Many efforts have been recently devoted to the design and investigation of multicomponent pharmaceutical solids, such as salts and cocrystals. The experimental distinction between these solid forms is often challenging. Here, we show that the transformation of a salt into a cocrystal with a short hydrogen bond does not occur as a sharp phase transition but rather a smooth shift of the positional probability of the hydrogen atoms. A combination of solid-state NMR spectroscopy, X-ray diffraction, and diffuse reflectance measurements with density functional theory calculations that include nuclear quantum effects (NQEs) provides evidence of temperature-induced hydrogen atom shift in cocrystals with short hydrogen bonds. We demonstrate that for the predictions of the salt/cocrystal solid forms with short H-bonds, the computations have to include NQEs (particularly hydrogen nuclei delocalization) and temperature effects.

Department of Inorganic Chemistry Faculty of Science Charles University Prague Hlavova 2030 Prague 2 12840 Czech Republic

Department of Organic Chemistry Faculty of Science Charles University Prague Hlavova 2030 Prague 2 12840 Czech Republic

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo nám 2 Prague 6 160 00 Czech Republic

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