title: 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.
authors.affiliation: Merck Research Laboratories, Merck & Co., Rahway, New Jersey 07065-0900, USA. robert_wenslow@merck.com
authors.forename: Robert M
authors.initials: RM
authors.lastname: Wenslow
mesh_terms: D000577:Amides / Q000737:chemistry*; D000631:Aminopyridines / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D004304:Dosage Forms; D005462:Fluorine Radioisotopes; D009682:Magnetic Resonance Spectroscopy; D018727:Muscarinic Antagonists / Q000737:chemistry*; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000737:chemistry*; D013696:Temperature
chemical_list: D000577:Amides; D000631:Aminopyridines; D004304:Dosage Forms; D005462:Fluorine Radioisotopes; D018727:Muscarinic Antagonists; C470637:N-(1-((2-aminopyridin-6-yl)methyl)piperidin-4-yl) alpha-(3,3-difluorocyclopentyl)phenylethanamide; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic