Study of drug supersaturation and precipitation mechanisms in vitro under simulated in vivo conditions

One of the key processes for drug absorption after oral administration is drug dissolution in the gastrointestinal (GI) tract fluids. Due to the use of complex drug delivery systems or changes in the physiological properties of the GI tract, supersaturation and precipitation of drugs can also occur. In vitro models that simulated various physiological parameters were developed within the doctoral dissertation to investigate drug dissolution, supersaturation, and precipitation. Using a pH shift method, drug precipitation was studied in a simple precipitation model with an innovative approach to simultaneously monitor the particle size distribution and concentration of the dissolved drug. Furthermore, we also developed several biorelevant models with separately simulated selected GI tract parameters: in vivo pH profiles along the GI tract, the gastric emptying kinetics of co-ingested water, and a combination of pH value and lipid concentration representing the gastric conditions at different times after ingestion of a meal. The sample preparation procedure and HPLC method were also developed in experiments with simulated fed state conditions to determine the amount of dissolved drug in the whole sample and its partitioning between the lipid and aqueous phases of the medium. Typical changes in the particle size distribution were observed in the precipitation model. The particles also increased the measured absorbances in a wavelength-dependent or wavelength-independent way concerning the particle size, thus also affecting the calculated amount of the dissolved drug. A distinctive effect of the simulated physiological parameters in biorelevant models on drug behaviour was observed, however, the solubility of drugs in tested media controlled the influence of other simulated parameters on drug behaviour. Since supersaturation and precipitation also occurred in biorelevant models, the identified precipitation mechanisms from the precipitation model were successfully translated into biorelevant models. This enabled a better understanding of the complex processes of model drug behaviour after oral administration, including drug dissolution, supersaturation, and precipitation.