Research paper Simulation of fasting gastric conditions and its importance for the in vivo dissolution of lipophilic compounds Maria Vertzoni a , Jennifer Dressman b , James Butler c , John Hempenstall c , Christos Reppas a, * a Laboratory of Biopharmaceutics and Pharmacokinetics, School of Pharmacy, University of Athens, Athens, Greece b Department of Pharmaceutical Technology, J.W. Goethe University Frankfurt/Main, Germany c GlaxoSmithKline R&D, Ware, Hertfordshire, UK Received 28 January 2005; accepted in revised form 8 March 2005 Available online 12 May 2005 Abstract In this study, the importance of accurate simulation of fasting gastric environment for the assessment of the absorption process of two model lipophilic compounds, GR253035X (weak base) and atovaquone (non-ionizable), was assessed. Dissolution profiles were constructed in previously proposed simulated gastric fluids and in a new medium that comprises only of components that have been recovered from the fasting stomach. Dissolution data obtained in a more physiologically relevant medium led to better correlation between the simulated and actual intralumenal dissolution vs. time profiles for GR253035X. In contrast, accurate simulation of gastric environment did not affect the simulated plasma profile of atovaquone. Accurate simulation of the fasting gastric contents may be crucial for the assessment of the absorption profile of lipophilic weak bases. q 2005 Elsevier B.V. All rights reserved. Keywords: Dissolution; Fasted state; Gastric composition; GR253035X; Atovaquone; Weak base 1. Introduction Media proposed to date for assessing dissolution in the fasting gastric contents do not constitute the best possible reflection of the in vivo situation, because they do not contain certain physiological substances that may affect dissolution characteristics, such as pepsin [1], they contain substances which are not physiologically relevant, such as artificial surfactants [2,3], or, they contain substances, such as pepsin or bile salts, at non-physiologically relevant concentrations [4,5]. Therefore, in order to screen for reliable and reproducible performance of dosage forms under gastric conditions, it would be highly desirable to develop gastric media which more adequately reflect physiological conditions [6]. For highly soluble compounds, dissolution during gastric residence is not important to the absorption profile regardless of dosing conditions (e.g. [7]). Similarly, dissolution during residence in the fasting stomach does not seem to be important for lipophilic compounds with weakly acidic characteristics (pK a w3.5–5.5), because dissolution in stomach contributes little to the overall dissolution whereas the pH conditions in the small intestine favor fast and often complete dissolution [8,9]. For lipophilic weak bases or non-ionizable compounds, there are no direct data showing the importance of dissolution during gastric residence on the absorption profile. Opposite to weak acids, weak bases dosed in the fasted state are expected to be primarily dissolved during residence in stomach (e.g. [10]). For non-ionizable compounds, in vitro data suggest that, although the extent of dissolution is higher in the fasted small intestine, the difference from fasting stomach is not dramatic (e.g. [11]). The objectives of this study were twofold. The first was to prepare a medium that reflects the actual gastric composition in the fasting state according to published physiological data. The second was to address the importance of adequate European Journal of Pharmaceutics and Biopharmaceutics 60 (2005) 413–417 www.elsevier.com/locate/ejpb 0939-6411/$ - see front matter q 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ejpb.2005.03.002 * Corresponding author. Laboratory of Biopharmaceutics and Pharma- cokinetics, School of Pharmacy, University of Athens, Panepistimiopolis, Zografou, Athens 157 71, Greece. Tel.: C30 210 727 4678; fax: C30 210 727 4027. E-mail address: reppas@pharm.uoa.gr (C. Reppas).