Beyond pH: Acid/Base Relationships in Frozen and Freeze-Dried Pharmaceuticals

Stability of the majority of pharmaceuticals and biopharmaceuticals depends on acidity/basicity of the environment. In aqueous solutions, acidity/basicity is commonly expressed using proton activity scale, pH, while definition and experimental measurements of acid-base relationships in frozen and freeze-dried materials are less straightforward. The chapter starts with a brief summary of the current understanding of several critical aspects of pH and apparent acidity/basicity as related to freezing and freeze-drying, whereas the main part of the chapter is focused on areas which are underrepresented in the pharmaceutical literature, with both overview of the literature and previously unpublished data presented. In particular, the following topics are covered: (i) Hammett acidity function and pH-equivalent (pH_eq); (ii) Factors which impact apparent solid-state acidity in lyophiles; (iii) Solid-state acidity and chemical instability of lyophiles; (iv) Freezing fundamentals: quasi-liquid layer, polarity of the freeze-concentrated solution, and the Workman-Reynolds potential. Potential directions for future studies in this field are also outlined.