Role of Excipients in Moisture Sorption and Physical Stability of Solid Pharmaceutical Formulations.

Abstract

The interaction of moisture with pharmaceutical solids is crucial to an understanding of water-based processes, e.g. manufacturing processes or prediction of solid dosage form stability and shelf life. Sorbed moisture of either the active pharmaceutical ingredient (API) or excipients in the pharmaceutical formulation can result in unexpected processing-induced phase transformations (PITs). Phase transformations in formulations can lead to instability in physicochemical, biopharmaceutical, and processing properties of products. Thus correct selection of excipients helps to control PIT and can improve the storage stability of the final formulations. The aim of this thesis was to study the effect of water in different excipients and explain the water-excipient interactions with special regard to the formulation and manufacturing of solid forms. This study examines the moisture sorption properties of several excipients with different degree of crystallinity after storage at various levels of humidity. This facilitates comparison of excipients regarding to preformulation stage, and thus helps predict the solid-state stability and interactions of the final formulations. The degree of crystallinity of excipients had a significant effect on the stability of formulation. The crystallinity of excipients was correlated with the ability of the excipients to inhibit hydrate formation of two model APIs. Only amorphous, hygroscopic excipient in the formulation was able to inhibit hydrate formation of API at relatively high water contents during wet granulation. Slightly hygroscopic partially crystalline excipient hindered hydrate formation of API at low water contents. Non-hygroscopic crystalline excipient could even enhance the hydrate formation of API. In general, the more amorphous the excipient, the more water was absorbed into its structure and the slower was the rate of API hydrate formation. With low water contents, a spectroscopic approach enabled phase transformations in the formulation to be identified even though there were excipients in the formulation. Finally, the effect of temperature changes on the dehydration behaviour of formulations and solid-state properties of excipients was evaluated. Process temperature and excipients used in the formulation had a significant influence on phase transitions.