P. Macheras

Unusual solubility behaviour of cyclosporin A in aqueous media

Abstract— The solubility of cyclosporin A was determined in water and in Sorensen buffers at pH 1.2 and 6.6 at temperatures ranging from 5 to 37°C. No differences in solubility behaviour were observed among the three aqueous media. Solubility was found to be inversely proportional to the temperature in each medium, indicating that the heat of solution was exothermic in each case.

The power law can describe the 'entire' drug release curve from HPMC-based matrix tablets: a hypothesis.

The purposes of this study were to (i) re-examine the relevance of Higuchi equation and the power law using both simulated and experimental release data in conjunction with the linearized, in terms of t(1/2), percent of drug release plots, (ii) demonstrate that the power law describes the entire drug release profile of several experimental data, and (iii) point out a physically based hypothesis for the successful use of power law in describing the entire drug release profile. Simulated data generated from the equation of power law were further analyzed using linear regression analysis in accord with the Higuchi equation. The analysis revealed that data generated from the equation of power law can be misinterpreted as obeying the Higuchi equation. The use of power law in describing the entire drug release curve from HPMC-based matrix tablets is validated by direct fit of power law equation to published data of other authors. A hypothesis based on the nonclassical diffusion of the solutes in the HPMC matrices is used to interpret the successful use of the power law in describing the entire release profile.

Drug dissolution studies in milk using the automated flow injection serial dynamic dialysis technique

Abstract The application of flow injection serial dynamic dialysis (FISDD) technique to monitor dissolution studies in complex media is described. The method is based on the study of the kinetics of the simultaneous dissolution and dialysis processes. Commercial formulations of salicylamide, propantheline bromide, nitrofurantoin and acetaminophen were used to investigate the utility of the FISDD technique for studying the dissolution of drugs in low fat milk. The latter was utilized as a food simulating medium. Dissolution studies were also conducted in phosphate buffer of pH 6.5. In each case the FISDD system was coupled with the rotating basket apparatus. The determination of the dialyzable drugs was performed automatically by the FIA analyzer. A fully automated monitoring of dissolution of drugs in milk and buffer was achieved. In all cases the dissolution rate of drugs in milk was lower than the corresponding rate in the aqueous buffer. The potential significance of this system with respect to the in vitro study of dissolution of drugs in food simulating media is discussed. This system could be used either to reveal or explore food-drug and/or food-formulation interactions anticipated or observed in vivo.

Drug binding and solubility in milk

The binding and solubility of nitrofurantoin, piroxicam, indomethacin, prednisolone, diazepam, dicumarol, and griseofulvin in milk were determined at 15, 25, and 37°C in bovine milk samples with fat contents of 0.75 and 3.50%. Drug binding to milk components was independent of drug concentration over the drug concentration studied, and the fat content of milk strongly affected binding values of most of the listed drugs. Further, drug binding increased with decreasing temperatures for most of the drugs examined. The solubility of all drugs is greatly enhanced in milk compared to their aqueous solubility (pH 6.5 phosphate buffer). The high solubility cannot be accounted for solely on the basis of drug binding to milk components. An attempt is made to correlate the binding and solubility data with physicochemical properties of the drugs (logP, pKa, aqueous solubility). The potential significance of these findings is discussed with regard to preparation and in vivo delivery of drugs from drug–milk formulations.

Bioavailability and Bioequivalence: Focus on Physiological Factors and Variability

This is a summary report of the EUFEPS & COST B25 conference on Bioavailability and Bioequivalence which focused on physiological factors and variability. This conference was held at The Royal Olympic Hotel in the centre of Athens (Greece) during the 1–2 of October in 2007. The issues discussed in the conference involved physiological factors affecting drug absorption, the role of pre-systemic effects on bioavailability (BA), the impact of variability in bioequivalence (BE) studies, and a final closing panel session on unresolved issues in BA/BE regulations. Several important aspects of drug absorption were highlighted. It was presented how the complexity of gastrointestinal (GI) physiology and the site dependent absorption can impact on drug BA. Similarly, the effects of food and formulation were also studied. The second session focused on integrating the complexities of GI into modeling the inter-individual variability of absorption and the prediction of first-pass metabolism from in-vitro data. The necessity to measure metabolites, the value of Biopharmaceutical Classification System (BCS), and the more recently proposed Biopharmaceutical Drug Disposition Classification System (BDDCS) were assessed as well. This session closed with presentations of pharmacokinetic software delegates. In the second day of the conference, the problem of high intra-subject variability in BE studies was analyzed. Study design considerations, the use of multiple-dose studies and the role of statistics in BE were also highlighted. Finally, the current thinking of regulatory authorities (EMEA and US-FDA) was presented. The conference closed with a last session on unresolved issues in the regulatory level.

Effect of elevated viscosity in the upper gastrointestinal tract on drug absorption in dogs

The objectives of these studies were, first, to determine the effect of elevated luminal viscosity on the gastrointestinal absorption of four model drugs and, second, to identify the key processes influencing drug absorption under elevated viscosity conditions. Studies were conducted in vitro and in healthy female mongrel dogs under fasting conditions. In the canine model, both the rate and extent of paracetamol and hydrochlorothiazide absorption were significantly decreased by the coadministration of 15 g guar gum dissolved in 500 ml normal saline. In the case of cimetidine, the rate but not extent of absorption was decreased. Owing to the high variability in the data, no statistically based conclusion could be drawn about the effects of coadministered guar gum on the oral absorption of the poorly soluble mefenamic acid. Based on the in vitro data, it appears that substantial reductions in the dissolution rate of paracetamol, hydrochlorothiazide and cimetidine account for the effects observed in vivo. It is concluded that the effect of an elevation in the intraluminal viscosity on drug absorption is greatest for highly soluble drugs, and results from a combination of a decrease in dissolution rate and gastric emptying rate.

Dissolution of 4 controlled-release theophylline formulations in milk

Abstract The disissolution of 4 controlled-release theophylline formulations was studi9d in a low-fat (0.75%) milk and in a buffer of pH 6.5. A flow-injection dialysis-UV spectrophotometric method was developed to determine the drug in the milk samples. Calibration curves were linear up to 250 μg/ml for theophylline and aminophylline and up to 450 μg/ml for choline theophyllinate, with detection limits of 18.5, 5.4, and 14.7 μg/ml, respectively, in a 5.0 ml minimum sample volume. Lower dissolution profiles in milk than in buffer were observed for 3 of the formulations examined. One theophylline formulation exhibited relatively similar dissolution profiles in both media. The use of milk as a food-simulating medium in dissolution studies is suggested for the in vitro evaluation of the release rate of drugs from controlled-release formulations. The proposed technique can be applied in such studies.

Development of a reaction-limited model of dissolution: application to official dissolution tests experiments.

A reaction-limited model for drug dissolution is developed assuming that the reaction at the solid-liquid interface is controlling the rate of dissolution. The dissolution process is considered as a bidirectional chemical reaction of the undissolved drug species with the free solvent molecules, yielding the dissolved species of drug complex with solvent. This reaction was considered in either sink conditions, where it corresponds to the unidirectional case and the entire amount of the drug is dissolved, or reaching chemical equilibrium, which corresponds to saturation of the solution. The model equation was fitted successfully to dissolution data sets of naproxen and nitrofurantoin formulations measured in the paddle and basket apparatuses, respectively, under various experimental conditions. For comparative purposes these data were also analyzed using three functions based on the diffusion layer model. All functions failed to reveal the governing role of saturation solubility in the dissolution process associated with the diffusion layer model when the conditions for the valid estimation of saturation solubility, established theoretically in this study, were met by the experimental set up employed. Overall, the model developed provides an interesting alternative to the classic approaches of drug dissolution modeling, quantifying the case of reaction-limited dissolution of drugs.

An in vitro model for exploring CR theophylline-milk fat interactions

Abstract The dissolution of the controlled-release theophylline formulations, Theodur tablet and Theodur sprinkle capsule, was studied in buffer of pH 6.5 and in milk with varying fat contents i.e. 0.1%, 2.0%, 5.0% and 7.5%. The topographical dissolution characterization made was based on a three-dimensional format with independent variables, time and percent fat content of milk. This plot revealed that the dissolution of capsule was markedly lower in all types of milk than in buffer. The dissolution of tablet was higher in milk with 0.1% fat content and slightly higher in milk with 2.0% and 5.0% fat content when compared to that in buffer. The dissolution of tablet in milk with 7.5% fat content was initially lower and then became progressively faster than observed in the aqueous medium. Binding experiments of theophylline to milk with 0.1% and 2.0% fat content, using concentrations encountered during the dissolution process, showed no significant interaction between theophylline and milk. The dissolution data clearly indicate a milk fat content dependent interaction between theophylline formulations and milk. In vivo data reported in literature and observed under “high fat meal” conditions were correlated with the dissolution data. Linear correlations were established in all cases. It was concluded that the 7.5% fat content milk mimics more closely the “high fat meal” conditions. This would aid the development of an appropriate dissolution test capable of simulating non-fasting conditions.

Determination of Association Constants in Cyclodextrin/Drug Complexation Using the Scatchard Plot: Application to β-Cyclodextrin-Anilinonaphthalenesulfonates

The appropriate Scatchard equation was developed for a system involving the formation of 1:1 and 1:2 substrate: cyclodextrin complexes. Simulation of this system was performed under the most common experimental conditions encountered in this type of study. The use of the equation allows for nonlinear least-squares estimation of the association constants. The interaction of the model compounds 1-anilino-8-naphthalenesulfonate (1,8-ANS) and 2(p-toluidinyl)-6-naphthalenesulfonate (2,6-TNS) with β-cyclodextrin (β-CD) was used to evaluate the theoretical model. Binding experiments were performed using either potentiometric titration or fluorimetric detection. The experimental data for 1,8-ANS/β-CD fit well to the 1:1 binding model, with an association constant of 87 ± 1 M−1. The association constants of the 1:1 and 1:2 2,6-TNS/β-CD complexes utilizing direct potentiometry were 3737 ± 6 and 149 ± 2 M−l. It is shown that fluorimetry can give biased estimates for the association constants of the complexation 2,6-TNS/β-CD, since the assumption of an equivalent quantum yield of bound species is not valid.