Mechanochemical Synthesis of the Catechol-Theophylline Cocrystal: Spectroscopic Characterization and Molecular Structure

Featured Application ATR-IR spectroscopy allowed to determine the modification of the solid form of theophylline. Pharmaceutical cocrystallization offers the possibility to modify the physicochemical and biopharmaceutical properties of active pharmaceutical ingredients. The mechanochemical synthesis and spectroscopic characterization of the catechol-theophylline (CAT-TEO) cocrystal is reported. The cocrystal was prepared by the solvent-assisted grinding method. The ATR-IR spectroscopy study allowed to determine the formation of the cocrystal because the O-H and C=O stretching bands in the CAT-TEO cocrystal were shifted with respect to the starting materials, suggesting the formation of the C=O center dot center dot center dot H-O hydrogen bond interaction. Infrared spectroscopy also allowed to discard hydration of the cocrystal, and polymorphic transitions of the starting products as a consequence of the mechanochemical grinding. The X-ray powder diffraction and thermal studies confirmed the formation of a new solid phase. In the solid state C-13 NMR spectra of the cocrystal, the signals were shifted with respect to the starting products. The C-13 NMR chemical shifts of the CAT-TEO cocrystal were simulated by using the gauge including the atomic orbital (GIAO) method. These results showed a good correlation between the experimental and calculated C-13 NMR results. Theoretical calculations and natural bonding orbital analysis (NBO) at a B3LYP/6-31G(d,p) level of theory were performed to obtain structural information of the cocrystal.

Automated summary

Featured Application ATR-IR spectroscopy was used to investigate the modification of the solid form of theophylline, and pharmaceutical cocrystallization was found to alter the properties of active pharmaceutical ingredients. The mechanochemical synthesis and spectroscopic characterization of the catechol-theophylline cocrystal revealed the formation of a new solid phase. Experimental and theoretical results showed a good correlation between the chemical shifts in the C-13 NMR spectra of the cocrystal, providing valuable insights into the structure and properties of the cocrystal.