Characterization of carbamazepine-baicalein cocrystal using terahertz time-domain spectroscopy: Implications for solubility and hepatotoxicity

Carbamazepine (CBZ) suffers from low solubility and dose-dependent hepatotoxicity. Baicalein (BAI), a liver-protective flavonoid, shares similar solubility limitations. Here we report the first synthesis of a CBZ-BAI cocrystal in a 1:1 M ratio via slow evaporation. The cocrystal was comprehensively characterized using terahertz time-domain spectroscopy from 0.2 to 2.2 THz, Raman spectroscopy from 50 to 2000 cm −1 , powder X-ray diffraction, and differential scanning calorimetry. Density functional theory DFT calculations were performed to assign the vibrational modes. The THz absorption spectrum shows the disappearance of the characteristic peaks of CBZ at 1.22 and 1.81 THz and of BAI at 1.21 and 2.18 THz. Importantly, a new peak emerges at 1.90 THz, which DFT assigns to hydrogen bonding vibrations between the –CONH 2 group of CBZ and the C O group of BAI, thus confirming cocrystal formation. Raman spectroscopy further supports this through changes in the 724 to 1310 cm −1 region. In simulated intestinal fluid at pH 6.8, the cocrystal improves CBZ solubility by 18% from 150.0 to 177.1 μg/mL and makes practically insoluble BAI detectable at 0.12 μg/mL. CCK-8 assays on mouse hepatocytes NCTC 1469 show that the cocrystal increases cell viability from 59.6% for CBZ alone to 76.1% at 12 h and from 61.9% to 68.3% at 24 h, indicating that cocrystal formation markedly reduces CBZ-induced hepatotoxicity. The CBZ-BAI cocrystal thus represents a promising strategy to simultaneously enhance solubility and mitigate drug-induced hepatotoxicity.