Hirsh, David A., Anuradha V. Wijesekara, Scott L. Carnahan, Ivan Hung, Joseph W. Lubach, Karthik Nagapudi, and Aaron J. Rossini. “Rapid Characterization of Formulated Pharmaceuticals Using Fast MAS 1H Solid-State NMR Spectroscopy.” Molecular Pharmaceutics 16, no. 7 (July 1, 2019): 3121–32.
Active pharmaceutical ingredients (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 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, twodimensional experiments, and 1H spin diﬀusion periods. Selective saturation pulses eﬃciently suppress the broad 1H SSNMR signals from the most commonly encountered excipients such as lactose and cellulose, allowing observation of high-frequency API 1H NMR signals. 1H SSNMR provides a 1−3 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 minutes. The 1H SSNMR spectra can be used for quantiﬁcation, provided calibrations are performed on a standard sample with known API loading.