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

Cecilie Maria Madsen, Kung-I Feng, Andrew Leithead, Nicole Canfield, Søren Astrup Jørgensen, Anette Müllertz, Thomas Rades

Research output: Contribution to journalJournal articleResearchpeer-review

26 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalEuropean Journal of Pharmaceutical Sciences
Volume111
Pages (from-to)311-319
Number of pages9
ISSN0928-0987
DOIs
Publication statusPublished - Jan 2018

Keywords

  • Journal Article

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