminution de la taille des particules et une hétérogénéité de tailles accrue intensifient le mottage. L’analyse des poudres commerciales a confirmé ces résultatUn autre résultat marquant de ce travail est le développement d’un test de mottage accéléré, qui permet de classer des poudres de lactose en fonction de leur tendance au mottage en moins d’une journée, après un stockage à 50°C et 60% d’HR. Un test similaire implémenté sur chaque site de production permettrait l’identification rapide des lots à risque avant expédition. Grâce à la meilleure compréhension des mécanismes de mottage fourni par ce travail, les industriels peuvent cibler les étapes critiques du procédé à optimiser pour prévenir le mottage du lactose. / Driven by the growth in the infant formula market, lactose production is increasing worldwide, and the requirements for the product quality are becoming stricter. Caking, or the unwanted agglomeration of lactose powder particles, is synonym of poor quality for the customers and should therefore be prevented to avoid large economic loss. Focusing on the process–product relationship, this PhD project aimed at finding the critical parameters and understanding the caking mechanisms in lactose powder in order to establish means to limit caking. In samples from pilot production, impurities (i.e. non-lactose components) were shown to increase moisture sorption and caking. The particle size distribution of the powder also exhibited a large effect on caking. Indeed, smaller particles and a broader distribution were characterized by enhanced moisture sorption and stronger caking, which were explained by a larger impurity content and surface area and more contact points.Analyses on the commercial powder confirmed these results and revealed the instability of the water activity during storage of the powder after drying, which was linked to caking in the bags. This PhD project also addressed an essential need in the dairy industry, i.e. the development of an accelerated caking test. Samples from different production sites were discriminated in terms of caking in less than a day, using appropriate test conditions (50°C and 60% RH). A similar test implemented at all sites would highlight batches with a high caking tendency before shipment to the customers. The better understanding of th