Structural Investigation of Cocrystal Formed Between Theophylline and Nicotinamide Based on Terahertz and Raman Spectroscopy

Pharmaceutical cocrystals present a promising avenue for enhancing the physicochemical properties of active pharmaceutical ingredients by modifying intermolecular interactions among raw materials. Theophylline, a methylpurine drug commonly used in respiratory treatments, has limited bioavailability in vivo due to its poor water solubility. In this study, a theophylline–nicotinamide cocrystal was successfully synthesized using the solid-state grinding method. Both the parent materials and the theophylline–nicotinamide cocrystal were characterized using terahertz and Raman spectroscopy. The terahertz spectra exhibited significant differences in the absorption peak between the experimental cocrystal and the parent materials, which were further corroborated by similar findings in the Raman spectra. In addition, density functional theory was employed to optimize the structure of the theophylline–nicotinamide cocrystal and identify its corresponding vibrational modes. Furthermore, intermolecular interactions were analyzed through the independent gradient model based on Hirshfeld partition analysis and Hirshfeld surface analysis. The results demonstrate that the integration of terahertz and Raman spectroscopy with theoretical calculations provides valuable insights into the molecular-level formation of cocrystals. This approach offers crucial information for the analysis of weak interactions in pharmaceutical cocrystals, which is essential for their design and optimization.