The number of options available to drug discovery scientists to enhance the solubility of poorly soluble compounds by conventional formulation approaches is limited. In most cases, drug formulation is oriented toward the creation of a supersaturated solution upon contact with aqueous environment, often combined with solubilizing agents and precipitation inhibitors. The most popular formulations for achieving this target are the lipid-based formulations called self-emulsifying and self-microemulsifying drug delivery systems, SEDDS and SMEDDS, respectively. They offer enhanced absorption and hence enhanced oral bioavailability of lipophilic drugs, presenting the drug in solubilized form in vivo, avoiding dissolution, which can be the rate limiting step in drug absorption for sparingly soluble drugs. The production of high energy or rapid dissolving solid state formulations using drug particle engineering to enhance drug solubility and bioavailability is also applied. These formulations include solid dispersions, nanoparticles, co-ground mixtures etc. Furthermore, the development of prodrugs is also a useful strategy to improve the physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically potent compounds, and thereby increase the developability and usefulness of a potential drug. Up to now, most medications were made for adults and children's requirements were not taken into account. Since the recent adoption of Paediatric Regulations in the U.S. and E.U., there is a greater demand for age-appropriate medicines for children. The challenges in paediatric formulation development are mostly associated with the difficulty in defining design requirements for the intended dosage form that is most appropriate for the target patient population, due to the diversity of the paediatric population (range of ages, physical size and capabilities) that varies significantly from birth to age 12 yrs old along with the dosage flexibility. The last years there has been an effort to develop solid paediatric formulations that deliver the appropriate dose in a ``user friendly{''} way and to find alternative drug delivery vehicles, such as mini-tablets, dairy products, and new taste masking techniques in order to improve drug acceptability. In addition, alternative routes of administration have been proposed such as inhalation and nasal administration.

To develop a dose dependent version of BCS and identify a critical dose after which the amount absorbed is independent from the dose. We utilized a mathematical model of drug absorption in order to produce simulations of the fraction of dose absorbed (F) and the amount absorbed as function of the dose for the various classes of BCS and the marginal cases in between classes. Simulations based on the mathematical model of F versus dose produced patterns of a constant F throughout a wide range of doses for drugs of Classes I, II and III, justifying biowaiver claim. For Classes I and III the pattern of a constant F stops at a critical dose Dose(cr) after which the amount of drug absorbed, is independent from the dose. For doses higher than Dose(cr), Class I drugs become Class II and Class III drugs become Class IV. Dose(cr) was used to define an in vivo effective solubility as S-eff = Dose(cr)/250 ml. Literature data were used to support our simulation results. A new biopharmaceutic classification of drugs is proposed, based on F, separating drugs into three regions, taking into account the dose, and Dose(cr), while the regions for claiming biowaiver are clearly defined.

Introduction: Nowadays, reducing medication costs is vital for health care agencies. Prescription of generic drug products can help lower these expenses. A generally accepted assumption is that therapeutic equivalence, between a generic and a brand-name medication, can be claimed if bioequivalence is demonstrated. Areas covered: This article reviews the current regulatory procedures on bioequivalence testing. Special focus is placed on the guidelines recommended by the European Medicines Agency and the US Food and Drug administration. The authors also describe the evolution of these issues and the alternatives proposed in the literature. Expert opinion: Defining bioequivalence, as the condition of no significant differences in the extent and rate of absorption between the generic and the brand-name medication, sounds simple. However, the scientific and regulatory basis of bioequivalence appears rather complicated in practice. Even though the regulatory authorities have elucidated many issues, several aspects of bioequivalence assessment are still unresolved. Examples, of these open questions, in bioequivalence, include the assessment of complex drugs, such as biologics and iron-carbohydrates, the assessment of immunosuppressive agents as well as the role that pharmacogenomics plays in bioequivalence.

To explore the comparative performance of the recently proposed bioequivalence (BE) approaches, FDA(s) and EMA(s), by the FDA working group on highly variable drugs and the EMA, respectively; to compare the impact of the GMR-constraint on the two approaches; and to provide representative plots of % BE acceptance as a function of geometric mean ratio, sample size and variability. Simulated BE studies and extreme GMR versus CV plots were used. Three sequence, three period crossover studies with two treatments were simulated using four levels of within-subject variability. The FDA(s) and EMA(s) approaches were identical when variability was < 30%. In all other cases, the FDA(s) method was more permissive than EMA(s). The major discrepancy was observed for variability values > 50%. The GMR-constraint was necessary for FDA(s), especially for drugs with high variabilities. For EMA(s), the GMR-constraint only became effective when sample size was large and variability was close to 50%. A significant discrepancy in the performances of FDA(s) and EMA(s) was observed for high variability values. The GMR-constraint was essential for FDA(s), but it was of minor importance in case of the EMA(s).