This thesis describes improved methods for the characterization of pure and formulated solid active pharmaceutical ingredients (APIs) by solid-state nuclear magnetic resonance (SSNMR) spectroscopy. APIs can be prepared in many different solid forms and phases that affect their physicochemical properties and suitability for oral dosage forms. The development and commercialization of dosage forms require analytical techniques that can determine and quantify the API phase in the final drug product. 13C solid-state NMR (SSNMR) spectroscopy is widely employed to characterize pure and formulated solid APIs; however, 13C SSNMR experiments on dosage forms with low API loading are often challenging due to low sensitivity and interference from excipients. Here, fast magic angle spinning (MAS) 1H SSNMR experiments are shown to be applicable for the rapid characterization of low drug load formulations. Diagnostic 1H SSNMR spectra of APIs within tablets are obtained by using combinations of frequency-selective saturation and excitation pulses, 2D experiments, and 1H spin diffusion periods. 1H SSNMR provides a one to three orders of magnitude reduction in experiment time compared to standard 13C SSNMR experiments, enabling diagnostic SSNMR spectra of dilute APIs within tablets to be obtained within a few minutes.

We introduce fast MAS 1H{14N} Frequency Selective (FS)-HMQC experiments, analogous to solution SOFAST HMQC experiments, which provides a factor 2-3 improvement in sensitivity which corresponds to a factor 4 to 9 reductions in experiment times compared to conventional HMQC SSNMR experiments. Using this method 1H-14N through bond and through space correlation spectra can be acquired in minutes on model compounds and a few hours from more challenging samples. 1H{14N} FS RESPDOR experiments were then used to measure the N-H interatomic distances for two pharmaceutically important compounds. These measurements were used to determine the protonation states of APIs and assign them as salts or cocrystals.