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Crystals 2017, 7(2), 40; doi:10.3390/cryst7020040

Agglomeration Control during Ultrasonic Crystallization of an Active Pharmaceutical Ingredient

KU Leuven, Department of Chemical Engineering, Celestijnenlaan 200 F Box 2424, 3001 Leuven, Belgium
KU Leuven, Faculty of Engineering Technology, Agoralaan Building B Box 8, 3590 Diepenbeek, Belgium
Author to whom correspondence should be addressed.
Academic Editor: Judy Lee
Received: 16 January 2017 / Revised: 1 February 2017 / Accepted: 2 February 2017 / Published: 8 February 2017
(This article belongs to the Special Issue Advances in Ultrasound Stimulated Crystallization)
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Application of ultrasound during crystallization can efficiently inhibit agglomeration. However, the mechanism is unclear and sonication is usually enabled throughout the entire process, which increases the energy demand. Additionally, improper operation results in significant crystal damage. Therefore, the present work addresses these issues by identifying the stage in which sonication impacts agglomeration without eroding the crystals. This study was performed using a commercially available API that showed a high tendency to agglomerate during seeded crystallization. The crystallization progress was monitored using process analytical tools (PAT), including focus beam reflectance measurements (FBRM) to track to crystal size and number and Fourier transform infrared spectroscopy (FTIR) to quantify the supersaturation level. These tools provided insight in the mechanism by which ultrasound inhibits agglomeration. A combination of improved micromixing, fast crystal formation which accelerates depletion of the supersaturation and a higher collision frequency prevent crystal cementation to occur. The use of ultrasound as a post-treatment can break some of the agglomerates, but resulted in fractured crystals. Alternatively, sonication during the initial seeding stage could assist in generating nuclei and prevent agglomeration, provided that ultrasound was enabled until complete desupersaturation at the seeding temperature. FTIR and FBRM can be used to determine this end point. View Full-Text
Keywords: ultrasound; crystallization; Active Pharmaceutical Ingredient (API); agglomeration; crystal shape; Process Analytical Technology (PAT) ultrasound; crystallization; Active Pharmaceutical Ingredient (API); agglomeration; crystal shape; Process Analytical Technology (PAT)

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Gielen, B.; Jordens, J.; Thomassen, L.C.J.; Braeken, L.; Van Gerven, T. Agglomeration Control during Ultrasonic Crystallization of an Active Pharmaceutical Ingredient. Crystals 2017, 7, 40.

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