Correlation Between Dissolution Profiles of Salt-Form Drugs in Biorelevant Bicarbonate Buffer and Oral Drug Absorption: Importance of Dose/ Fluid Volume Ratio.

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 decreased pH_bulk below the first pK_a of the drugs.

Conclusion: The use of clinical Dose/FV was important for improving the correlation between the biorelevant dissolution profiles and Fa for salt-form drugs.