Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)


Industrial and Physical Pharmacy

Committee Chair

Lynne S. Taylor

Committee Member 1

Stephen Byrn

Committee Member 2

Tonglei Li

Committee Member 3

Sheri Shamblin


Salt forms of the active pharmaceutical ingredient (API) are commonly encountered in the pharmaceutical industry. About half of marketed pharmaceutical products contain the salt form of the API. Salt disproportionation, where the salt converts to the free form, is an important concern for pharmaceutical products containing the salt form of a drug. This is because conversion of the salt to the free form decreases the solubility and/or alters the reactivity, potentially resulting in a decrease in product quality. However, many of the factors dictating the tendency of a given salt to undergo disproportionation remain to be elucidated. In particular, the role of the solid-state properties and crystal structure of the salt on the disproportionation reaction is unknown. In this study, by utilizing various model salts of weakly basic compounds, we have shown how differences in the both solid forms as well as the crystal structure of salt in general can led to differences in its disproportionation. The results of these studies indicated that the salts structures involving intermediate water molecules as a bridge between API and counterion are resistant to disproportionation. Salts having a crystalline arrangement where the salt bridge is shielded or those forming dual salt bridges are also shown to stable against disproportionation. On the other hand, amorphous salts which lack long range ordered molecular packing are shown to highly prone to disproportionation. By understanding the correlation of solid form, crystal structure, and excipient properties to disproportionation, we can rationally design stable salt formulations.