Influence of Secondary Interactions on the Structure, Sublimation Thermodynamics, and Solubility of Salicylate:4-Hydroxybenzamide Cocrystals. Combined Experimental and Theoretical Study

Cocrystal
screening of 4-hydroxy­benzamide with a number of
salicylates (salicylic acid, SA; 4-amino­salicylic acid, PASA;
acetyl­salicylic acid, ASA; and salicyl­salicylic acid,
SSA) was conducted to confirm the formation of two cocrystals, [SA+4-OHBZA]
(1:1) and [PASA+4-OHBZA] (1:1). Their structures were determined using
single-crystal X-ray diffraction, and the hydrogen-bond network topology
was studied. Thermodynamic characteristics of salicylic acid cocrystal
sublimation were obtained experimentally. It was proved that PASA
cocrystallization with 4-OHBZA makes the drug more stable and prevents
the irreversible process of decarboxylation of PASA resulting in formation
of toxic 3-amino­phenol. The pattern of non-covalent interactions
in the cocrystals is described quantitatively using solid-state density
functional theory followed by Bader analysis of the periodic electron
density. It has been found that the total energy of secondary interactions
between synthon atoms and the side hydroxyl group of the acid molecule
in [SA+4-OHBZA] (1:1) and [PASA+4-OHBZA] (1:1) cocrystals is comparable
to the energy of the primary acid–amide hetero­synthon.
The theoretical value of the sublimation enthalpy of [SA+4-OHBZA],
231 kJ/mol, agrees fairly well with the experimental one, 272 kJ/mol.
The dissolution experiments with [SA+4-OHBZA] have proved that the
relatively large cocrystal stability in relation to the stability
of its components has a negative effect on the dissolution rate and
equilibrium solubility. The [PASA+4-OHBZA] (1:1) cocrystal showed
an enhancement of apparent solubility compared to that of the corresponding
pure active pharmaceutical ingredient, while their intrinsic dissolution
rates are comparable.