title: Influence of Secondary Interactions on the Structure, Sublimation Thermodynamics, and Solubility of Salicylate:4-Hydroxybenzamide Cocrystals. Combined Experimental and Theoretical Study.
abstract: 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.
authors.affiliation: †G.A. Krestov Institute of Solution Chemistry, Russian Academy of Sciences, 1, Academicheskaya, 153045 Ivanovo, Russian Federation.
authors.forename: Alex N
authors.initials: AN
authors.lastname: Manin
authors.affiliation: †G.A. Krestov Institute of Solution Chemistry, Russian Academy of Sciences, 1, Academicheskaya, 153045 Ivanovo, Russian Federation.
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Voronin
authors.affiliation: ‡Mendeleev University of Chemical Technology, 9, Miusskaya Square, 125047 Moscow, Russia.
authors.forename: Anastasia V
authors.initials: AV
authors.lastname: Shishkina
authors.affiliation: ‡Mendeleev University of Chemical Technology, 9, Miusskaya Square, 125047 Moscow, Russia.
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Vener
authors.affiliation: §Institute of General and Inorganic Chemistry, Russian Academy of Sciences, Leninskii Prosp. 31, 119991 Moscow, Russia.
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Churakov
authors.affiliation: †G.A. Krestov Institute of Solution Chemistry, Russian Academy of Sciences, 1, Academicheskaya, 153045 Ivanovo, Russian Federation.
authors.forename: German L
authors.initials: GL
authors.lastname: Perlovich
mesh_terms: D001549:Benzamides / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D044367:Phase Transition; D011789:Quantum Theory; D012459:Salicylates / Q000737:chemistry*; D012995:Solubility; D013816:Thermodynamics
chemical_list: D001549:Benzamides; D012459:Salicylates; C103544:4-hydroxybenzamide; C014182:salicylsalicylic acid