Solvent Redistribution Method To Determine Solubility and Aggregation: High Throughput, Accuracy, and Sustainability

The pharmaceutical industry is responsible for 4.4% of global CO₂ emissions. Assays used in drug discovery and development are major contributors to waste, including solubility measurements. These are either accurate but slow and energy-intensive (HPLC, centrifugation, filtration), contributing significantly to global CO₂ emissions, or fast and economical but inaccurate (turbidity/nephelometry). Here, we exploit the sensitivity of high-throughput angle-resolved second harmonic scattering to detect nanoscale interfacial fluctuations in the solvent around the solute. Classical nucleation theory and nonlinear light scattering modeling show that, prior to aggregation, the solvent interfacial area changes drastically. This leads to changes in the standard deviation of the intensity at specific scattering angles, which can be used to obtain insights into the solubilizing mechanism. Exploiting the coherent nature of the emission, the detection limit for solubility/aggregation is reduced from ∼1 μM to ∼1 nM, achieving over a thousandfold sustainability gain, potentially permitting a reduction in the pharmaceutical industry's global CO₂ emissions by ∼3.5%.