X‑ray and NMR Crystallography Studies of Novel Theophylline Cocrystals Prepared by Liquid Assisted Grinding

Two
new cocrystals of theophylline were prepared by liquid assisted
grinding. While compound 1 (theophylline:4-aminosalicylic
acid 2:1) was characterized by single crystal X-ray diffraction, the
crystal structure of compound 2 (theophylline:4-aminobenzoic
acid 1:1) was determined by combining X-ray powder diffraction (XRPD),
solid-state NMR and DFT calculations. The use of 1D/2D 1H high-resolution solid-state NMR techniques provided structural
insight on local length scales revealing internuclear proximities
and relative orientations between the building blocks of compound 2, thus providing information on the type of hydrogen bond
synthons formed. DFT calculations were also employed to generate meaningful
structures and calculate NMR 1H and 13C chemical
shifts to further validate the XRPD model. Compound 2 shows an unusual structure, in which the amino groups do not participate
in hydrogen bonds, while compound 1 exhibits an extended
hydrogen-bonding network, in which planar subunits can be recognized.