14 N- 1 H HMQC solid-state NMR as a powerful tool to study amorphous formulations - an exemplary study of paclitaxel loaded polymer micelles.

Amorphous drug-polymer formulations are complex materials and often challenging to characterize, even more so if the small molecule component itself is increasingly complex. In this work, we present ¹⁴ N- ¹ H HMQC magic-angle spinning (MAS) NMR experiments in the solid state as a promising tool to study amorphous formulations. Poly(2-oxazoline) based polymer micelles loaded with different amounts of the cancer drug paclitaxel serve to highlight the possibilities offered by these experiments: while the dense core of these polymeric micelles prevents NMR spectroscopic analysis in solution and the very similar ¹⁵ N chemical shifts hamper a solid-state NMR characterization based on this nucleus, ¹⁴ N is a very versatile alternative. ¹⁴ N- ¹ H HMQC experiments yield well-separated signals, which are spread over a large ppm range, and provide information on the symmetry of the nitrogen environment and probe ¹⁴ N- ¹ H through-space proximities. In this way, the overall complexity can be narrowed down to specific N-containing environments. The results from the experiments presented here represent a valuable puzzle piece, which helps to improve the structural understanding of drug-polymer formulations. It can be straightforwardly combined with complementary NMR spectroscopic experiments and other analytical techniques.