Combined second harmonic and linear light scattering as a tool for solubility and aggregation screening
Loading...
Author (Corporation)
Publication date
2026
Type of student thesis
Course of study
Type
01A - Journal article
Editors
Editor (Corporation)
Supervisor
Parent work
European Journal of Pharmaceutical Sciences
Special issue
DOI of the original publication
Link
Related research data
Series
Series number
Volume
225
Issue / Number
Pages / Duration
107624
Patent number
Publisher / Publishing institution
Elsevier
Place of publication / Event location
Edition
Version
Programming language
Assignee
Practice partner / Client
Abstract
Poor aqueous solubility and complex supersaturation behaviour of small-molecule drugs require rapid, material-sparing analytical tools that capture incipient aggregation and phase separation events under non-equilibrium conditions. This work evaluated a miniaturised optical platform that combined second harmonic scattering (SHS) with linear light scattering (LLS) driven by an ultrafast 1030 nm laser to monitor supersaturated solutions of 12 poorly water-soluble drugs prepared by DMSO solvent shift in 384-well plates. LLS and SHS signals were recorded after 1 h and 24 h and compared with apparent solubilities from a parallel solvent-shift HPLC assay. LLS, which reports on particle size/number, detected precipitation onsets typically close to or below HPLC values and could resolve particle formation down to ∼ 0.1 µM for pimozide, substantially exceeding the sensitivity of standard nephelometric methods. SHS, which is sensitive to interfacial asymmetry and nonlinear susceptibility, often showed onsets and complex peak-drop-rise patterns that deviated from LLS, particularly for lopinavir, loratadine, and ritonavir, indicating structurally distinct, largely centrosymmetric drug-rich assemblies above the solubility limit. Orthogonal characterization by scanning electron microscopy, Capflex (capillary flow with a hydrophobic fluorescent tracer), and confocal fluorescence microscopy provided independent evidence for droplet-like or amorphous drug-rich domains that preceded bulk precipitation. Together, the results showed that combined SHS-LLS enabled highly sensitive detection of precipitation, while revealing multistep, non-classical aggregation pathways in pharmaceutical supersaturated systems.
Keywords
Subject (DDC)
Event
Exhibition start date
Exhibition end date
Conference start date
Conference end date
Date of the last check
ISBN
ISSN
0928-0987
1879-0720
1879-0720
Language
English
Created during FHNW affiliation
Yes
Strategic action fields FHNW
Publication status
Published
Review
peer-reviewed
Open access category
Gold
License
Citation
Kalasová, J., Tarun, O., & Kuentz, M. (2026). Combined second harmonic and linear light scattering as a tool for solubility and aggregation screening. European Journal of Pharmaceutical Sciences, 225, 107624. https://doi.org/10.1016/j.ejps.2026.107624