Investigation of the fundamental basis of hygroscopicity in pharmaceutical salts and the consequent impact on physical and chemical stability

Despite the well-known detrimental effect of moisture on the stability of many pharmaceutical active ingredients, to date a firm molecular-level mechanistic understanding of the processes involved in both moisture uptake and resultant chemical reactivity has not been realized. One main objective of this research was to investigate the underlying mechanisms governing moisture uptake in pharmaceutical salts and concomitantly investigate the physico-chemical state of water at the surface. Another goal was to better understand the phenomena responsible for chemical and physical instability of pharmaceutical salts, both in the pure form and within mixtures of various types of excipients. In order to probe the state of water on the surface of pharmaceutical salts, a modified x-ray photoelectron spectroscopy (XPS) experimental setup and method was developed, enabling exposure to high partial pressures of water in an environment protected from ambient conditions. The surface of model hydrochloride salts was shown to induce dissociation of water. Salt disproportionation to the free base in the presence of moisture was evaluated in the presence of various excipients and rationalized based on the properties of the salt, together with the properties of excipients. The impact of the counterion on the chemical stability of a model hydrolyzable pharmaceutical crystalline compound was explored in the solid state. The nature of the counterion was found to have a profound influence on chemical stability. In addition, the impact of surface impurities on the thermodynamics of moisture sorption and the subsequent impact on the reactivity of a model salt were explored. One of the important findings of this work was evidence for solvation of ions at the surface of the salts investigated under conditions which were thermodynamically unfavorable with respect to solution thermodynamics. Finally, important solid-state properties of pharmaceutical salts with relevance to developability were shown to be dependent on a number of properties of the counterion, for a series of crystalline salts of a model pharmaceutical compound