Interaction of valdecoxib with β-cyclodextrin:: Experimental and molecular modeling studies

This study aimed to investigate the effect of beta-cyclodextrin on aqueous solubility and dissolution rate of valdecoxib and also to get an insight of molecular interactions involved in formation of valdecoxib-beta-cyclodextrin inclusion complex. Phase solubility analysis indicated complex with possible stoichiometry of 1:1 and a stability constant of 234.01 M-1. Thermodynamic studies in water indicated exothermic nature of inclusion complexation. Valdecoxib-beta-cyclodextrin complexes (1:1 M) were prepared by kneading method, solution method and freeze-drying method. The complex was characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (P-XRD), Fourier transform infrared (FTIR) spectroscopy and nuclear magnetic resonance (H-1-NMR) spectroscopy. Molecular modeling was used to help establish the mode of interaction of beta-cyclodextrin with valdecoxib. H-1-NMR analysis suggested that the unsubstituted phenyl ring of valdecoxib display favorable interaction with the hydrophobic cavity of beta-cyclodextrin, which was confirmed by molecular dynamic simulations. An inclusion complex model has been established for explaining the observed enhancement of solubility of valdecoxib in water by beta-cyclodextrin. Dissolution studies in water showed that the valdecoxib in freeze-dried complex dissolved much faster than the uncomplexed drug and physical mixture. This improvement in dissolution rate is attributed to the increased solubility and wettability due to encapsulation along with decreased crystallanity caused by complex formation, which is evident by DSC and P-XRD studies.