Mechanism of Process-Induced Salt-to-Free Base Transformation of Pharmaceutical Products

The pH-solubility profiles of a model drug in salt form were established and the mechanism of salt-to-free base form transformation was investigated by increasing pH of the system. Wet massing experiments together with suspension experiments were performed to investigate the effects of excipients on the stability of the salt form. It was found that nucleation of the free base did not happen at pH_max but that instead a new boundary, the pH_metastable, had to be reached before transformation occurred. It was also demonstrated that some excipients influence the stability of the drug, which can help find excipients that previously would have been excluded on basis of a pH higher than pH_max but still lower than pH_metastable.