Determination of stability constant values of flurbiprofen-cyclodextrin complexes using different techniques

Three new experimental approaches for calculating the stability constant (K,,) of complexes of flurbiprofen with natural P-cyclodextrin (beta Cyd) and the hydroxyethyl- (HE beta Cyd) and the methyl- (Me beta Cyd) derivatives were tested and compared to the classic phase-solubility procedure: (a) the membrane permeation technique through a lipophilic synthetic membrane permeable to the drug but not to the Cyd molecules, by analysing the permeation profiles with a non-linear least-squares method; (b) the affinity capillary electrophoresis (ACE) technique, where K,, were calculated from the relationship between Cyd concentration in solution and drug electrophoretic mobility, using three different linear plotting methods; (c) the molecular modeling technique, based on the relationship between the docking energies and the experimental K-st values. The study allowed evaluation of the advantages and limits of each examined method, providing a useful guide for the choice of the most suitable one depending on the kind of host-guest system to be investigated. The K-st values obtained with the various techniques were rather different, probably due to the very different experimental conditions required by each one. However, all the methods indicated the methyl-derivative as the most powerful complexing agent for the drug, showing the general trend: K-st(Me beta Cyd) >> K-st(HE beta Cyd) > K-st(beta Cyd). Only in the case of the ACE method was an inversion of the trend found between HE beta Cyd and beta Cyd; this was probably due to the lower molecular weight of the natural Cyd, which, in this case, became more important in determining the complex electrophoretic mobility than the different affinity of the drug for these two Cyds. (c) 2004 Elsevier B.V. All rights reserved.