Reduction of the ¹³C cross-polarization experimental time for pharmaceutical samples with long T₁ by ball milling in solid-state NMR

Many pharmaceutical samples have notably long ¹H T₁ (proton spin-lattice relaxation time), leading to lengthy experiments lasting several days in solid-state NMR studies. In this work, we propose the use of ball milling on the pharmaceutical samples to reduce the ¹H T₁, which also leads to enhanced sensitivity in {¹H}-¹³C Cross-Polarization (CP) experiments due to reduced particle sizes and increased surface areas of the samples. Experimentally, we determined that depending on the substrates and milling time, the signal-to-noise ratio (S/N) of a 1D ¹³C CP spectrum can be increased by a factor of 3–6, which means that the experimental time can be shortened by a factor of 9–36. Furthermore, the application of simple ball-milling within a short time avoids the amorphization of the studied samples such that no signal due to amorphous state is observed in the ¹³C CP spectrum. This simple ball milling method used for sensitivity enhancement can be further applied in the SS-NMR studies of pharmaceutical samples.