Rapid Characterization of Formulated Pharmaceuticals Using Fast MAS ¹H Solid-State NMR Spectroscopy

Abstract

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, two-dimensional 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.