Study On Polymorphism Of Etoricoxib

Etoricoxib is a selectively cyclooxygenase-2 inhibitor mainly used to treat diseases like osteoarthritis.Five polymorphic forms and two hydrates of etoricoxib have been reported so far.The relative stability of form I and form IV has been determined.Moreover,the crystal structures of these two forms and hemihydrate have also been solved.In this work,etoricoxib is selected as the model medicine to further study on polymorphism.New etoricoxib solvates were prepared in the solvents with hydrogen bond donors including formamide,ethylene glycol,1,2-propylene glycol,methanol and acetic acid at room temperature.A new solvate can also be obtained in acetonitrile in slurry experiments at low temperature.The crystal structures of etoricoxib form V and methanol/water solvate were solved.The molecules in form V are contacted by C-H…O to form ring motif which is non-existent in form I.The solvent molecules in the structure of methanol/water solvate are treated as substitutional disorders.The methanol and water molecules are located in the same position in the crystal lattice but would not exist at the same time.The methanol molecules are linked with the drug molecules by weak hydrogen bond CH…O.However,there is no molecular interaction between water molecules and etoricoxib molecules.The relative stability of form I and form V was confirmed by many methods.Form I and form V were supposed to be enantiotropic according to heat of fusion rule.Dynamic method was used to measure the solubility of two polymorphs in ethanol,isopropyl alcohol,acetone,butanone,ethyl acetate and acetonitrile from 278.15 K to 313.15 K and form V is found to be the thermodynamically stable form in the experimental temperature range.Thermodynamic transition temperature is determined as(353.45±0.10)K by combining solution-mediated polymorphic transformation experiments and bisection strategy.Pure form V would not transform to form I at high temperature below the melting temperature of form V.However,form V could be successfully induced to transform to form I by using form I as seed crystals at the same temperature.