Three-Dimensional NMR Spectroscopy of Fluorinated Pharmaceutical Solids under Ultrafast Magic Angle Spinning

Abstract

High-resolution solid-state analysis of multicomponent molecular systems, e.g., pharmaceutical formulations, is a great challenge. Solid-state nuclear magnetic resonance (ssNMR) spectroscopy plays a critical role in the characterization of solid dosage forms due to its capabilities of chemical identification, quantification, and structural elucidation at a molecular level. However, the low NMR sensitivity as well as the high spectral complexity and low drug loading of multicomponent products hinder an in-depth investigation of the active pharmaceutical ingredient (API) at the natural isotopic abundance. Herein, we developed two new three-dimensional (3D) ssNMR methods, including 1H–19F–1H and 19F–19F–1H correlations and successfully applied them to characterize a fluorinated drug molecule, aprepitant, and its commercial nanoparticulate formulation EMEND (Merck & Co, Inc., Kenilworth, NJ, USA). These 1H-detection methods utilize the significantly enhanced sensitivity and resolution of 1H and 19F afforded by 60 kHz ultrafast magic angle spinning (MAS) and enable the analysis of milligram samples. The 3D techniques simultaneously provide homonuclear 1H–1H and 19F–19F, and heteronuclear 1H–19F correlations of the crystalline aprepitant without interferences from other pharmaceutical components in the drug product. Moreover, our results demonstrate that 19F is a highly sensitive spin for probing molecular details of fluorinated drug substances in solid formulations, due to its high isotopic abundance, large gyromagnetic ratio, and absence of signal interference from pharmaceutical excipients, as well as for characterizing structural properties of a broad range of fluorine-containing materials.

Fast 19F Magic-Angle Spinning Nuclear Magnetic Resonance for the Structural Characterization of Active Pharmaceutical Ingredients in Blockbuster Drugs

“…Fluorine or, specifically, the 100% abundant magnetically active 19 F isotope is a powerful NMR beacon that has gained considerable attention as a unique probe in small-molecule pharmaceuticals and biological molecules. − 19 F, a spin- 1/2 nucleus, possesses very high sensitivity, similar to 1 H (0.85 vs 1), and 19 F chemical shifts are exquisitely sensitive to the local structural and electronic environment, spanning a range of over 300 ppm . Given the prevalence of fluorinated drugs and fluorine’s advantageous spectroscopic properties, it is surprising that fluorine NMR has been underutilized for analyzing pharmaceutical formulations compared to 1 H and 13 C: to date, there are very few reports of 19 F-based structural characterization of APIs in drug formulations, − and little systematic data have been published. 19 F MAS NMR offers a sensitive and convenient probe to complement 1 H and 13 C studies of pharmaceutical formulations.…”

Fast 19F Magic Angle Spinning NMR Crystallography for Structural Characterization of Fluorine-Containing Pharmaceutical Compounds

“…While 19 F NMR has been extensively applied in the analysis of fluorinated organic and biological molecules in solution, − magic angle spinning (MAS) NMR studies remain relatively scarce. − This, in part, is due to (i) strong dipolar couplings that result in broad lines, requiring high-power 1 H and 19 F decoupling with specialized hardware and (ii) relatively low sensitivity in heteronuclear polarization transfer experiments in the common regime of MAS frequencies, below 30 kHz. Increasing the MAS frequencies to 40 kHz and above results in significant improvements in sensitivity and resolution, − yielding substantially narrowed 19 F lines, even in the absence of 1 H decoupling. ,, Furthermore, homonuclear 19 F– 19 F recoupling experiments, such as two-dimensional (2D) radio frequency driven recoupling (RFDR) and delays alternating with nutation for tailored excitation (DANTE)-RFDR, are effective and can be used for interfluorine distance measurements, including in multispin systems. ,,, In particular, long-range 1 H– 19 F and 19 F– 19 F interatomic distances together with 19 F– 13 C contacts ,,, are indispensable parameters in structure elucidations.…”

Enzymatic synthesis of fluorinated compounds

“…Nowadays, PET has become a valuable tool for detecting pathology in the clinical field. Fluorine is a typical positron emitter due to its long half-life (t 1/2 = 110 min), high isotope abundance, large gyromagnetic ratio, sensitivity, and specificity (Clark and O’Hagan 2017 ; da Silva et al 2018 ; Lu et al 2019 ; Troelsen et al 2020 ; Yamamoto et al 2019 ). Since 2-fluorinated glycosides are more stable than glycosides, they can be used as active probes (Sadurni and Gilmour 2018 ).…”