Differentiating and Quantifying Two Different Amorphous Phases of a Drug Substance in Tablet Formulation by ¹⁵N...

A sensitive solid-state ¹⁵N NMR method was developed to allow for differentiation and quantification of amorphous drug substance (DS) potassium salt, amorphous DS free form, and their crystalline counterparts in the presence of excipients in a tablet formulation. To achieve the desired sensitivity, ¹⁵N-enriched DS crystalline potassium salt was used to prepare tablets. The tablets were stressed at multiple elevated temperature and relative humidity conditions to assess the extent of DS amorphization and ensuing salt disproportionation with the goal of determining if any free DS form (amorphous or crystalline) was generated. In contrast to the potassium salt, the free DS form was known to present a chemical degradation liability. This work confirmed the mechanism of the DS degradation being the amorphization-mediated salt disproportionation and, by evaluating the routes to amorphization, determined the risk of degradation during the life cycle of the drug product.