Characterization and Property Study of Binary Cocrystal of L-methyldopa and D-mannitol Using Terahertz Spectroscopy and Density Functional Theory

Hypertension directly or indirectly accounts for over 10% of maternal deaths. L-methyldopa is a safe antihypertensive for pregnant women, yet its low aqueous solubility substantially reduces bioavailability. This study enhances L-methyldopa's solubility in simulated gastric and intestinal fluids through cocrystallization with D-mannitol, thereby improving bioavailability. The cocrystal was synthesized via slow solvent evaporation. Then, multiple characterization techniques including powder X-ray diffraction (PXRD), Raman spectroscopy (Raman), scanning electron microscopy (SEM), and differential scanning calorimetry-thermogravimetric analysis (DSC-TGA) were employed to confirm the formation of cocrystals and verify the crystal structure and purity. Subsequently, a terahertz time-domain spectroscopy (THz-TDS) system was used to measure the spectral properties of D-mannitol, L-methyldopa, physical mixture, and cocrystal, and it was found that terahertz absorption spectroscopy can effectively characterize the formation of cocrystals. Furthermore, we also performed DFT calculations to simulate the crystal structures of D-mannitol, L-methyldopa, and the corresponding cocrystal. By comparing the experimental and simulated terahertz absorption spectra, it was found that they showed good agreement. High-performance liquid chromatography (HPLC) measurements showed that, compared with pure L-methyldopa, the solubility of L-methyldopa in the cocrystal in simulated intestinal fluid and gastric fluid increased by 53% and 67% respectively. DSC-TGA analysis confirmed significantly enhanced thermal stability of the cocrystal. This work provides valuable methodological insights for pharmaceutical cocrystal development.