Characterizing the structure of a p-aminosalicylic acid and nicotinamide drug cocrystal via terahertz spectroscopy

Abstract

p-Aminosalicylic acid (PAS) is an antibacterial drug, but its low solubility severely limits its absorption and clinical application. A drug cocrystal is a distinct solid-state form of a drug obtained via the introduction of a cocrystal former (CCF) to optimize the physicochemical properties (such as solubility) of the active pharmaceutical ingredient (API), thereby improving drug absorption. This study used PAS as the API and nicotinamide (NCT) as the CCF to prepare the PAS–NCT drug by a grinding method. The absorption spectra of PAS, NCT, the PAS–NCT cocrystal and physical mixed samples were obtained using terahertz time-domain spectroscopy (THz-TDS) in the frequency range of 0.4–2.0 THz. The results showed that no new characteristic peaks appeared in the physically mixed sample, while a new characteristic peak was observed in the cocrystal at 1.64 THz. Density functional theory (DFT) calculations indicated that the theoretical spectra are highly consistent with experimental results. On this basis, the weak interactions in PAS, NCT, and drug cocrystal systems were quantitatively analyzed using energy decomposition analysis based on forcefield (EDA-FF) combined with the electrostatic potential (ESP) method. The results indicate that the dispersion effect in the NCT system is relatively weak, which is not conducive to stable internal molecular binding. In cocrystal systems, there are strong hydrogen bonding interactions between the API molecule and the CCF molecule, which promote cocrystal synthesis. The solubility test showed that the solubility of the PAS cocrystal increased by more than 20 times. Research has confirmed that a drug cocrystal can significantly enhance drug solubility, providing an important reference for improving drug physicochemical properties, especially solubility.