Tetramethylpyrazine Cocrystals with Cinnamic Acid and Its Derivatives: Crystal Structures, Theoretical Computations, and Sublimation Behavior Studies

Tetramethylpyrazine (TMP) is used clinically to treat cardiovascular disease and ischemic cerebrocardial vascular disease. However, the high sublimation tendency of TMP leads to its physical instability. In this study, we successfully synthesized and comprehensively characterized four cocrystals formed by TMP with cinnamic acid and its derivatives. These cocrystals effectively mitigated the sublimation tendency of TMP, demonstrating their potential for stabilizing the active pharmaceutical ingredient. Through detailed density functional theory calculations, we systematically investigated the stability mechanisms of these cocrystals, revealing that both the number and distribution of polar groups, governing the formation of strong hydrogen bonds, and the presence and distribution of weak hydrogen bonds jointly contribute to their stability. Furthermore, we explored the intricate relationships among cocrystal stability, hydrogen bonding patterns, and crystal growth mechanisms, offering novel avenues for the rational design and optimization of cocrystals in drug development. This study not only enhances our understanding of cocrystal stability and crystal growth mechanisms but also provides valuable insights for drug innovation, paving the way for future theoretical guidance and practical references in drug design and optimization.