Understanding hydrate formation in aqueous pharmaceutical environments

The general objective of this project was to develop a mechanistic understanding of phase transformations occurring during high-shear wet granulation of pharmaceutical formulations. Processing-induced transformations are of great interest to the pharmaceutical industry, since such changes in solid-state form may lead to changes in bioavailability and chemical stability of the drug product. By understanding the mechanism underlying phase transformations during high-shear wet granulation, suitable excipients and processing parameters can be selected in order to avoid future changes to the solid state of the drug. Several model hydrate forming compounds with different aqueous solubilities were selected. Initially the effect of processing parameters on the transformation kinetics was investigated. This was followed by screening the effect of common pharmaceutical excipients on the conversion rate. The aim of such studies was to determine which specific properties of the drug and what extrinsic factors would have the greatest impact on the kinetics of phase transformations. It was found that excipients have the largest effect on the transformation kinetics. Further studies were conducted to understand the basis for the excipient effects. In addition to developing this mechanistic understanding, analytical methodologies were evolved and implemented to monitor the occurrence of processing-induced transformations