title: In vivo predictive dissolution: transport analysis of the CO2 , bicarbonate in vivo buffer system.
abstract: Development of an oral in vivo predictive dissolution medium for acid drugs with a pKa in the physiological range (e.g., Biopharmaceutics Classification System Class IIa) requires transport analysis of the complex in vivo CO2 /bicarbonate buffering system. In this report, we analyze this buffer system using hydrodynamically defined rotating disk dissolution. Transport analysis of drug flux was predicted using the film model approach of Mooney et al based on equilibrium assumptions as well as accounting for the slow hydration reaction, CO2 + H2 O → H2 CO3 . The accuracy of the models was compared with experimentally determined results using the rotating disk dissolution of ibuprofen, indomethacin, and ketoprofen. The equilibrium and slow hydration reaction rate models predict significantly different dissolution rates. The experimental results are more accurately predicted by accounting for the slow hydration reaction under a variety of pH and hydrodynamic conditions. Although the complex bicarbonate buffering system requires further consideration given its dynamic nature in vivo, a simplifying irreversible reaction (IRR) transport analysis accurately predicts in vitro rotating disk dissolution rates of several carboxylic acid drugs. This IRR transport model provides further insight into bicarbonate buffer and can be useful in developing more physiologically relevant buffer systems for dissolution testing.
authors.affiliation: University of Michigan, College of Pharmacy, Ann Arbor, Michigan 48109.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Krieg
authors.affiliation: McGill University, Department of Chemical Engineering, Montreal, Quebec H3A 2B2, Canada.
authors.forename: Seyed Mohammad
authors.initials: SM
authors.lastname: Taghavi
authors.affiliation: University of Michigan, College of Pharmacy, Ann Arbor, Michigan 48109. Electronic address: geamidon@umich.edu.
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Amidon
authors.affiliation: University of Michigan, College of Pharmacy, Ann Arbor, Michigan 48109.
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Amidon
mesh_terms: D001639:Bicarbonates / Q000737:chemistry*; D002021:Buffers; D002245:Carbon Dioxide / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D004058:Diffusion; D004867:Equipment Design; D006863:Hydrogen-Ion Concentration; D007052:Ibuprofen / Q000737:chemistry*; D007213:Indomethacin / Q000737:chemistry*; D007660:Ketoprofen / Q000737:chemistry*; D007700:Kinetics; D008956:Models, Chemical; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000295:instrumentation / Q000379:methods
chemical_list: D001639:Bicarbonates; D002021:Buffers; D002245:Carbon Dioxide; D007660:Ketoprofen; D007052:Ibuprofen; D007213:Indomethacin
keywords: acid-base equilibria; diffusion; dissolution; in vitro models; mathematical model; physicochemical; transport