INTRODUCTION

The physical stability of pharmaceutical materials (e.g., excipients, active ingredients, intermediates) and drug products is an important property to consider when developing any new medicine, as the following considerations illustrate:

• Physical changes have been the cause of some high-profile product recalls and reductions in product shelf-life (1). Recalls have occurred for a drug product from the US marketplace due to changes in the unexpected appearance of a more stable and less soluble crystal form and for a transdermal system after crystals formed unexpectedly and compromised its efficacy.

• As recently as the 1980s, the screening of drug substances for polymorphism and for the ability to form salts/co-crystals and hydrates/solvates ("pseudopolymorphs") was not routine at many companies. Hence, there was limited awareness of the risks of physical transformations occurring during the manufacture, storage, and use of pharmaceutical dosage forms (2).

• Since the 2000s, there has been a marked increase in the use of amorphous drug substances and intermediates, increasing the probability of physical instability occurring because of recrystallization (3).

• There has been an increased understanding of the risks of developing salt forms of weak bases, which can disproportionate in the presence of excipients commonly used to manufacture immediate-release solid oral dosage forms (4).