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 H-1 T-1 (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 H-1 T-1, which also leads to enhanced sensitivity in {H-1}-C-13 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 C-13 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 C-13 CP spectrum. This simple ball milling method used for sensitivity enhancement can be further applied in the SS-NMR studies of pharmaceutical samples.