Early pharmaceutical profiling to predict oral drug absorption: current status and unmet needs.
Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the pharmaceutical profiling methods available, with focus on in silico and in vitro models typically used to forecast active pharmaceutical ingredient's (APIs) in vivo performance after oral administration. An overview of the composition of human, animal and simulated gastrointestinal (GI) fluids is provided and state-of-the art methodologies to study API properties impacting on oral absorption are reviewed. Assays performed during early development, i.e. physicochemical characterization, dissolution profiles under physiological conditions, permeability assays and the impact of excipients on these properties are discussed in detail and future demands on pharmaceutical profiling are identified. It is expected that innovative computational and experimental methods that better describe molecular processes involved in vivo during dissolution and absorption of APIs will be developed in the OrBiTo. These methods will provide early insights into successful pathways (medicinal chemistry or formulation strategy) and are anticipated to increase the number of new APIs with good oral absorption being discovered.
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
Biologics and Pharmaceutical Science, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark.
René
R
Holm
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Søren Astrup
SA
Jørgensen
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.
Per
P
Artursson
Novartis Pharma AG, Novartis Campus, CH-4056 Basel, Switzerland.
Stefania
S
Beato
Pharmaceutical Development, AstraZeneca R&D, Mölndal, Sweden.
Anders
A
Borde
Sirius Analytical Instruments Ltd., Riverside, Forest Row Business Park, Forest Row, East Sussex RH18 5DW, UK.
Karl
K
Box
ChemPharm Development, Johnson & Johnson Pharmaceutical Research & Development, 2340 Beerse, Belgium.
Marcus
M
Brewster
Institute of Pharmaceutical Technology, Goethe Universität, 60438 Frankfurt/Main, Germany.
Jennifer
J
Dressman
Basic Pharmaceutical Sciences, Merck Research Laboratories, Merck & Co., Inc., USA.
Kung-I
KI
Feng
Strathclyde Institute for Pharmacy and Biomedical Sciences, Robertson Wing, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, Scotland, UK.
Gavin
G
Halbert
Institute of Pharmaceutical Technology, Goethe Universität, 60438 Frankfurt/Main, Germany.
Edmund
E
Kostewicz
Drug Product Design, Pfizer PGRD, Sandwich, Kent CT13 9NJ, UK.
Mark
M
McAllister
Material Science and Early Characterization, Bayer Pharma AG, Research Site Wuppertal-Aprath, Germany.
Uwe
U
Muenster
Institute of Pharmaceutical Technology, Goethe Universität, 60438 Frankfurt/Main, Germany.
Julian
J
Thinnes
Sirius Analytical Instruments Ltd., Riverside, Forest Row Business Park, Forest Row, East Sussex RH18 5DW, UK.
Robert
R
Taylor
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Anette
A
Mullertz
D000284:Administration, Oral; D000818:Animals; D001702:Biopharmaceutics / Q000379:methods*; D002626:Chemistry, Pharmaceutical; D003198:Computer Simulation; D005079:Excipients / Q000737:chemistry; D005750:Gastric Juice / Q000737:chemistry / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000502:physiology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D007419:Intestinal Secretions / Q000737:chemistry / Q000378:metabolism; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*; D010599:Pharmacokinetics; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods*
D005079:Excipients; D004364:Pharmaceutical Preparations
Absorption; Biorelevant media; Intestinal fluid; Pharmaceutical profiling; Physicochemical properties; Preformulation