The Kinetic Story of Tailor-made Additives in Polymorphic Systems: New Data and Molecular Insights for p-Aminobenzoic Acid

We report on the nucleation and growth kinetics of the α and β polymorphs of p-aminobenzoic acid (pABA) in the presence of two additives: 4-amino-3-nitrobenzoic acid (ANBA) and 4-amino-3-methoxybenzoic acid (AMBA). While the presence of additives slowed down the nucleation kinetics of both forms, they had a much larger impact on the growth kinetics of the α-form than the β-form. This allowed the nucleation and growth, for the first time, of the β-form (a form much harder to crystallize) in conditions which would normally afford the α-form. Given our previous findings that the nucleation and growth of α pABA is primarily controlled by aromatic stacking, our additive design strategy was based primarily on the idea that additives could be selected to attach strongly to pABA stacks while at the same time disrupting adjacent molecules. Such a strategy was successful in selective polymorph inhibition of α; this was possible because the growth of β-form is controlled by interactions other than aromatic stacks. More generally, our study also confirms that additives designed to modify the growth of macroscopic crystals also inhibit their nucleation.