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

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Pharmaceutical Sciences
• Biopharmaceutics

Background:

• Predicting oral drug absorption is crucial for pharmaceutical development.
• High-dose free acid drugs often exhibit solubility-limited absorption.
• Existing dissolution testing methods may not accurately reflect in vivo conditions for these drugs.

Purpose of the Study:

• To evaluate biorelevant bicarbonate buffer (BCB) dissolution testing for predicting oral absorption of high-dose free acid drugs.
• To compare BCB with other buffer systems and dose-to-fluid volume ratios (Dose/FV) for predictive accuracy.

Main Methods:

• Dissolution tests were performed using valsartan and naproxen as model compounds.
• Buffers included biorelevant bicarbonate buffer (BCB), phosphate-PRB (PPB), and USP phosphate buffer.
• Clinical and compendial Dose/FV ratios were employed, simulating physiological conditions.

Main Results:

• BCB and PPB with clinical Dose/FV maintained lower pH and reduced dissolved drug concentrations, aligning with in vivo solubility limitations.
• This approach accurately predicted the dose-dependent fraction of a dose absorbed (Fa) for the model drugs.
• USP buffer and compendial Dose/FV overestimated Fa due to less pronounced pH reduction and higher dissolved concentrations.

Conclusions:

• Dissolution testing in BCB or PPB with a clinical Dose/FV significantly improves the in vivo predictability of oral absorption for high-dose free acid drugs.
• This biorelevant approach offers a more accurate assessment of drug performance compared to standard compendial methods.
• The findings support the use of biorelevant media in dissolution testing for enhanced drug development.