Physico-chemical characterization of aspirated and simulated human gastric fluids to study their influence on the intrinsic dissolution rate of cinnarizine.

To elucidate the critical parameters affecting drug dissolution in the human stomach, the intrinsic dissolution rate (IDR) of cinnarizine was determined in aspirated and simulated human gastric fluids (HGF). Fasted aspirated HGF (aspHGF) was collected from 23 healthy volunteers during a gastroscopic examination. Hydrochloric acid (HCl) pH 1.2, fasted state simulated gastric fluid (FaSSGF), and simulated human gastric fluid (simHGF) developed to have rheological, and physico-chemical properties similar to aspHGF, were used as simulated HGFs. The IDR of cinnarizine was significantly higher in HCl pH 1.2 (952 ± 27 µg/(cm2·min)) than in FaSSGF pH 1.6 (444 ± 7 µg/(cm2·min)), and simHGF pH 2.5 (49 ± 5 µg/(cm2·min)) due to the pH dependent drug solubility and viscosity differences of the three simulated HGFs. The shear thinning behavior of aspHGF had a significant impact on the IDR of cinnarizine, indicating that the use of FaSSGF, with viscosity similar to water, to evaluate gastric drug dissolution, might overestimate the IDR by a factor of 100-10.000, compared to the non-Newtonian, more viscous, fluids in the human stomach. The developed simHGF simulated the viscosity of the gastric fluids, as well as the IDR of the model drug, making it a very promising medium to study gastric drug dissolution in vitro.

Effect of composition of simulated intestinal media on the solubility of poorly soluble compounds investigated by design of experiments.

The composition of the human intestinal fluids varies both intra- and inter-individually. This will influence the solubility of orally administered drug compounds, and hence, the absorption and efficacy of compounds displaying solubility limited absorption. The purpose of this study was to assess the influence of simulated intestinal fluid (SIF) composition on the solubility of poorly soluble compounds. Using a Design of Experiments (DoE) approach, a set of 24 SIF was defined within the known compositions of human fasted state intestinal fluid. The SIF were composed of phospholipid, bile salt, and different pH, buffer capacities and osmolarities. On a small scale semi-robotic system, the solubility of 6 compounds (aprepitant, carvedilol, felodipine, fenofibrate, probucol, and zafirlukast) was determined in the 24 SIF. Compound specific models, describing key factors influencing the solubility of each compound, were identified. Although all models were different, the level of phospholipid and bile salt, the pH, and the interactions between these, had the biggest influences on solubility overall. Thus, a reduction of the DoE from five to three factors was possible (11-13 media), making DoE solubility studies feasible compared to single SIF solubility studies. Applying this DoE approach will lead to a better understanding of the impact of intestinal fluid composition on the solubility of a given drug compound.

Early pharmaceutical profiling to predict oral drug absorption: current status and unmet needs.

Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the pharmaceutical profiling methods available, with focus on in silico and in vitro models typically used to forecast active pharmaceutical ingredient's (APIs) in vivo performance after oral administration. An overview of the composition of human, animal and simulated gastrointestinal (GI) fluids is provided and state-of-the art methodologies to study API properties impacting on oral absorption are reviewed. Assays performed during early development, i.e. physicochemical characterization, dissolution profiles under physiological conditions, permeability assays and the impact of excipients on these properties are discussed in detail and future demands on pharmaceutical profiling are identified. It is expected that innovative computational and experimental methods that better describe molecular processes involved in vivo during dissolution and absorption of APIs will be developed in the OrBiTo. These methods will provide early insights into successful pathways (medicinal chemistry or formulation strategy) and are anticipated to increase the number of new APIs with good oral absorption being discovered.