Structure analysis and insight into hydrogen bond and van der waals interactions of etoricoxib cocrystals and cocrystal solvate

Abstract

Etoricoxib (ETR) is a non-ionizable BCS class II drug with no typical hydrogen bond donors and low solubility in water. Cocrystal was proved to be a good strategy to improve bioavailability. In this work, the excess enthalpy (△Hex) was used to shorten the time of the screening of ETR cocrystals. Six cocrystals of ETR and one cocrystal solvate have been synthesized and characterized. The dissolution experiments showed that all cocrystals performed a higher apparent solubility compared with ETR Form Ⅴ. To gain insight into the intermolecular interactions of cocrystals, the crystal structures have been solved by single crystal X-ray diffraction and other analysis methods. The average local ionization energy (ALIE) analysis shows that pyridine nitrogen is more susceptible to be attacked by the electrophiles than sulfonyl oxygen. Therefore, O-H···N rather than O-H···O hydrogen bond dominates the formation of supramolecular synthons. Van der Waals (vdW) force is another main driving force that works together with hydrogen bonds to form basic units of ETR-CT cocrystal and ETR-HQ-MeOH cocrystal solvate. The hydrogen bond strength of all the ETR cocrystals and cocrystal solvate was calculated by atoms-in-molecules theory, which was rationalized by natural population analysis. Overall, our work presents the structure analysis of six newly formed ETR cocrystals and one cocrystal solvate, which provides a deeper insight into intermolecular interactions of cocrystals at the molecular level.