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

Abstract

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.

Mechanochemical Synthesis and Physicochemical Characterization of Previously Unreported Praziquantel Solvates with 2-Pyrrolidone and Acetic Acid

“…The SSNMR analysis was instrumental in assisting the structure solution from powder data, checking the reliability of the solved structure in combination with DFT calculations [44,45] and evaluating possible hydrogen bond interaction between PZQ and the solvent molecules. Indeed, it is well known that in the case of molecular crystals, SS-NMR can provide several information such as number of independent molecules per unit cell [46], presence of solvent molecules in the crystal and assessment of the stoichiometry [47], identification of different crystal forms [46,47], evaluation of hydrogen bond interactions and network [48,49].…”

NMR crystallography of molecular organics

“…Figure 7. 15 N shifts clearly distinguished between alternative hydrogen bonding arrangements in a co-crystal between theophylline and pyridoxine hydrochloride, where one H could be forming an intramolecular H-bond with an O acceptor or intermolecular bond with an N acceptor [240]. A change of 15 N chemical shift of >13 ppm showed that relevant N is an acceptor in pure theophylline, but not in the co-crystal, while 14 N/ 1 H experiments confirmed the protonated N sites.…”

Continuous Manufacture and Scale-Up of Theophylline-Nicotinamide Cocrystals

“…This will provide greater bioavailability, whilst the drug molecule itself is unchanged, as all modifications occur at the supramolecular level (intermolecular interactions, hydrogen bonding, molecular packing) [ 10 , 11 , 12 ]. Studies have found that the multi layered structure of cocrystals improve the mechanical properties, give better flow properties and improve compressibility, which assists the dosage form preparation [ 13 , 14 ].…”