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<p>The purpose of the present study was to evaluate whether dissolution testing in biorelevant bicarbonate buffer (BCB) can predict the solubility-limited oral absorption of high-dose free acid drugs. Valsartan and naproxen were selected as model compounds exhibiting solubility-limited absorption at high doses. A biorelevant BCB solution (concentration: 10&#xa0;mM, initial pH (pH<sub>ini</sub>) = 6.5, buffer capacity (β) = 4.4&#xa0;mM/pH) (BCB), a phosphate buffer solution with the same pH and β (PPB), and a USP phosphate buffer solution (β = 27&#xa0;mM/pH, modified to pH<sub>ini</sub> 6.5) were employed for dissolution tests. The dose-to-fluid volume ratio (<i>Dose/FV</i>) was set to reflect the clinical or compendial conditions. The fraction of a dose absorbed in humans (<i>Fa</i>) predicted using a simple theoretical framework was compared with the clinical <i>Fa</i> calculated from pharmacokinetic data in the literature. When using BCB or PPB with the same β and the clinical <i>Dose/FV</i>, the bulk-phase pH after 4&#xa0;h (pH<sub>bulk</sub>, <sub>4&#xa0;h</sub>) was markedly lower than pH<sub>ini</sub> (&lt; pH 6.0 for naproxen, &lt; pH 5.0 for valsartan). Consequently, the dissolved drug concentration at 4&#xa0;h (<i>C</i><sub><i>dissolv, 4&#xa0;h</i></sub>) was markedly lower than the solubility at pH 6.5. Using <i>C</i><sub><i>dissolv, 4&#xa0;h</i></sub>, the dose dependency of <i>Fa</i> was appropriately predicted. In contrast, when using USP or the compendial <i>Dose/FV</i>, the pH<sub>bulk</sub>, <sub>4&#xa0;h</sub> and <i>C</i><sub><i>dissolv, 4&#xa0;h</i></sub> were less reduced, leading to an overestimation of <i>Fa</i>. Overall, the use of BCB or PPB and a clinical <i>Dose/FV</i> improved the <i>in vivo</i> predictability for high-dose free acid drugs.</p> Graphical Abstract <p></p>

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In vivo Predictive Dissolution Test Using Biorelevant Bicarbonate Buffer for High-dose Free Acid Drug

  • 期刊论文

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  • 发表日期：

    2026年6月30日

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  • Yuki Tarumi,
  • Kiyohiko Sugano

摘要

The purpose of the present study was to evaluate whether dissolution testing in biorelevant bicarbonate buffer (BCB) can predict the solubility-limited oral absorption of high-dose free acid drugs. Valsartan and naproxen were selected as model compounds exhibiting solubility-limited absorption at high doses. A biorelevant BCB solution (concentration: 10 mM, initial pH (pHini) = 6.5, buffer capacity (β) = 4.4 mM/pH) (BCB), a phosphate buffer solution with the same pH and β (PPB), and a USP phosphate buffer solution (β = 27 mM/pH, modified to pHini 6.5) were employed for dissolution tests. The dose-to-fluid volume ratio (Dose/FV) was set to reflect the clinical or compendial conditions. The fraction of a dose absorbed in humans (Fa) predicted using a simple theoretical framework was compared with the clinical Fa calculated from pharmacokinetic data in the literature. When using BCB or PPB with the same β and the clinical Dose/FV, the bulk-phase pH after 4 h (pHbulk, 4 h) was markedly lower than pHini (< pH 6.0 for naproxen, < pH 5.0 for valsartan). Consequently, the dissolved drug concentration at 4 h (Cdissolv, 4 h) was markedly lower than the solubility at pH 6.5. Using Cdissolv, 4 h, the dose dependency of Fa was appropriately predicted. In contrast, when using USP or the compendial Dose/FV, the pHbulk, 4 h and Cdissolv, 4 h were less reduced, leading to an overestimation of Fa. Overall, the use of BCB or PPB and a clinical Dose/FV improved the in vivo predictability for high-dose free acid drugs.

Graphical Abstract