Journal
JOURNAL OF PHYSICAL CHEMISTRY B
Volume 124, Issue 25, Pages 5271-5283Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jpcb.0c02131
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Funding
- NSF support through the University of Wisconsin Materials Research Science and Engineering Center [DMR-1720415]
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Crystalline and amorphous materials usually possess distinct physicochemical properties due to major variations in long-range and local molecular packings. Enhanced fundamental knowledge of the molecular details of crystalline-to-amorphous interconversions is necessary to correlate the intermolecular structure to material properties and functions. While crystal structures can be readily obtained by X-ray crystallography, the microstructure of amorphous materials has rarely been explored due to a lack of high-resolution techniques capable of probing local molecular structures. Moreover, there is increasing interest in understanding the molecular nature of amorphous solids in pharmaceutical sciences due to the widespread utilization of amorphous active pharmaceutical ingredients (APIs) in pharmaceutical development for solubility and bioavailability enhancement. In this study, we explore multidimensional C-13 and F-19 magic angle spinning (MAS) NMR spectroscopy to study the molecular packing of amorphous posaconazole (POSA) in conjunction with the crystalline counterpart. Utilizing methods integrating homonuclear and heteronuclear H-1, C-13, and F-19 correlation spectroscopy and atomic F-19-to-C-13 distance measurements, we identified the major differences in molecular packing between crystalline and amorphous POSA. The intermolecular head-tohead interaction along the molecule's major axis, as well as the head-to-tail molecular packing perpendicular to the major axis in POSA crystals, was recapitulated by MAS NMR. Furthermore, critical intermolecular distances in the crystal lattice were determined. Most importantly, the head-to-tail contact of two neighboring molecules was found to be preserved in amorphous POSA, suggesting localized molecular order, whereas crucial interactions for head-to-head packing are absent in the amorphous form resulting in longrange disorder. Our study, likely one of the first documented examples, provides molecular-level structural details to understand the molecular mechanism of crystalline-to-amorphous conversion of fluorine-containing drug substances occurring in drug processing and development and establish a high-resolution experimental protocol for investigating amorphous materials.
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