Study On Solid Forms Screening And Mechanism Of Molecular Self-assembly Of Etoricoxib

As the crystallization media or the component of crystal structure,solvent properties have a great influence on the molecular self-assembly process of solid forms.Understanding the role of solvent properties,such as H-bond donor（HBD）and acceptor（HBA）ability,polarity,as well as solvent size in the formation of different forms contributes to solid form control at molecular level.In this study,a series of solvents screening experiments have been conducted to investigate the effect of solvent properties on the formation of different solid forms by using etoricoxib（ETR）as a model drug.Besides,the influence mechanism of solvent properties on the self-assembly process of different forms was revealed in combination of crystal structure analysis,DFT calculation,and solution Fourier transform infrared（FTIR）spectrum analysis in the molecular scale.Six new ETR solvates were obtained in ethylene glycol,1,2-propanediol,formamide,methanol,dimethyl sulfoxide,and N-methyl-pyrrolidone solution by solid form screening experiments,and their single crystal structure were resolved successfully.Based on the analysis of suspension results and solvent properties,it was found that the solvent HBD ability determines the formation of ETR forms I and V,while the solvent polarity capacity drives the formation of ETR solvates.Solvent-centric molecule pairwise interaction energies calculations and topological analysis indicate that the strong intermolecular electrostatic interactions between solvents and their surrounding molecules are the main driving forces for the formation of ETR solvates.Solvents with higher polarity are easier to be integrated into the lattice of ETR to form corresponding solvates based on intermolecular strong electrostatic interactions.The molecular electrostatic potential analysis manifests that the origin of intermolecular strong electrostatic interactions steams from ETR-solvent intermolecular electrostatic potential complementary.The solution FTIR spectrum analysis further showed that solvents with higher polarity indeed have stronger binding ability with ETR so that they are easier to from solvates with ETR.However,in solvents systems with lower polarity,the-OH group of the HBD type solvents can form strong H-bond with ETR,while the-CH₃ group of the HBA type solvents molecule can form weak H-bond with ETR.The differences of the solvent-solute intermolecular interactions strength is possible to result in the crystallization of form I in the HBD type solvents and form V in the HBA type solvents.The crystal structure analysis of forms I and V,molecular potential analysis,as well as Gibbs free energy barrier calculations indicate that the prenucleation dimer of form I prefer to be formed in HBD type solvents with lower polarity due to solute-solvent strong H-bonding interactions,while the solute-solvent intermolecular weak H-bonding interactions facilitates the formation of form V prenucleation dimer in the HBA type solvents with lower polarity.Thus,ETR form I prefers to be formed in HBD type solvents with lower polarity,while form V tends to be formed in the HBA type solvents with lower polarity.