Elucidation of hydrogen bonding networks in theophylline cocrystals by 1H-detected 17O and 14N solid-state NMR spectroscopy.

Determining hydrogen bonding networks and proton positions in pharmaceutical cocrystals remains challenging, particularly for microcrystalline materials and systems involving strong hydrogen bonds and partial proton transfer. Here, we demonstrate a strategy that combines fast magic-angle spinning (MAS) solid-state NMR with 1H-detected 17O → 1H and 1H{14N} heteronuclear correlation experiments to directly probe hydrogen bonding interactions in theophylline-carboxylic acid cocrystals. Facile 17O enrichment of carboxylic acid coformers (benzoic, oxalic, maleic, and malonic acids) was achieved by isotope exchange with 17O-enriched water under mild conditions. Isotope exchange reactions can be easily monitored by 17O solution NMR spectroscopy. Two-dimensional 17O → 1H D-RINEPT and 1H{14N} D-HMQC spectra recorded with variable dipolar recoupling times enable assignment of overlapping 1H resonances and provide site-specific identification of intermolecular hydrogen bonds between theophylline and carboxylic acid coformers. High magnetic field SSNMR experiments (up to 25.8 T) further enhance 17O spectral resolution and enable resolution of overlapping 17O resonances associated with distinct hydroxyl, carbonyl, and dynamically exchanging oxygen environments. Complementary 1H spin-diffusion and dipolar double-quantum experiments corroborate intermolecular contacts and confirm cocrystal formation. Experimental 17O and 14N solid-state NMR parameters are in good agreement with Gauge Including Projector Augmented Wave (GIPAW) density functional theory (DFT) calculations. Together, these results establish a practical multinuclear SSNMR approach for identifying hydrogen bonding networks in pharmaceutical cocrystals and other multicomponent organic solids.