Rapid Quantification of Pharmaceuticals via (1)H Solid-State NMR Spectroscopy

[Image: see text] The physicochemical properties of active pharmaceutical ingredients (APIs) can depend on their solid-state forms. Therefore, characterization of API forms is crucial for upholding the performance of pharmaceutical products. Solid-state nuclear magnetic resonance (SSNMR) spectroscopy is a powerful technique for API quantification due to its selectivity. However, quantitative SSNMR experiments can be time consuming, sometimes requiring days to perform. Sensitivity can be considerably improved using (1)H SSNMR spectroscopy. Nonetheless, quantification via (1)H can be a challenging task due to low spectral resolution. Here, we offer a novel (1)H SSNMR method for rapid API quantification, termed CRAMPS–MAR. The technique is based on combined rotation and multiple-pulse spectroscopy (CRAMPS) and mixture analysis using references (MAR). CRAMPS–MAR can provide high (1)H spectral resolution with standard equipment, and data analysis can be accomplished with ease, even for structurally complex APIs. Using several API species as model systems, we show that CRAMPS–MAR can provide a lower quantitation limit than standard approaches such as fast MAS with peak integration. Furthermore, CRAMPS–MAR was found to be robust for cases that are inapproachable by conventional ultra-fast (i.e., 100 kHz) MAS methods even when state-of-the-art SSNMR equipment was employed. Our results demonstrate CRAMPS–MAR as an alternative quantification technique that can generate new opportunities for analytical research.