You cannot fight the pressure: Structural rearrangements of active pharmaceutical ingredients under magic angle spinning

• Published in: Magnetic resonance in chemistry 2022-06, Vol.60 (6), p.572-582
• Main Authors: Scheidel, Sebastian, Östreicher, Laurina, Mark, Isabelle, Pöppler, Ann‐Christin
• Format: Article
• Language: English
• Subjects: 19F; 1H‐13C HETCOR; API; Crystal structure; Crystallinity; Experiments; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; MAS; NMR; NMR spectroscopy; Nuclear magnetic resonance; Pharmaceutical Preparations; Pharmaceuticals; Phase transitions; solid‐state NMR; structural changes; XRPD
• ISSN: 0749-1581; 1097-458X
• DOI: 10.1002/mrc.5267

Although solid‐state nuclear magnetic resonance (NMR) is a versatile analytical tool to study polymorphs and phase transitions of pharmaceutical molecules and products, this work summarizes examples of spontaneous and unexpected (and unwanted) structural rearrangements and phase transitions (amorphous‐to‐crystalline and crystalline‐to‐crystalline) under magic angle spinning (MAS) conditions, some of them clearly being due to the pressure experienced by the samples. It is widely known that such changes can often be detected by X‐ray powder diffraction (XRPD); here, the capability of solid‐state NMR experiments with a special focus on 1H‐13C frequency‐switched Lee–Goldburg heteronuclear correlation (FSLG HETCOR)/MAS NMR experiments to detect even subtle changes on a molecular level not observable by conventional 1D NMR experiments or XRPD is presented. Furthermore, it is shown that a polymorphic impurity combined with MAS can induce a crystalline‐to‐crystalline phase transition. This showcases that solid‐state NMR is not always noninvasive and such changes upon MAS should be considered in particular when compounds are studied over longer time spans. Structural changes of different amorphous and crystalline active pharmaceutical ingredients under magic angle spinning (MAS) conditions due to the increased pressure are shown. The possibility of detecting such changes by X‐ray powder diffraction, 19F MAS NMR, and 1H‑13C FSLG HETCOR/MAS NMR spectra is discussed with the latter being able to detect even subtle changes on the molecular level. Polymorphic impurities can further influence these transformations showcasing that solid‐state NMR is not always noninvasive.