A high-throughput micro-scale workflow to quantify molecularly dissolved drug concentrations under solubilizing...

Area of Science:

• Pharmacokinetics
• Drug Discovery
• Analytical Chemistry

Background:

• Solubilizing agents enhance drug solubility but can reduce oral exposure by decreasing unbound drug fractions.
• Accurate measurement of molecularly dissolved drug concentrations is crucial but experimentally challenging.
• Existing methods for determining free drug concentrations are complex and time-consuming.

Purpose of the Study:

• To develop a micro-scale in vitro workflow, the comparative micro-scale mass transfer assay (CMMTA), for quantifying unbound drug concentrations.
• To establish a rapid and efficient screening tool for early-stage drug development.

Main Methods:

• Developed a 96-well microtiter plate assay (PermeaPlain™) to correlate passive drug permeation with donor buffer concentration.
• Measured drug permeation from micellar solutions in simulated intestinal fluids (FaSSIF and FeSSIF).
• Derived unbound drug concentrations using the established correlation and validated against equilibrium dialysis and microdialysis.

Main Results:

• Established a linear correlation between riluzole permeation and its concentration in buffer.
• Successfully quantified molecularly dissolved drug concentrations in micellar solutions using CMMTA.
• Demonstrated that CMMTA can simultaneously determine standard curves and samples under various solubilizing conditions within hours.
• Validated CMMTA results against established free drug concentration measurement methods.

Conclusions:

• The CMMTA workflow accurately quantifies unbound drug concentrations in the presence of solubilizing agents.
• CMMTA provides a rapid, micro-scale, and cost-effective screening tool for early drug development.
• This assay facilitates better prediction of oral drug absorption influenced by micellization.