Tracking the cocrystal formation of curcumin and pyrogallol by terahertz spectroscopy

Abstract

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, where pyrogallol (PYR) is identified as 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 CUR-PYR cocrystal achieved by neat milling. THz spectral fingerprints reveal structural changes at molecular level, characterized by the gradual disappearance of peak at 1.64 THz, 2.24 THz, and 2.72THz for physical mixture and progressive existence of peak at 2.42 THz for 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 strong correlation with R²=0.9450 and Pearson's coefficient of 0.9790 and 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 detection of amorphous phases and monitoring of cocrystallization processes in solid-state transformations.