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Purpose <p>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.</p> Methods <p>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 (<i>Fa</i>) was predicted by a simple theoretical framework for oral drug absorption using equilibrium solubility at pH 6.5 (<i>S</i><sub><i>eq,pH6.5</i></sub>) or average dissolved drug concentration in the dissolution tests (<i>C</i><sub><i>dissolv,AV</i></sub>).</p> Results <p><i>Fa</i> was adequately predicted using <i>S</i><sub><i>eq,pH6.5</i></sub> for LVFX FF and STFX FF, however, underpredicted for CPFX HCl (tenfold), GRNX MS (twofold), and TFLX TS (sevenfold). When compendial <i>Dose/FV</i> was used for the dissolution test of CPFX HCl, bulk pH (pH<sub>bulk</sub>) remained unchanged and <i>C</i><sub><i>dissolv,AV</i></sub> ≈ <i>S</i><sub><i>eq,pH6.5</i></sub>, resulting in a tenfold underprediction of <i>Fa</i>. Using clinical <i>Dose/FV</i>, pH<sub>bulk</sub> was decreased, <i>C</i><sub><i>dissolv,AV</i></sub> was increased, resulting in adequate <i>Fa</i> prediction. Similarly, for GRNX MS and TFLX TS, <i>Fa</i> predictability was improved using <i>C</i><sub><i>dissolv,AV</i></sub> at clinical <i>Dose/FV</i>. In these conditions, <i>C</i><sub><i>dissolv,AV</i></sub> &gt; <i>S</i><sub><i>eq,pH6.5</i></sub> due to decreased pH<sub>bulk</sub> below the first p<i>K</i><sub><i>a</i></sub> of the drugs.</p> Conclusion <p>The use of clinical <i>Dose/FV</i> was important for improving the correlation between the biorelevant dissolution profiles and <i>Fa</i> for salt-form drugs.</p>

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

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  • 发表日期：

    2025年4月4日

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  • Yuki Tarumi,
  • Yuji Higashiguchi,
  • Kiyohiko Sugano

摘要

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 (Seq,pH6.5) or average dissolved drug concentration in the dissolution tests (Cdissolv,AV).

Results

Fa was adequately predicted using Seq,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 (pHbulk) remained unchanged and Cdissolv,AV ≈ Seq,pH6.5, resulting in a tenfold underprediction of Fa. Using clinical Dose/FV, pHbulk was decreased, Cdissolv,AV was increased, resulting in adequate Fa prediction. Similarly, for GRNX MS and TFLX TS, Fa predictability was improved using Cdissolv,AV at clinical Dose/FV. In these conditions, Cdissolv,AV > Seq,pH6.5 due to decreased pHbulk below the first pKa 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.