Selective crystallization of pyrazinamide polymorphs in supramolecular gels: Synergistic selectivity by mimetic gelator and solvent

A mimetic gelator designed to incorporate the chemical structure of pyrazinamide (PZA), a highly polymorphic drug, has been synthesized. Metastable Forms β and δ of PZA were obtained from supramolecular gel phase crystallization in nitrobenzene and DMSO, respectively, using a bis(urea) gelator designed to mimic the structure of PZA. This is the only known way to access the pure Form β at room temperature. In contrast, concomitant crystallization of a mixture of metastable polymorphs and the most thermodynamically stable form were obtained from solution crystallization. By analyzing the intermolecular interactions of PZA in the mimetic gel phase crystallization, it is proposed that the mimetic gelator and solvent can influence the nucleation behavior by close interaction with the carbonyl group to select PZA Forms β and δ.