Kinetic Barriers to Disproportionation of Salts of Weakly Basic Drugs

Disproportionation is a major issuein formulations containingsalts of weakly basic drugs. Despite considerable interest in riskassessment approaches for disproportionation, the prediction of salt-to-baseconversion remains challenging. Recent studies have highlighted severalconfounding factors other than pH(max) that appear to playan important role in salt disproportionation and have suggested thatkinetic barriers need to be considered in addition to the thermodynamicdriving force when assessing the risk of a salt to undergo conversionto parent free base. Herein, we describe the concurrent applicationof in situ Raman spectroscopy and pH monitoring toinvestigate the disproportionation kinetics of three model salts,pioglitazone hydrochloride, sorafenib tosylate, and atazanavir sulfate,in aqueous slurries. We found that even for favorable thermodynamicconditions (i.e., pH >> pH(max)),disproportionation kinetics of the salts were very different despiteeach system having a similar pH(max) . Theimportance of free base nucleation kinetics was highlighted by theobservation that the disproportionation conversion time in the slurriesshowed the same trend as the free base nucleation induction time.Pioglitazone hydrochloride, with a free base induction time of <1min, rapidly converted to the free base in slurry experiments. Incontrast, atazanavir sulfate, where the free base induction time wasmuch longer, took several hours to undergo disproportionation in theslurry for pH >> pH(max). Additionally, we alteredan established thermodynamically based modeling framework to accountfor kinetic effects (representing the nucleation kinetic barrier)to estimate the solid-state stability of salt formulations. In conclusion,a solution-based thermodynamic model is mechanistically appropriateto predict salt disproportionation in a solid-state formulation, whenkinetic barriers are also taken into consideration.