The binding of naproxen, ketoprofen, phenylbutazone, salicyclic acid, azapropazone, and indobufen to bovine serum albumin was studied by applying the potentiometric ion probe technique. An ion-selective electrode for the ion probe 1-anilino-8-naphthalenesulfonate was utilized for the purposes of this study. A modified site-oriented competitive binding model was used for the estimation of the drugs' binding parameters, considering different number of binding sites on the competing binding class(es) for the probe and the drug. Calculations v,ere based exclusively on the concentration data of the free probe. The model's ability for accurate estimations of binding parameters was evaluated by simulation studies. The following values of binding parameters were found at 25 degrees C for the drugs under study; naproxen, n(1) = 9.1, k(1) = 9.4 X 10(5) M(-1); ketoprofen, n(1) = 8.8, k(1) = 10.8 X 10(5) M(-1); phenylbutazone, n(1) = 3.2, k(1) = 1.4 X 10(5) M(-1); salicylic acid, n(1) = 2.6, k(1) = 1.8 X 10(5) M(-1), n(2) = 21.5, k(2) = 1.0 X 10(4) M(-1); azapropazone, n(1) = 0.5, k(1) = 7.8 X 10(5) M(-1), n(2) = 26.3, k(2) = 1.9 X 10(4) M(-1); indobufen, n(1) = 5.8, k(1) = 5.8 X 10(5) M(-1), n(2) = 19.9, k(2) = 3.8 X 10(5) M(-1), where n(i) the number of binding sites of the i class and k(i) the corresponding association constant.

The partial area method has been suggested for the assessment of the absorption rate in bioequivalence studies. This paper provides a theoretical basis for the estimation of the optimal cutoff time point of the partial areas for drugs with one compartment model disposition. The analysis is performed by using the appropriate equations which relate the normalized (in terms of the extent of absorption) partial areas with time expressed in terms of multiples of half-life. Provided that the quality of experimental data ensures precise estimation of the parameters, the t(max) of the formulation with the faster absorption characteristics is generally the most practical cutoff time point for calculation of the normalized partial areas, when a drug follows one compartment model disposition with linear absorption.

The application of flow-injection analysis (FIA) to automated dissolution studies of sustained-release formulations is described. The long-term stability of the dissolution-FIA analyser was checked during unattended operation for 42 h. The construction of multiple calibration curves with the so-called electronic dilution FIA procedure was used to extend the linear range of the determination. The computer-controlled FIA system and the principles of associated software are described and applied to dissolution studies of sustained-release formulations of iron(II) using its sensitive reaction with the colour reagent, ferrozine. The extended linear range of the determination is 1-130 ppm iron(II) and the precision (RSD) better than 3% (n = 3).

The aqueous solubility of cyclosporin A (CyA) in the presence of various concentrations of TPGS ranging from 0.01 to 0.50 mM was studied at three temperatures (5, 20, and 37-degrees-C). Compared to previously reported solubility data in triple distilled water, solubility in the presence of TPGS was significantly increased at all temperatures. Surface tension and light scattering measurements showed that solubilization in TPGS multimers is the main mechanism responsible for the increased CyA solubility at 20-degrees-C and 37-degrees-C. In contrast, the increased CyA solubility at 5-degrees-C appears to be mediated by other mechanism(s), such as association of TPGS with CyA. These data substantiate the view that the enhanced bioavailability of CyA, when coadministered with TPGS in patients suffering from cholestasis, is due to the increased solubility of CyA in the presence of TPGS.

A flow-injection dynamic dialysis technique is presented for the determination of binding parameters of drugs to cyclodextrins (CDs). The automated system consists of a flow-injection unit, the sample loop of which is the receiving compartment of a dialyser unit, and a home made timing module for operation control through two flow switching solenoid valves. The procedure of binding studies is rapid and yields reproducible results. Binding parameters of CD-micromolecule complexes was calculated using the Scatchard model. Typical examples of the binding of p-nitrophenol with alpha-CD(K-as=1.56x10(3) M(-1) at pH 7.4 and 2.06x10(3) M(-1) at pH 9.0), salicylic acid with beta-CD (K-as=3.8 x 10(2) M(-1) at pH 1.5 and 51 M(-1) at pH 7.4) and ibuprofen with beta-CD (K-as=2.2x10(2) M(-1) at pH 2.5) are presented and the binding constants obtained are compared to literature values. 1:1 stoichiometry was found in all cases and within run precision ranged from 2 to 14% R.S.D. The between run precision for the binding of p-nitrophenol to alpha-CD was 2% (n=3).

The binding of diflunisal to hydroxypropyl-beta-cyclodextrin (HPbetaCD), bovine serum albumin (BSA), human serum albumin (HSA), normal human plasma, and mixed solutions of HPbetaCD/protein was studied at 25-degrees-C, pH 7.4, by potentiometry using an electrode selective to diflunisal. The experimental data for diflunisal/HPbetaCD fit well to the 1:1 binding model. The binding of diflunisal with each of the studied proteins was compatible with a model having two independent classes of binding sites. The binding of diflunisal in mixed solutions HPbetaCD/BSA, HPbetaCD/HSA, and HPbetaCD/plasma increased considerably when the HPbetaCD concentration was increased. The binding behavior of the two biomolecules in the mixed solutions of HPbetaCD/BSA or HPbetaCD/HSA was described with an `'additive'' model formulated on the basis of the estimates of the binding parameters of diflunisal derived from the separate experiments with each one of the binders tested. The lower than theoretical binding observed in HPbetaCD/plasma solutions was ascribed to the competitive displacement of diflunisal from the HPbetaCD cavity by plasma cholesterol.