Dissolution profiles of high-dose salt-form drugs in bicarbonate buffer and phosphate buffer

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery
• Physical Chemistry

Background:

• Accurate prediction of oral drug absorption is crucial for pharmaceutical development.
• Dissolution testing is a key in vitro method for predicting in vivo drug performance.
• High-dose drugs present unique challenges in dissolution due to buffer capacity limitations.

Purpose of the Study:

• To compare dissolution profiles of high-dose drug salts in bicarbonate buffer (BCB) and phosphate buffer (PPB).
• To investigate the impact of pH changes in the bulk phase on drug dissolution.
• To evaluate the utility of BCB with clinically relevant dose/fluid volume ratios for predicting oral absorption.

Main Methods:

• Theoretical calculation and experimental validation of pH titration curves for BCB and PPB.
• Dissolution testing of various drug salts (acid counterion, weak base counterion, free acid) at clinical doses (125-800 mg).
• Alignment of dose/fluid volume ratio (Dose/FV) with clinical conditions.

Main Results:

• Phosphate buffer (PPB) showed a lower pH at 4 hours compared to bicarbonate buffer (BCB) across all tested drug salts.
• Drug salts with acid counterions exhibited 1.2 to 2.6-fold lower area under the dissolution curve in BCB versus PPB.
• Marked precipitation was observed in BCB, with less pronounced or absent precipitation in PPB.

Conclusions:

• Bicarbonate buffer (BCB) may be more suitable than phosphate buffer (PPB) for predicting the oral absorption of high-dose drug salts.
• Using a clinically equivalent Dose/FV in BCB can enhance the predictive value of dissolution tests.
• Understanding buffer capacity and pH changes is critical for in vitro-in vivo correlation.