Automated small-scale in vitro transfer model as screening tool for the prediction of in vivo-dissolution and precipitation of poorly solubles

Publication date: Available online 12 December 2018Source: International Journal of PharmaceuticsAuthor(s): Christian Jede, Christian Wagner, Holger Kubas, Christian Weber, Markus Weigandt, Mirko Koziolek, Werner WeitschiesAbstractPrecipitation testing, especially for weakly basic APIs, represents a key parameter in drug substance characterization during early development stages, where the amount of API available is limited. Therefore, it was the aim of this study to develop an automated small-scale in vitro transfer model to characterize the supersaturation and precipitation behavior of two poorly water-soluble drugs. Following automation and scale-down of the standard transfer model, the developed small-scale model was used to assess the impact of gastrointestinal variability, i.e. gastric pH, gastric emptying, and gastrointestinal fluid volumes, on supersaturation and precipitation of two weakly basic model compounds, ketoconazole and a new chemical entity from the research laboratories of Merck KGaA, MSC-A. The experiments revealed that variations in gastrointestinal parameters affected the in vitro behavior of ketoconazole, but not of MSC-A. Elevated gastric pH, as it can result from co-medication with acid-reducing drugs, resulted in lower degrees of supersaturation for both substances. This result is in agreement with the observation that the oral bioavailability of ketoconazole is lowered when proton pump inhibitors are co-administered. The small-scale transfer model ...
Source: International Journal of Pharmaceutics - Category: Drugs & Pharmacology Source Type: research