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Anal Chem. 2017 Nov 7;89(21):11460-11467. doi: 10.1021/acs.analchem.7b02639. Epub 2017 Oct 18.

Multimodal Nonlinear Optical Imaging for Sensitive Detection of Multiple Pharmaceutical Solid-State Forms and Surface Transformations.

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Division of Pharmaceutical Chemistry and Technology, University of Helsinki , Viikinkaari 5E, 00014 Helsinki, Finland.
Division of Pharmaceutical Biosciences, University of Helsinki , Viikinkaari 5E, 00014 Helsinki, Finland.
Dodd-Walls Centre for Photonic and Quantum Technologies, Department of Chemistry, University of Otago , Dunedin 9016, New Zealand.
Laboratory of Chemistry and Bioengineering, Tampere University of Technology , Korkeakoulunkatu 8, 33720 Tampere, Finland.
Biomedicum Imaging Unit, University of Helsinki , Haartmaninkatu 8, 00014 Helsinki, Finland.


Two nonlinear imaging modalities, coherent anti-Stokes Raman scattering (CARS) and sum-frequency generation (SFG), were successfully combined for sensitive multimodal imaging of multiple solid-state forms and their changes on drug tablet surfaces. Two imaging approaches were used and compared: (i) hyperspectral CARS combined with principal component analysis (PCA) and SFG imaging and (ii) simultaneous narrowband CARS and SFG imaging. Three different solid-state forms of indomethacin-the crystalline gamma and alpha forms, as well as the amorphous form-were clearly distinguished using both approaches. Simultaneous narrowband CARS and SFG imaging was faster, but hyperspectral CARS and SFG imaging has the potential to be applied to a wider variety of more complex samples. These methodologies were further used to follow crystallization of indomethacin on tablet surfaces under two storage conditions: 30 °C/23% RH and 30 °C/75% RH. Imaging with (sub)micron resolution showed that the approach allowed detection of very early stage surface crystallization. The surfaces progressively crystallized to predominantly (but not exclusively) the gamma form at lower humidity and the alpha form at higher humidity. Overall, this study suggests that multimodal nonlinear imaging is a highly sensitive, solid-state (and chemically) specific, rapid, and versatile imaging technique for understanding and hence controlling (surface) solid-state forms and their complex changes in pharmaceuticals.

[Indexed for MEDLINE]

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