Combined computational/experimental investigation of new cocrystals of the drug bosentan

We report the discovery of new cocrystals of bosentan, a drug used in the treatment of pulmonary artery hypertension, with succinic acid, resorcinol, and 4-hydroxybenzoic acid through a combined virtual/experimental cocrystal screening. The X-ray structure of the bosentan/succinic acid cocrystal shows a network of H-bonds involving both components, which have been studied energetically using DFT calculations. The succinic acid molecules interact with one of the pyrazine rings of bosentan establishing an energetically significant lpMIDLINE HORIZONTAL ELLIPSIS pi interaction. Moreover, they form homodimers stabilized by antiparallel COMIDLINE HORIZONTAL ELLIPSISCO interactions. This set of interactions has been rationalized using molecular electrostatic potential (MEP) surfaces, the quantum theory of atoms-in-molecules (QTAIM), and the noncovalent interaction plot (NCIplot).

Automated summary

New cocrystals of bosentan with succinic acid, resorcinol, and 4-hydroxybenzoic acid have been discovered through a virtual/experimental cocrystal screening. The X-ray structure of the bosentan/succinic acid cocrystal reveals a network of H-bonds and various other interactions, which have been studied energetically. Notably, the succinic acid molecules establish an energetically significant lpMIDLINE HORIZONTAL ELLIPSIS pi interaction with one of the pyrazine rings of bosentan.