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 1H SSNMR spectroscopy. Nonetheless, quantification
via 1H can be a challenging task due to low spectral resolution.
Here, we offer a novel 1H 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 1H
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.