Combined second harmonic and linear light scattering as a tool for solubility and aggregation screening

Area of Science:

• Pharmaceutical Sciences
• Analytical Chemistry
• Materials Science

Background:

• Poor aqueous solubility of small-molecule drugs presents challenges in formulation and delivery.
• Understanding supersaturation and aggregation is crucial for predicting drug behavior and stability.
• Rapid, material-sparing analytical tools are needed to study non-equilibrium conditions.

Purpose of the Study:

• To evaluate a miniaturized optical platform combining SHS and LLS for monitoring drug precipitation.
• To assess the platform's ability to capture incipient aggregation and phase separation events.
• To investigate nonclassical aggregation pathways in supersaturated drug solutions.

Main Methods:

• Utilized an ultrafast 1030 nm laser-driven optical platform combining SHS and LLS.
• Monitored supersaturated solutions of 12 poorly water-soluble drugs prepared by DMSO solvent shift in 384-well plates.
• Recorded LLS and SHS signals at 1 h and 24 h, comparing with HPLC apparent solubilities.

Main Results:

• LLS detected precipitation onsets near or below HPLC values, with high sensitivity (down to ~0.1 µM for pimozide).
• SHS revealed distinct aggregation patterns deviating from LLS, indicating structurally unique drug-rich assemblies.
• Orthogonal characterization confirmed droplet-like or amorphous domains preceding bulk precipitation.

Conclusions:

• The combined SHS-LLS platform enables highly sensitive precipitation detection in pharmaceutical systems.
• The study revealed multistep, nonclassical aggregation pathways in supersaturated drug solutions.
• This approach provides valuable insights into drug behavior under non-equilibrium conditions.