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

Abstract

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 ¹⁴N–¹H 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 ¹⁵N chemical shifts hamper a solid-state NMR characterization based on this nucleus, ¹⁴N is a very versatile alternative. ¹⁴N–¹H 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 ¹⁴N–¹H 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.