Novel Strategy to Control Polymorph Nucleation of Gamma Pyrazinamide by Preferred Intermolecular Interactions during Heterogeneous Nucleation

Pyrazinamide is usually nucleated from solution as a dimeric form; it has rarely been reported in the γ form (chain structure) crystallized from solution, especially from aqueous solution. Here, we designed a novel way to obtain the γ form of pyrazinamide from aqueous solution. Specific templates were applied to disturb the intrinsic self-association of pyrazinamide molecules and prevent the formation of the dimer structure. In this paper, the heterosynthon design method was applied in pyrazinamide heterogeneous nucleation, in which sulfonamides were chosen as the templates. In the presence of sulfonamide templates, hydrogen bonds between the carbonyl moiety of the amide group in pyrazinamide molecules and the sulfonamide moiety of sulfonamide template molecules were formed; these preferred intermolecular interactions protected the carbonyl groups of PZA, facilitating assembly of PZA molecules in a chain via N–H···N′ and nucleating as the γ form of PZA. This is the first time that the heterosynthon design method was applied to screen effective templates, which can control and select the desired polymorph in heterogeneous nucleation.