Using paramagnetic dopants to investigate spontaneous cocrystal formation via in situ solid-state NMR

Location

PANEL: Chemistry Honors: Pharmaceutics and Essential Biological Molecules
Science Center A126, Nancy Schrom Dye Lecture Hall

Document Type

Presentation

Start Date

5-13-2022 3:00 PM

End Date

5-13-2022 5:00 PM

Abstract

Cocrystals, or multi-component molecular crystals, can offer a potential solution to pharmaceutical challenges related to solubility and bioavailability. In pharmaceutics, cocrystals are comprised of an active pharmaceutical ingredient (API) and an excipient coformer. Several cocrystal systems are known to form spontaneously in the sold state, but the mechanisms of this formation are unknown. By tracking cocrystal formation in situ using solid-state NMR, it may be possible to detect chemical shift-resolved mechanistic intermediates. Previous in situ studies have been hindered by long spin-lattice relaxation times of small molecule coformers. Here we show that paramagnetic doping of cocrystals and their components significantly increases NMR signal averaging for individual and in situ experiments and does not alter crystal structure or chemical shift. These studies were complemented by the development of methods for growing large, high-quality single crystals for use in future single-crystal NMR experiments. Single crystals for pure and paramagnetically doped theophylline and oxalic acid were successfully grown via slow evaporation in a variety of solvent mixtures and cataloged using a polarized light microscope. While we were not able to find evidence of a chemical shift-resolved intermediate, further study using paramagnetic dopants is required. Future work includes investigating doped cocrystal formation at a higher magic angle spinning speed to eliminate spinning sidebands and using doped single crystals for in situ single-crystal NMR.

Keywords:

Cocrystals, Solid-state nuclear magnetic resonance, Spin-lattice relaxation, Paramagnetic doping

Notes

Presenter: Lauren Schaffer

Project Mentor(s)

Manish Mehta, Chemistry and Biochemistry

2022

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May 13th, 3:00 PM May 13th, 5:00 PM

Using paramagnetic dopants to investigate spontaneous cocrystal formation via in situ solid-state NMR

PANEL: Chemistry Honors: Pharmaceutics and Essential Biological Molecules
Science Center A126, Nancy Schrom Dye Lecture Hall

Cocrystals, or multi-component molecular crystals, can offer a potential solution to pharmaceutical challenges related to solubility and bioavailability. In pharmaceutics, cocrystals are comprised of an active pharmaceutical ingredient (API) and an excipient coformer. Several cocrystal systems are known to form spontaneously in the sold state, but the mechanisms of this formation are unknown. By tracking cocrystal formation in situ using solid-state NMR, it may be possible to detect chemical shift-resolved mechanistic intermediates. Previous in situ studies have been hindered by long spin-lattice relaxation times of small molecule coformers. Here we show that paramagnetic doping of cocrystals and their components significantly increases NMR signal averaging for individual and in situ experiments and does not alter crystal structure or chemical shift. These studies were complemented by the development of methods for growing large, high-quality single crystals for use in future single-crystal NMR experiments. Single crystals for pure and paramagnetically doped theophylline and oxalic acid were successfully grown via slow evaporation in a variety of solvent mixtures and cataloged using a polarized light microscope. While we were not able to find evidence of a chemical shift-resolved intermediate, further study using paramagnetic dopants is required. Future work includes investigating doped cocrystal formation at a higher magic angle spinning speed to eliminate spinning sidebands and using doped single crystals for in situ single-crystal NMR.