¹⁹F Solid-State NMR Spectroscopic Investigation of Crystalline and Amorphous Forms of a Selective Muscarinic M₃ Receptor Antagonist, in Both Bulk and Pharmaceutical Dosage Form Samples

ABSTRACT

The purpose of the following investigation was to display the utility of ¹⁹F solid-state nuclear magnetic resonance (NMR) in both distinguishing between solid forms of a selective muscarinic M₃ receptor antagonist and characterizing the active pharmaceutical ingredient in low-dose tablets. Ambient- and elevated-temperature solid-state ¹⁹F fast (15 kHz) magic-angle spinning (MAS) NMR experiments were employed to obtain desired spectral resolution in this system. Ambient sample temperature combined with rotor frequencies of 15 kHz provided adequate ¹⁹F peak resolution to successfully distinguish crystalline and amorphous forms in this system. Additionally, elevated-temperature ¹⁹F MAS NMR further characterized solid forms through ¹⁹F resonance narrowing brought about by the phenomenon of solvent escape. Similar solvent dynamics at elevated temperatures were utilized in combination with ambient-temperature ¹⁹F MAS NMR analysis to provide excipient-free spectra to unambiguously identify the active pharmaceutical ingredient (API) conversion from crystalline Form I to the amorphous form in low-dose tablets. It is shown that ¹⁹F solid-state NMR is exceptionally powerful in distinguishing amorphous and crystalline forms in both bulk and formulation samples.

• ¹⁹F NMR
• Fast MAS
• Polymorphism
• Solid-state NMR
• Tablets