Pharmaceutical Co-Crystals of Pyrazinecarboxamide (PZA) with Various Carboxylic Acids: Crystallography, Hirshfeld Surfaces, and Dissolution Study

Three new pharmaceutical co-crystals:
1 PZA-MA (malonic acid),
2 PZA-SA (succinic acid, a new polymorph of a reported one), and 3
PZA-GA (glutaric acid) have been prepared and characterized by differential
scanning calorimetry (DSC), thermogravimetric analyses (TGA), and
single-crystal X-ray diffraction. Wherein, PZA formed 1:1 co-crystals
with MA and GA by acid–amide and acid–py heterosynthon,
while it formed 2:1 co-crystal with SA by amide–amide homosynthon
in addition to acid–amide and acid–py heterosynthon.
Their melting points follow the order, PZA-GA < PZA-MA < PZA-SA,
which are lower than the melting points of the individual components.
Hirshfeld surface analysis revealed that N–H···O
hydrogen bonding and π···π interactions
for PZA in them follow the order: PZA-MA > PZA-SA > PZA-GA,
while
H–H and O–O interactions follow the order: PZA-MA <
PZA-SA < PZA-GA. We also compared the Hirshfeld surfaces of the
present co-crystals with the nine reported PZA co-crystals, which
obtained important results. The studies of the solubility and dissolution
showed a semiempirical inverse relationship with the melting point:
the solubility follows the order, PZA-SA < PZA-GA < PZA-MA and
dissolution rate follows the order, PZA-SA < PZA-MA < PZA-GA.