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.

Solving the enigma of weak fluorine contacts in the solid state: a periodic DFT study of fluorinated organic crystals

“…52 Eqn 2, which was used to estimate the E latt values, allows the lattice energy to be divided into different terms. 114,115 The contributions of the C-H/O and C-H/F-C interactions are comparable and responsible for more than 2/3 of E latt ( Table 3). This means that both interactions can play a signicant structure-directing role in organic crystals without conventional H-bonds or other relatively strong intermolecular interactions.…”

Optimising the in vitro and in vivo performance of oral cocrystal formulations via spray coating

“…Overall, the spray coating has allowed the formation of pure cocrystals (i.e. not contaminated with either API or coformer) compared with other techniques such as spray drying and solvent evaporation, probably because lower temperatures are required during the evaporation of the solvent and the risk of sublimation is minimised [36].…”

Estudo Térmico, Caracterização Espectroscópica e Difração de Raio X do Cocristal de Ácido Salicílico com Ácido Nicotínico Obtido por Síntese Mecanoquímica

“…Um cocristal farmacêutico pode ser definido como um sólido cristalino multicomponente contendo duas ou mais partes, sendo estas um ingrediente farmacologicamente ativo (API, do inglês "Active Pharmacological Ingredient) neutro e um coformador neutro, unidos por interações não-covalentes como interações de hidrogênio, dipolo-dipolo e , [5][6][7] sendo uma boa alternativa para melhorar propriedades físico-químicas de um principio ativo, como, por exemplo, sua solubilidade [8], estabilidade [9,10] e, portanto sua biodisponibilidade [11].…”