Differential Cocrystallization Behavior of Isomeric Pyridine Carboxamides toward Antitubercular Drug Pyrazinoic Acid

Pyrazinoic
acid, the active form of the antitubercular pro-drug
Pyrazinamide, is an amphiprotic molecule containing carboxylic acid
and pyridine groups and therefore can form both salts and cocrystals
with relevant partner molecules. Cocrystallization of pyrazinoic acid
with isomeric pyridine carboxamide series resulted in a dimorphic
mixed-ionic complex with isonicotinamide and in eutectics with nicotinamide
and picolinamide, respectively. It is observed that with alteration
of the carboxamide position, steric and electrostatic compatibility
issues between molecules of the combination emerge and affect intermolecular
interactions and supramolecular growth, thus leading to either cocrystal
or eutectic for different pyrazinoic acid–pyridine carboxamide
combinations. Intermolecular interaction energy calculations have
been performed to understand the role of underlying energetics on
the formation of cocrystal/eutectic in different combinations. On the other hand,
two molecular salts with piperazine and cytosine and a gallic acid
cocrystal of the drug were obtained, and their X-ray crystal structures
were also determined in this work.