Unraveling the Hydrogen Bond Network in a Theophylline–Pyridoxine Salt Cocrystal by a Combined X-ray Diffraction, Solid-State NMR, and Computational Approach

The formation of a codrug, a cocrystal formed by two active pharmaceutical ingredients (APIs), between theophylline (THEO) and pyridoxine·HCl (PyrH+Cl–) is reported. The THEO PyrH+Cl– drug–drug cocrystal could turn out to be interesting in the pharmaceutical field because these two APIs are concurrently administered for asthma treatment. The codrug was characterized by a combined experimental and computational investigation by means of single crystal X-ray diffraction (SCXRD), solid-state NMR (SSNMR), and density functional theory (DFT) calculations. An exhaustive SSNMR study was performed to unravel the complex network of hydrogen bond interactions which was poorly defined by SCXRD. Several advanced two-dimensional SSNMR spectra such as 1H DQ MAS, 13C–1H HETCOR, 14N–1H J- and D-HMQC were acquired, taking advantage of the resolution and sensitivity improvement provided by indirect detection pulse sequences and very fast MAS at 70 kHz. These experiments, supported and completed by DFT calculations, were fundamental in accurately determining the position of hydrogen atoms and thus in elucidating the hydrogen bond network. They also allowed defining the ionic character of the drug–drug cocrystal, which can be more properly defined as a drug–drug salt cocrystal.