Correlation Between Dissolution Profiles of Salt-Form Drugs in Biorelevant Bicarbonate Buffer and Oral Drug Absorption: Importance of Dose/ Fluid Volume Ratio
Abstract
Abstract Purpose The purpose of this study was to investigate the correlation between the dissolution profiles of salt-form drugs in biorelevant bicarbonate buffer and oral drug absorption. Methods Ciprofloxacin HCl (CPFX HCl), garenoxacin mesylate (GRNX MS), tosufloxacin tosylate (TFLX TS), levofloxacin free-form (LVFX FF), and sitafloxacin free-form (STFX FF) were employed as model drugs. Bicarbonate buffer fasted state simulated intestinal fluid (BCB-FaSSIF) was used as a biorelevant dissolution medium (pH 6.5, BCB 10 mM (floating lid method), taurocholic acid (3 mM) and lecithin (0.75 mM)). The fraction of a dose absorbed in humans ( Fa ) was predicted by a simple theoretical framework for oral drug absorption using equilibrium solubility at pH 6.5 ( S eq,pH6.5 ) or average dissolved drug concentration in the dissolution tests ( C dissolv,AV ). Results Fa was adequately predicted using S eq,pH6.5 for LVFX FF and STFX FF, however, underpredicted for CPFX HCl (tenfold), GRNX MS (twofold), and TFLX TS (sevenfold). When compendial Dose/FV was used for the dissolution test of CPFX HCl, bulk pH (pH bulk ) remained unchanged and C dissolv,AV ≈ S eq,pH6.5 , resulting in a tenfold underprediction of Fa . Using clinical Dose/FV , pH bulk was decreased, C dissolv,AV was increased, resulting in adequate Fa prediction. Similarly, for GRNX MS and TFLX TS, Fa predictability was improved using C dissolv,AV at clinical Dose/FV . In these conditions, C dissolv,AV > S eq,pH6.5 due to…
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