Quantifying Pharmaceutical Formulations from Proton Detected Solid-State NMR under Ultrafast Magic Angle Spinning

Probing form conversions of active pharmaceutical ingredients in solid dosages is critical for understanding the physicochemical stability of drug substances in formulations. The multicomponent and low drug loading nature of drug products often results in challenges to quantify the phase stability, at a low detection limit and with the chemical resolution that differentiate drug molecules and excipients, for routine laboratory techniques. Recent advancement of ultrafast magic angle spinning (UF-MAS) enables proton-detected solid-state nuclear magnetic resonance (ssNMR) techniques to characterize pharmaceutical materials with enhanced resolution and sensitivity. This study demonstrates one of the first documented cases implementing 60 kHz UF-MAS techniques to quantify the minor content of pioglitazone free base (PIO-FB) in a binary system with its hydrochloride salt (PIO-HCl) and a multicomponent formulation with typical excipients. One-dimensional ¹H methods can unambiguously differentiate the two forms and exhibit a limit of detection at 1.77% (w/w). Moreover, we extended it to a two-dimensional ¹H-¹H correlation for minimizing peak overlap and successfully quantifying approximately 2.0% (w/w) PIO-FB in a multicomponent formulation. These results have demonstrated that ¹H ssNMR as a novel method to quantify solid dosages at a higher resolution and faster acquisition than conventional ¹³C techniques.