Monitoring the baicalein-betaine cocrystal process by terahertz spectroscopy

Cocrystallization has emerged as a general strategy to enhance the physicochemical properties of active pharmaceutical ingredients (APIs), particularly for those derived from traditional Chinese medicine (TCM) with limited solubility and bioavailability. As the prerequisite, it is important to investigate the cocrystallization process. Among all the analytical techniques, terahertz (THz) spectroscopy is advantageous, as cocrystallization is driven by intermolecular interactions, which intrinsically share the same energy level as THz photon. In this work, cocrystallization of baicalein (BAI) and betaine (BTN) is achieved by liquid-assisted grinding and characterized by THz-TDS. The spectral evolution of fingerprints for both substrate and cocrystal is further selected as main focus to describe the cocrystallization behavior. The peak intensity exhibits a gradual decline in the physical mixture at 1.53 THz and a simultaneous rise in cocrystal at 1.27 THz, enabling real-time tracking of the reaction progress. By extracting the normalized peak intensity at 1.27 THz as a function of grinding time and fitting it with the Johnson-Mehl-Avrami-Kolmogorov (JMAK) model, the cocrystal formation is described as a three-dimensional nucleation-and-growth process with an Avrami exponent of 3. The terahertz spectra of BAI-BTN cocrystal have been calculated using density functional theory simulations. The findings offer valuable insights and establish key reference data for investigating the molecular configurations and interactive mechanisms in BAI-BTN cocrystals. It demonstrates the feasibility of THz spectroscopy to monitor the cocrystallization process, which provides insights of optimizing the TCM-derived API with enhanced therapeutic efficacy.