pH-metric solubility. 2: correlation between the acid-base titration and the saturation shake-flask solubility-pH...

Area of Science:

• Pharmaceutical Sciences
• Analytical Chemistry
• Physical Chemistry

Background:

• Accurate determination of intrinsic solubility and solubility-pH profiles is crucial for drug development.
• Traditional methods like shake-flask assays can be time-consuming and labor-intensive.
• Ionizable drug substances exhibit pH-dependent solubility, significantly impacting their bioavailability and formulation.

Purpose of the Study:

• To compare a novel potentiometric acid-base titration method with the standard shake-flask method for determining intrinsic solubility and solubility-pH profiles.
• To validate the accuracy and efficiency of the potentiometric titration technique.
• To report solubility constants derived from the potentiometric method.

Main Methods:

• Solubility-pH profiles of twelve generic drugs were determined using both potentiometric titration and a traditional shake-flask method.
• The shake-flask method involved 24-hour shaking, filtration, and HPLC assay with UV detection.
• Potentiometric titrations were performed to generate solubility data.

Main Results:

• The potentiometric titration method showed excellent agreement with the shake-flask method, with a correlation coefficient (r²) of 0.978.
• Potentiometrically derived intrinsic solubilities for the twelve drugs were reported, spanning a wide range.
• The new method demonstrated a wide dynamic range, estimated at seven orders of magnitude.

Conclusions:

• The potentiometric titration method is a reliable and efficient technique for determining solubility-pH profiles of ionizable drug substances.
• This method offers significant advantages in speed and data generation compared to conventional equilibrium measurements.
• The potentiometric approach is a valuable tool for preformulation, development, and potentially discovery scientists.