In Viv o Predictive Dissolution: Transport Analysis of the CO 2 , 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.

In vitro dissolution methodology, mini-Gastrointestinal Simulator (mGIS), predicts better in vivo dissolution of a weak base drug, dasatinib

“…The experimental condition like fluid transfer rate and dissolution media could be modified to more biorelevant conditions for better prediction. Especially for dissolution media, several different dissolution media like bicarbonate and FaSSIF buffers have been tested to predict better in vivo dissolution of oral products (Do et al, 2011;Fei et al, 2013;Kambayashi and Dressman, 2013; Krieg et al, 2014;Taupitz et al, 2013). The implementation of biorelevant media into mGIS could improve the prediction of in vivo dissolution.…”

“…Incorporating those in vivo environmental factors into an in vitro dissolution apparatus would be necessary to predict more reasonable in vivo dissolution. Newer dissolution methodologies, that consider the in vivo physiological conditions, have been investigated (Barker et al, 2014;Bevernage et al, 2013;Brouwers et al, 2011;Carino et al, 2010;Carlert et al, 2010;Dickinson et al, 2012;Dressman et al, 1998;Koziolek et al, 2013aKoziolek et al, , 2013dKrieg et al, 2014;Mudie et al, 2012;Perez de la Cruz Moreno et al, 2006;Psachoulias et al, 2012Psachoulias et al, , 2011Takeuchi et al, 2014;Vertzoni et al, 2010). TNO intestinal model (TIM-1), especially, is an advanced dissolution model to capture most of the physiological conditions in the GI tract (Barker et al, 2014;Brouwers et al, 2011;Dickinson et al, 2012;Koziolek et al, 2013aKoziolek et al, , 2013d.…”

In Vivo Predictive Dissolution: Comparing the Effect of Bicarbonate and Phosphate Buffer on the Dissolution of Weak Acids and Weak Bases

“…However, in the aqueous boundary layer and at the surface of dissolving drug, the reaction rate kinetics are critically important to consider and it was shown by Krieg et al that the CO 2 –bicarbonate buffer behave according to Reaction (2). …”

FaSSIF-V3, but not compendial media, appropriately detects differences in the peak and extent of exposure between reference and test formulations of ibuprofen

“…But if, on the other hand, the compound has a poor self-buffering effect like ibuprofen, e.g. indomethacin, drug dissolution would be highly dependent on total buffer concentration [26,50]. For this reason, studies need to be conducted with a wider range of Class 2a drugs to determine whether the results for ibuprofen can be generalized.…”

“…Matching bench lab dissolution buffers and bicarbonate buffer, the predominant buffer species in the human small intestine under fasting conditions [47], in terms of pH 0 depends not only on buffer-related properties but also on drug-related properties [19][20]26,[48][49][50][51]. If the Class 2a compound possesses a relatively high intrinsic solubility, e.g.…”