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

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Τίτλος: Combined second harmonic and linear light scattering as a tool for solubility and aggregation screening.
Συγγραφείς: Kalasová J; University of Basel, Department of Pharmaceutical Sciences, Klingelbergstrasse 50, 4052 Basel, Switzerland; University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Institute for Pharma Technology and Biotechnology, Hofackerstrasse 30, 4132 Muttenz, Switzerland., Tarun O; ORYL Photonics SA, 1066, Route de la Corniche 5B, Epalinges, Switzerland., Kuentz M; University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Institute for Pharma Technology and Biotechnology, Hofackerstrasse 30, 4132 Muttenz, Switzerland. Electronic address: martin.kuentz@fhnw.ch.
Πηγή: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2026 Oct 01; Vol. 225, pp. 107624. Date of Electronic Publication: 2026 Jul 28.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Elsevier Science B.V Country of Publication: Netherlands NLM ID: 9317982 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0720 (Electronic) Linking ISSN: 09280987 NLM ISO Abbreviation: Eur J Pharm Sci Subsets: MEDLINE
Imprint Name(s): Publication: Amsterdam : Elsevier Science B.V
Original Publication: Amsterdam ; New York : Elsevier, c1993-
Ιατρικοί όροι (MeSH): Pharmaceutical Preparations*/chemistry , Scattering, Radiation*, Solvents/chemistry ; Chromatography, High Pressure Liquid ; Light ; Particle Size ; Phase Separation ; Solubility
Περίληψη: 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.
(Copyright © 2026 The Authors. Published by Elsevier B.V. All rights reserved.)
Competing Interests: Declaration of competing interest Orly Tarun is the CEO of Oryl Photonics SA, but otherwise the authors declare that they have no known competing financial interests that could have appeared to influence the work reported in this paper.
Contributed Indexing: Keywords: Amorphous drug; High-throughput screening; Linear light scattering; Liquid-liquid phase separation; Second harmonic scattering; Ultrafast laser
Substance Nomenclature: 0 (Pharmaceutical Preparations)
0 (Solvents)
Entry Date(s): Date Created: 20260728 Date Completed: 20260818 Latest Revision: 20260819
Update Code: 20260820
DOI: 10.1016/j.ejps.2026.107624
PMID: 42521104
Βάση Δεδομένων: MEDLINE
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  Data: Combined second harmonic and linear light scattering as a tool for solubility and aggregation screening.
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  Data: <searchLink fieldCode="AU" term="%22Kalasová+J%22">Kalasová J</searchLink>; University of Basel, Department of Pharmaceutical Sciences, Klingelbergstrasse 50, 4052 Basel, Switzerland; University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Institute for Pharma Technology and Biotechnology, Hofackerstrasse 30, 4132 Muttenz, Switzerland.<br /><searchLink fieldCode="AU" term="%22Tarun+O%22">Tarun O</searchLink>; ORYL Photonics SA, 1066, Route de la Corniche 5B, Epalinges, Switzerland.<br /><searchLink fieldCode="AU" term="%22Kuentz+M%22">Kuentz M</searchLink>; University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Institute for Pharma Technology and Biotechnology, Hofackerstrasse 30, 4132 Muttenz, Switzerland. Electronic address: martin.kuentz@fhnw.ch.
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  Data: 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.<br /> (Copyright © 2026 The Authors. Published by Elsevier B.V. All rights reserved.)
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  Data: Declaration of competing interest Orly Tarun is the CEO of Oryl Photonics SA, but otherwise the authors declare that they have no known competing financial interests that could have appeared to influence the work reported in this paper.
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  Data: <i>Keywords: </i>Amorphous drug; High-throughput screening; Linear light scattering; Liquid-liquid phase separation; Second harmonic scattering; Ultrafast laser
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        Text: English
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        Type: general
      – SubjectFull: Chromatography, High Pressure Liquid
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