Assessing the Risk of Salt Disproportionation Using Crystal Structure and Surface Topography Analysis

Salt disproportionation is a major issue for pharmaceutical products containing a salt form of a weakly basic drug, because conversion to the free base during processing or storage in the presence of excipients may negatively impact stability and bioperformance of the drug product. Several factors influencing disproportionation tendency have been elucidated; however, a complete mechanistic understanding of this phenomenon is still lacking. Specifically, it is unclear if the crystal structure of the salt plays a role, beyond influencing the salt solubility. Herein, by utilizing model compounds with similar pKa and pHmax values, and hence similar thermodynamic driving forces for disproportionation, we demonstrate that salt crystal structure appears to play a major role in influencing disproportionation tendency. Some salts with low pHmax values were found to be resistant to disproportionation, while other systems transformed to the free base following contact with the basic excipient, magnesium stearate. For salts that converted to the free base, the new crystal phase was imaged using atomic force microscopy and scanning electron microscopy. Based on these images, it was concluded that conversion occurred via a nucleation and growth process; i.e., transformation involved considerable structural rearrangement. Extensive crystallographic analysis provided some insight, suggesting that the packing and intermolecular interactions around the salt bridge may influence the susceptibility of the salt to conversion to the free base when challenged with a basic microenvironment. Thus, evaluation of disproportionation risk requires consideration not only of pHmax, but also salt crystal structure, whereby different solid state forms of a given salt may present different risk levels for conversion to free base. Further studies of correlations between crystal structure and disproportionation tendency are clearly warranted to ensure the development of robust salt formulations.