High-throughput analysis of aqueous drug solubility, supersaturation, and aggregation behaviour using second harmonic...

Area of Science:

• Analytical Chemistry
• Physical Chemistry
• Pharmaceutical Sciences

Background:

• Aqueous solubility is critical for drug absorption and bioavailability.
• Existing solubility assays present limitations in accuracy, speed, and resource use.
• Developing novel, efficient methods for solubility assessment is essential.

Purpose of the Study:

• To introduce and validate a new drug solubility assessment method using non-resonant second harmonic scattering (SHS).
• To compare SHS-derived solubility data with traditional High-Performance Liquid Chromatography (HPLC) measurements.
• To investigate drug supersaturation propensity and self-assembly behavior using the SHS platform.

Main Methods:

• Non-resonant second harmonic scattering (SHS) was employed to detect interfacial water molecule fluctuations.
• Apparent solubility of 14 poorly water-soluble drugs was measured via SHS and compared to HPLC data.
• Supersaturation propensity and self-assembly behavior (micellization) were evaluated using SHS.

Main Results:

• A strong correlation (r=0.9273) was observed between SHS and HPLC solubility data.
• Ketoconazole and tamoxifen showed superior supersaturation performance, linked to their thermal properties.
• SHS detected micelle-like self-assembly for five model drugs above their solubility limits.

Conclusions:

• Non-resonant SHS is a promising analytical tool for drug solubility determination.
• The SHS method offers a versatile, high-throughput format with minimal consumption.
• SHS provides molecular-level insights into drug aggregation and self-assembly.