Attempted construction of minoxidil: carboxylic acid cocrystals; 7 salts and 1 cocrystal resulted

Cocrystallization experiments between the active pharmaceutical ingredient (API) minoxidil and a variety of pharmaceutically acceptable cocrystal formers (coformers) were carried out. Our initial efforts were centered around utilizing the various hydrogen bonding acceptor moieties on the minoxidil framework, e. g., N-oxide, amino-pyridine, and piperidine, to probe, with a carboxylic acid, the delicate balance of competing intermolecular interactions and determine a hierarchical ranking of supramolecular synthons within a specific cocrystallization reaction. We successfully generated eight multi-component samples, which were analyzed by single-crystal X-ray diffraction revealing the formation of one cocrystal and seven salts. In all cases the API and coformers were connected through a carboxylate/N-hydroxide synthon or its neutral analog proving to be a robust interaction (occurring in 8/8 structures), even in the presence of other potentially disruptive hydrogen bonding moieties. Interestingly, the amino-pyridine and piperidine moieties (both effective hydrogen bond acceptors) never participated in forming hydrogen bonds with a carboxylic acid.