Tailoring Cocrystal and Salt Formation and Controlling the Crystal Habit of Diflunisal

Crystal habit modification of the drug diflunisal that normally grows into extremely thin, long needles has been achieved by breaking the stacking effect with the help of coformers. Eight new cocrystals are reported, along with three crystal structures. In all cases, ortho F disorder, often a feature in diflunisal structures was absent due to the presence of CH···F interactions. Co-milling diflunisal with oxalic acid produced 1:1 and 2:1 cocrystals. In contrast, in solution crystallization, oxalic acid played the role of an additive resulting in the crystallization of diflunisal form I rather than form III. To rationalize cocrystal formation, a statistical analysis of the Cambridge Crystallographic Data Centre database for aromatic o-hydroxy carboxylic acids was carried out. All cocrystals of o-hydroxy carboxylic acids with the COOH dimer motif have an electron-withdrawing group on one of the acids. COOH···N_ar motifs are formed preferentially over carboxylic homodimers in the presence of an N_ar coformer.