We highlight some physical and mathematical aspects relevant to the derivation and use of the Higuchi equation. More specifically, the application of the Higuchi equation to different geometries is discussed and Monte Carlo simulations to verify the validity of Higuchi law in one and two dimensions, as well as the derivation of the Higuchi equation under alternative boundary conditions making use of fractional calculus, are presented. (C) 2010 Elsevier B.V. All rights reserved.

Objectives This study was undertaken to investigate the effect of d-alpha-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) on the dissolution of carbamazepine (CBZ) commercial tablets (Tegretol (R)) as a function of temperature and to modify the reaction-limited model of dissolution for the description of classical supersaturated dissolution data. Methods Solubility studies were performed using various concentrations of (i) TPGS and (ii) silicon dioxide and microcrystalline cellulose, which are excipients of Tegretol (R) at 10, 25 and 37 degrees C. Dissolution studies were carried out using Tegretol (R) tablets, 200 mg/tab. Key findings The solubility of CBZ in the presence of TPGS was found to increase in a concentration-dependent manner at all temperatures studied. Classical supersaturated dissolution curves with concentration maxima higher than the corresponding solubility values in the presence of TPGS were observed only at 10 degrees C. The model developed was based on a time-dependant expression for the forward microconstant of the CBZ-TPGS reaction at the solid-liquid interface and it was fitted successfully to the dissolution data of CBZ in the presence of TPGS at 10 degrees C. Conclusions Vitamin E TPGS increased the solubility of CBZ at all temperatures studied. The modification of the reaction-limited model of dissolution allowed us to describe classical supersaturated dissolution curves.

Early prediction of human intestinal absorption is important in selection of potential orally administered drugs. Various computational models for prediction of the fraction of dose absorbed, Fa, have been developed. In 1989, a sigmoidal relationship between Fa and drug absorption potential was shown. Since then various physicochemical descriptors of molecules (lipophilicity, polar surface area, hydrogen bond descriptors) have been found to correlate with human intestinal absorption and various attempts in estimating Fa have been reported. Most studies rely on the presupposition that Fa is mainly dependent on drug's solubility, which drives the dissolution rate in the gastrointestinal (GI) fluids, and the rate of passive drug transport across the intestinal membrane. In the same vein, the biopharmaceutics classification system (BCS) and the relevant FDA guideline classify drugs in four categories according to their aqueous solubility and permeability. However, the biopharmaceutics drug disposition classification system (BDDCS) revealed the poor predictability of permeability estimates for Fa and the major role of transporters for GI uptake of drugs. The role of solubility in the reaction limited model of dissolution and the ubiquitous presence of supersaturated solubility-dissolution phenomena in the GI lumen, call for a more physiologically relevant consideration of GI absorption.

Areas covered in this review: In this review, we present the classic approach of bioequivalence assessment, some situations of special importance such as the role of metabolites and highly variable drugs, and the current regulatory state in North America and Europe. Special emphasis is given to the methods proposed for solving the problems caused by high variability such as multiple-dose studies, replicate designs, individual bioequivalence and the widening of bioequivalence limits. Other issues discussed include the concept of biowaivers and the rising field of the equivalence of biologicals (biosimilars). What the reader will gain: The reader will gain an understanding of why bioequivalence assessment is necessary, how it is performed and what one should be aware of when planning to conduct a bioequivalence study. Take home message: The aim of bioequivalence studies is to ensure comparable in vivo performance of two drug products. This is accomplished by performing an appropriate clinical study which should be capable of ensuring the drug's safety and efficacy for consumers with less human exposure and costs of producing.

Recently, the European Medicines Agency (EMA) issued a new guideline on the investigation of bioequivalence (BE). In case of highly variable drugs, this guideline proposes that the acceptance limits for C-max can gradually be expanded as a function of within-subject variability (CVWR). Actually, these BE limits exhibit leveling-off properties since they are not allowed to scale continuously, but only up to CVWR = 50%. To avoid the risk of accepting two drug products which may differ significantly, this EMA guideline also proposes the use of a secondary constraint criterion on the geometric mean ratio (GMR) of the two products under comparison. Aim of this study was to explore the leveling-off properties of the new EMA limits in comparison to other approaches, as well as to assess the impact of the complementary GMR criterion on the ability to declare bioequivalence. Simulated bioequivalence studies and extreme GMR plots were used to assess the performance of the EMA limits. Three sequence, three period (3 x 3) crossover studies with two treatments (T and R) were simulated. The R product was considered to be administered twice, while the T only once (i.e., TRR/RTR/RRT). Among others, this study revealed the leveling-off properties of the new EMA limits. It was also shown that the complementary GMR-constraint is only effective when a large sample size is used and at regions of CVWR close to 50%. This GMR-criterion begins to be effective at sample sizes around 60 and becomes more prominent as the number of subjects participating in the BE study increases. For CVWR values lower than 50%, the GMR-constraint has no role. In case of within-subject variabilities greater than 50%, the impact of the GMR-constraint diminishes due to the leveling-off properties of the EMA limits. Compared to the classic 0.80-1.25 or the extended 0.75-1.33 criteria, the new EMA limits are more liberal at high CVWR values and allow greater differences between the two drug products to be declared bioequivalent. Finally, this study showed that the use of an approximate value (0.760) on the scaling factor proposed by EMA, has no impact on the performance of the new BE limits compared to other more accurate approaches. (C) 2011 Elsevier B.V. All rights reserved.