Physical Stability of Salts of Weak Bases in the Solid-State

When selecting the physical form of an active pharmaceutical substance, there is often a question of when a molecule's pKa renders it too low for salt formation and formulation into a product that will be sufficiently physically stable to provide adequate shelf life. In the paper, a graph is provided that tabulates pKa values of active pharmaceuticals versus the salt or free base form that was chosen to be developed as an orally administered drug product. Tabulation of the data provides insight into where, if any, practical cutoff exists, under which salt formation should not be considered. Specific examples of disproportionation reactions are reviewed and are described in light of the concepts of pH maximum, pH microenvironment, and Gibbs free energy to gain further insight into when such reactions become favorable. The driving force for disproportionation reactions is substantially greater than that for polymorphic form conversion, and as a consequence, its probability of occurring in the solid-state is much greater when formulated in favorable microenvironments. Factors that influence the reaction rate are examined. It is concluded that each salt should be evaluated on the merit of its physical properties and often the most soluble salt will not be one's best choice. Unfortunately, compounds that stand to benefit the most from salt formation due to their exceptionally low intrinsic solubility are the ones that will be most likely to disproportionate if their pKa is relatively low. (C) 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:1607-1617, 2011