Taming the dynamics in a pharmaceutical by cocrystallization: investigating the impact of the coformer by solid-state NMR

• Published in: CrystEngComm Vol. 23; no. 39; pp. 6859 - 687
• Main Authors: Szell, Patrick M. J, Lewandowski, Józef R, Blade, Helen, Hughes, Leslie P, Nilsson Lill, Sten O, Brown, Steven P
• Format: Journal Article
• Language: English
• Published: Cambridge Royal Society of Chemistry 11.10.2021
• Subjects: Constraints; Crystal structure; Crystallinity; Dynamic stability; Dynamics; NMR spectroscopy; Organic compounds; Pharmaceuticals; Proline; Solid state
• ISSN: 1466-8033; 1466-8033
• DOI: 10.1039/d1ce01084k

Pharmaceuticals in their crystalline state may display a range of dynamics that can affect their physicochemical properties and chemical stability. With pharmaceutical cocrystals continuing to gain attention, there is an opportunity to investigate how the dynamics are changing in these new solid forms. Here, we investigate the dynamics in efavirenz, an anti-HIV drug, and a series of its cocrystals using a combination of DFT calculations and solid-state magic-angle spinning (MAS) NMR spectroscopy. We show that the crystalline form of efavirenz has a highly dynamic cyclopropyl group, and displays additional rocking motion. In contrast, the dynamics in the efavirenz cocrystals appear to be tamed, with the cyclopropyl group in the (efavirenz)( l -proline) cocrystal being the most constrained, and these constraints originating from a more favourable crystal packing in the cocrystals. The anti-HIV pharmaceutical efavirenz is highly dynamic in its crystalline state, and we show that these dynamics can be tamed through the introduction of a coformer.