Rapid throughput screening of apparent KSP values for weakly basic drugs using 96-well format.

Area of Science:

• Pharmaceutical Sciences
• Analytical Chemistry
• Drug Discovery

Background:

• Accurate salt solubility parameter (K(SP)) determination is crucial for drug development.
• Traditional methods are time-consuming and require significant drug quantities.
• High-throughput screening is needed for early-stage drug lead evaluation.

Purpose of the Study:

• To develop a rapid, high-throughput assay for estimating the salt solubility parameter (K(SP)).
• To enable early evaluation of salt-limited solubility for numerous drug candidates and counter-ions.
• To minimize drug consumption during solubility screening.

Main Methods:

• Robotic liquid handling for drug distribution in a 96-well plate format.
• Equilibration of drugs with various acids to induce precipitation.
• Rapid gradient High-Performance Liquid Chromatography (HPLC) analysis of filtrates.
• Iterative calculation of species concentrations using mass and charge balance equations.

Main Results:

• Developed a novel assay for K(SP) estimation with minimal drug quantities (approx. 10 mg).
• Achieved high correlation coefficients (>0.975) for eight drugs and 16 salts.
• Demonstrated excellent intra-day and inter-day reproducibility (<10%).
• Successfully translated conventional K(SP) measurements to a 96-well format.

Conclusions:

• The developed assay significantly increases throughput for salt solubility evaluation.
• It facilitates early-stage assessment of drug leads and counter-ion selection.
• The assay's dynamic range can be further expanded by adjusting concentrations.