Synergistic Effect of Urea Derivatives on Pyrazinamide Vapor Pressure and Crystal Growth

Abstract

Pyrazinamide has a relatively high vapor pressure, and different polymorphs can be obtained through sublimation crystallization. Additive molecules, such as 1,3-dimethylurea, interact with pyrazinamide during sublimation, which has been investigated by using crystallization times in the presence of different urea derivatives. The vapor pressure, interaction strength, and number and nature of functional groups available for interaction play a role in the effectiveness of the additive in decreasing crystallization times and function as efficient transporter molecules of pyrazinamide. NMR and calculations were used to characterize the interaction sites between pyrazinamide and additives in solution. These interactions leading to dimers and possibly higher-order aggregates increase the thermodynamic capacity to accept molecules in the vapor phase without exceeding the partial vapor pressures of the individual molecules. It increases the overall molecular presence in the vapor phase similar to how a deep eutectic is promoted by intermolecular interactions.