Tracking the cocrystal formation of curcumin and pyrogallol by terahertz spectroscopy

Cocrystallization is a promising strategy to enhance the physicochemical properties of active pharmaceutical ingredients (APIs). For instance, curcumin (CUR) is a polyphenol compound with limited solubility and stability, whereas pyrogallol (PYR) is identified as a potential cocrystal former (CCF). Conventional analytical techniques have been used to understand the cocrystallization mechanism, but the formation mechanism of the CUR–PYR cocrystal remains unclear. This study employs terahertz (THz) spectroscopy to track the formation of the CUR–PYR cocrystal achieved by neat milling. THz spectral fingerprints reveal structural changes at the molecular level, characterized by the gradual disappearance of peaks at 1.64 THz, 2.24 THz, and 2.72 THz for the physical mixture and the progressive appearance of a peak at 2.42 THz for the CUR–PYR cocrystal. By extracting the absorption intensity of THz spectra and conducting data fitting, the progress of cocrystal formation follows the generalized exponential function and Avrami, with R² over 97%. THz spectroscopy quantitatively detected the formation of a transient amorphous intermediate phase. THz crystallinity and spectral full width at half maximum, respectively, demonstrated a strong correlation with R² = 0.9450 and Pearson's coefficient of 0.9790 and an inverse relationship with R² = 0.9415 and Pearson's coefficient of −0.9703 with PXRD crystallinity. THz spectroscopy is validated as a robust technique for the detection of amorphous phases and monitoring of cocrystallization processes in solid-state transformations.