Revealing the critical role of template functional group ordering in the template-directed crystallization of pyrazinamide†
In template-directed crystallization, especially from solution, two pathways—homogenous nucleation and heterogeneous nucleation—often compete with each other, and the resultant pathway is strongly dependent upon crystallization conditions and template properties. Apart from the effects of molecular and stereochemical structures, the functional group ordering, the amount of template, and the applied solvents also play key roles in the resultant crystallization outcomes, but these are often overlooked. Herein, we systematically investigated these effects, in particular the functional group ordering of template hydrochlorothiazide and sulfathiazole, on the template-directed crystallization of pyrazinamide. It was found that the effectiveness of template regulation on the selective nucleation of γ form pyrazinamide is significantly affected by the amount of template and the solvent systems, where weak solute–solvent interactions facilitate template regulation. Surprisingly, the nucleation of γ form pyrazinamide can be directed by the ordering and specific orientation of the template functional groups hydrochlorothiazide or sulfathiazole. Functional group ordering is further proven to help the alignment of solute molecules and induce the nucleation of γ form. This work highlights the critical roles of functional group ordering and specific orientation on template-directed pharmaceutical crystallization.