Solvent-induced photophysical properties and stability of clonazepam and Chlordiazepoxide

Understanding how solvent environments influence the electronic behavior and molecular stability of nitrogen-based heterocyclic drugs is essential for optimizing their pharmaceutical performance in both ground and excited states. Such knowledge is vital for predicting drug stability, guiding formulation design, and determining suitable storage conditions. In this study, Clonazepam and Chlordiazepoxide-representative nitrogen-based heterocyclic drugs-were systematically investigated in fourteen solvents of varying polarity. Clonazepam exhibited a more pronounced intramolecular charge transfer (ICT), as evidenced by a greater dipole moment shift between the ground and excited states. Solvent-drug interactions were quantitatively analyzed using the Kamlet-Abboud-Taft (KAT) and Catalán models, revealing that solvent acidity and basicity predominantly govern the strength and nature of these interactions. A novel Dynamic Solvatochromic Indicator (DSI) was introduced as a complementary photophysical metric for evaluating molecular integrity and solvatochromic resilience, demonstrating that Clonazepam is more stable in hydrophobic media, whereas Chlordiazepoxide exhibits enhanced stability in polar environments. These findings underscore the critical role of solvent polarity and hydrogen-bonding capability in modulating drug behavior and provide practical insights for formulation development and solvent selection in drug delivery systems.