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Three-Dimensional NMR Spectroscopy of Fluorinated Pharmaceutical Solids under Ultrafast Magic Angle Spinning
Xingyu Lu1, Daniel Skomski1, Karen C Thompson1
1Merck Research Laboratories (MRLs), Merck & Co., Inc. , Kenilworth , New Jersey 07033 , United States.
Analytical Chemistry
|April 17, 2019
Summary
New 3D solid-state NMR methods enhance analysis of complex pharmaceutical formulations. These techniques improve characterization of active pharmaceutical ingredients (APIs) like aprepitant, even at low concentrations.
Area of Science:
- Analytical Chemistry
- Materials Science
- Pharmaceutical Sciences
Background:
- High-resolution solid-state analysis of multicomponent molecular systems, such as pharmaceutical formulations, presents significant challenges.
- Solid-state nuclear magnetic resonance (ssNMR) spectroscopy is crucial for characterizing solid dosage forms, enabling chemical identification, quantification, and structural elucidation.
- Low NMR sensitivity, spectral complexity, and low drug loading in multicomponent products limit in-depth analysis of active pharmaceutical ingredients (APIs) at natural isotopic abundance.
Purpose of the Study:
- To develop novel three-dimensional (3D) ssNMR methods for enhanced analysis of multicomponent pharmaceutical systems.
- To apply these new methods to characterize a fluorinated drug molecule, aprepitant, and its nanoparticulate formulation.
- To demonstrate the utility of fluorine-19 (19F) as a sensitive probe for solid-state NMR analysis of fluorinated compounds.
Main Methods:
- Development of two new 3D ssNMR techniques: 1H-19F-1H and 19F-19F-1H correlations.
- Application of ultrafast magic angle spinning (MAS) at 60 kHz to enhance sensitivity and resolution of 1H and 19F signals.
- Analysis of milligram-scale samples of aprepitant and its formulation.
Main Results:
- Successful characterization of crystalline aprepitant and its nanoparticulate formulation using the developed 3D ssNMR methods.
- Simultaneous acquisition of homonuclear 1H-1H, 19F-19F, and heteronuclear 1H-19F correlations without interference from other formulation components.
- Demonstration that 19F is a highly sensitive NMR spin for probing molecular details in solid formulations due to its favorable properties and lack of excipient interference.
Conclusions:
- The developed 3D ssNMR methods provide high-resolution solid-state analysis for challenging multicomponent pharmaceutical systems.
- These techniques enable sensitive and specific characterization of fluorinated APIs like aprepitant within complex formulations.
- Fluorine-19 (19F) NMR is a powerful tool for analyzing the structure and properties of a wide range of fluorine-containing materials in the solid state.
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