Effect of buffer species on the inclusion complexation of acidic drug celecoxib with cyclodextrin in solution

The interaction of celecoxib (Celox) with cyclodextrins (CDs) has been investigated by phase solubility techniques. In this study, the influences of CD type, pH, buffer type, buffer concentration and temperature on the tendency of Celox to form inclusion complexes with CDs were examined. The tendency of Celox to complex with CDs is in the order HP-beta-CD > beta-CD > gamma-CD > alpha-CD, where the complex formation constants (K-11) were 1377, 693, 126 and 60 M-1, respectively. Also ionization of the slightly acidic Celox (pK(a)=9.7) was found to reduce its tendency to complex (i.e., The K-11 values of Celox/beta-CD in 0.05 M phosphate buffer were 976 and 210 M-1 for neutral and ionized Celox, respectively). Increasing citrate and phosphate buffer concentration enhances the tendency of ionized Celox to complex with beta-CD as a result of a corresponding decrease in the inherent solubility (S-0) of the Celox anion, On the other hand, these two buffers interact differently with neutral Celox and beta-CD, where increasing phosphate buffer concentration at low pH enhances the complexation of neutral Celox by lowering S-0, while increasing citrate buffer concentration at low pH reduces complex formation as citrate buffer species, mainly citric acid, act as a solublizer and a competitor for Celox and beta-CD. The contribution of Celox hydrophobicity for complex stability constitutes about 77% of the driving force for complex stability. The complex formation of neutral Celox with beta-CD (Delta G(0) = -28.6 kJ/mol) is driven by both enthalpy (Delta H-0 = -21.7 kJ/mol) and entropy (Delta S-0 = 23.3 J/mol K) changes.