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Mol Pharm. 2018 Nov 5;15(11):5361-5373. doi: 10.1021/acs.molpharmaceut.8b00840. Epub 2018 Oct 9.

Understanding Dissolution and Crystallization with Imaging: A Surface Point of View.

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Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy , University of Helsinki , Viikinkaari 5 E , 00014 Helsinki , Finland.
Biomedicum Imaging Unit, Faculty of Medicine , University of Helsinki , Haartmaninkatu 8 , 00014 Helsinki , Finland.
Dodd-Walls Center 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.


The tendency for crystallization during storage and administration is the most considerable hurdle for poorly water-soluble drugs formulated in the amorphous form. There is a need to better detect often subtle and complex surface crystallization phenomena and understand their influence on the critical quality attribute of dissolution. In this study, the interplay between surface crystallization of the amorphous form during storage and dissolution testing, and its influence on dissolution behavior, is analyzed for the first time with multimodal nonlinear optical imaging (coherent anti-Stokes Raman scattering (CARS) and sum frequency generation (SFG)). Complementary analyses are provided with scanning electron microscopy, X-ray diffraction and infrared and Raman spectroscopies. Amorphous indomethacin tablets were prepared and subjected to two different storage conditions (30 °C/23% RH and 30 °C/75% RH) for various durations and then dissolution testing using a channel flow-through device. Trace levels of surface crystallinity previously imaged with nonlinear optics after 1 or 2 days of storage did not significantly decrease dissolution and supersaturation compared to the freshly prepared amorphous tablets while more extensive crystallization after longer storage times did. Multimodal nonlinear optical imaging of the tablet surfaces after 15 min of dissolution revealed complex crystallization behavior that was affected by both storage condition and time, with up to four crystalline polymorphs simultaneously observed. In addition to the well-known α- and γ-forms, the less reported metastable ε- and η-forms were also observed, with the ε-form being widely observed in samples that had retained significant surface amorphousness during storage. This form was also prepared in the pure form and further characterized. Overall, this study demonstrates the potential value of nonlinear optical imaging, together with more established solid-state analysis methods, to understand complex surface crystallization behavior and its influence on drug dissolution during the development of amorphous drugs and dosage forms.


amorphous; dissolution; indomethacin; nonlinear optics; polymorphism; surface crystallization

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