Automated small-scale in vitro transfer model as screening tool for the prediction of in vivo-dissolution and precipitation of poorly solubles
| Autor: | Markus Weigandt, Holger Kubas, Mirko Koziolek, Christian Jede, Christian Wagner, Werner Weitschies, Christian Weber |
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| Rok vydání: | 2018 |
| Předmět: |
Drug
media_common.quotation_subject Chemistry Pharmaceutical Pharmaceutical Science 02 engineering and technology 030226 pharmacology & pharmacy 03 medical and health sciences Automation 0302 clinical medicine In vivo medicine Chemical Precipitation Technology Pharmaceutical Dissolution media_common Supersaturation Chromatography Gastric Juice Gastric emptying Chemistry Precipitation (chemistry) Hydrogen-Ion Concentration 021001 nanoscience & nanotechnology Bioavailability Ketoconazole Gastric Emptying Pharmaceutical Preparations Solubility 0210 nano-technology medicine.drug |
| Zdroj: | International journal of pharmaceutics. 556 |
| ISSN: | 1873-3476 |
| Popis: | Precipitation 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 presented herein represents a valuable in vitro tool to assess the risk of drug precipitation, additionally covering a broad range of gastrointestinal parameters. |
| Databáze: | OpenAIRE |
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