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

Abstract

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.

Disentangling the Effect of Pressure and Mixing on a Mechanochemical Bromination Reaction by Solid‐State NMR Spectroscopy**

“…The spinning induced pressure during MAS has been used, for instance, to study the kinetics of the mechanochemical halogen bond formation involving triphenylphosphine oxide and paradiiodotetrafluorobenzene, [23] to induce polymorphic forms of sodium acetate obtained by solid-state dehydration of sodium acetate trihydrate, [24] and to observe the phase transitions (amorphous-to-crystalline and crystalline-to-crystalline) of active pharmaceutical ingredients (APIs), such as atorvastatin calcium, ezetimibe, and efavirenz. [25] Nonetheless, the mechanistic insights uniquely offered by the NMR analysis of mechanochemically-induced reactions, are required to shed light on the often unprecedented reactivity in ball-milling devices. This study thus aims at systematically investigating the potential of MAS solidstate NMR in characterizing an organic reaction performed in a ball mill by ex-and in situ methods.…”

Stability of Quadruple Hydrogen Bonds in an Ionic Liquid Environment

“…As the actual temperature in the MAS rotor could be up to 30 °C higher than the set value due to the frictional heating upon rotation, [27] we can state that there is no observable shift of the Hbond peaks at the temperature of T actual = 32-78 °C. Similarly, the presence of still associated UPy moieties can be also evidenced by their immobility in their 13 C NMR spectra (see 13 C NMR spectra recorded under cross polarization (CP) and direct excitation (DE) [27] ); b) 1 H MAS NMR spectra of samples cp0, cp25, cp50, and cp75 with different IL content (recorded at 5 °C actual sample temperature and a maximum stable MAS frequency of 15 kHz due to their gel nature under rotation). Though the DADA (donor-acceptor-donoracceptor) H-bonding array of UPy dimers is possible due to the tautomeric exchange, all the UPy dimers in this work are assumed to be in their most stable DDAA array.…”

“…[ 23,33 ] Upon heating from 23 to 53 °C, these peaks do not shift to lower ppm values, forming evidence for still un‐dissociated UPy moieties. As the actual temperature in the MAS rotor could be up to 30 °C higher than the set value due to the frictional heating upon rotation, [ 27 ] we can state that there is no observable shift of the H‐bond peaks at the temperature of T actual = 32–78 °C. Similarly, the presence of still associated UPy moieties can be also evidenced by their immobility in their 13 C NMR spectra (see 13 C NMR spectra recorded under cross polarization (CP) and direct excitation (DE) conditions in the Figure S2, Supporting Information).…”

“…Figure 1. Schematic illustration of the UPy dimer in their DDAA (donor-donor-acceptor-acceptor) H-bonding array and extracts from 1 H MAS NMR spectra of a) cp0 at variable temperatures, measured at 20 kHz and T set = 23, 33, 43, 48, 53 °C (with T actual with an additional 30 °C due to the frictional heating upon rotation[27] ); b) 1 H MAS NMR spectra of samples cp0, cp25, cp50, and cp75 with different IL content (recorded at 5 °C actual sample temperature and a maximum stable MAS frequency of 15 kHz due to their gel nature under rotation). Though the DADA (donor-acceptor-donoracceptor) H-bonding array of UPy dimers is possible due to the tautomeric exchange, all the UPy dimers in this work are assumed to be in their most stable DDAA array [17,23].…”

Auf dem Seziertisch: Wirkstoff‐ Polymer‐Formulierungen

“…Da bei der Messung durch die notwendige Probenrotation starke Kräfte auf die teilweise metastabilen (amorphen) Proben wirken, ist immer darauf zu achten, ob es zu Veränderungen, etwa Phasenumwandlungen kommt. 6) Neben der Untersuchung und Verbesserung der Transportmaterialien (Mizellen, Hydrogele) arbeiten wir an der Analyse intermolekularer Wechselwirkungen mit chemischen und biologischen Umgebungen. Simulationen ungeordneter Umgebungen runden die Experimente ab.…”