Is the full potential of the biopharmaceutics classification system reached?
In this paper we analyse how the biopharmaceutics classification system (BCS) has been used to date. A survey of the literature resulted in a compilation of 242 compounds for which BCS classes were reported. Of these, 183 compounds had been reported to belong to one specific BCS class whereas 59 compounds had been assigned to multiple BCS classes in different papers. Interestingly, a majority of the BCS class 2 compounds had fraction absorbed (FA) values >85%, indicating that they were completely absorbed after oral administration. Solubility was computationally predicted at pH 6.8 for BCS class 2 compounds to explore the impact of the pH of the small intestine, where most of the absorption occurs, on the solubility. In addition, the solubilization capacity of lipid aggregates naturally present in the intestine was studied computationally and experimentally for a subset of 12 compounds. It was found that all acidic compounds with FA>85% were completely dissolved in the pH of the small intestine. Further, lipids at the concentration used in fasted state simulated intestinal fluid (FaSSIF) dissolved the complete dose given of the most lipophilic (logD6.5>3) compounds studied. Overall, biorelevant dissolution media (pure buffer of intestinal pH or FaSSIF) identified that for 20 of the 29 BCS class 2 compounds with FA>85% the complete dose given orally would be dissolved. These results indicate that a more relevant pH restriction for acids and/or dissolution medium with lipids present better forecast solubility-limited absorption in vivo than the presently used BCS solubility criterion. The analysis presented herein further strengthens the discussion on the requirement of more physiologically relevant dissolution media for the in vitro solubility classification performed to reach the full potential of the BCS.
Department of Pharmacy, Uppsala University, Biomedical Centre, P.O. Box 580, SE-751 23 Uppsala, Sweden. Electronic address: christel.bergstrom@farmaci.uu.se.
Christel A S
CA
Bergström
Department of Pharmacy, Uppsala University, Biomedical Centre, P.O. Box 580, SE-751 23 Uppsala, Sweden.
Sara B E
SB
Andersson
Department of Pharmacy, Uppsala University, Biomedical Centre, P.O. Box 580, SE-751 23 Uppsala, Sweden.
Jonas H
JH
Fagerberg
Medical Products Agency, Scientific Expertise, Box 26, SE-751 03 Uppsala, Sweden.
Gert
G
Ragnarsson
Medical Products Agency, Scientific Expertise, Box 26, SE-751 03 Uppsala, Sweden.
Anders
A
Lindahl
D000284:Administration, Oral; D000818:Animals; D001702:Biopharmaceutics / Q000379:methods*; D003198:Computer Simulation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D008954:Models, Biological; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000145:classification* / Q000378:metabolism*; D010599:Pharmacokinetics; D015203:Reproducibility of Results; D012995:Solubility; D009626:Terminology as Topic
D004364:Pharmaceutical Preparations
Biopharmaceutics classification system; Biorelevant dissolution; Dose number; In silico; Poorly soluble; Solubility