Crystallization monitoring using simultaneous bright field and PlasDIC imaging

• Optical design and assembly of a simultaneous bright field and PlasDIC system.
• A novel video microscopy probe for in-line crystallization monitoring.
• Static and in situ image analysis algorithms for difficult images.
• Visualization of thin, transparent crystals, and 3D features or defects.
• PAT based on optical engineering, performance hardware, imaging algorithms, crystallization.

Crystal size, shape and form are critical factors governing the quality and safety of pharmaceutical products, with variation during crystal growth impacting downstream processes. Monitoring of crystallization is therefore paramount in ensuring end-product quality. In this work, a microscopy probe employing both bright field and PlasDIC techniques was developed as a process analytical technology to acquire and analyze crystal features under real-time conditions. The design benefits from not requiring electronics in the immersible component of the probe. Image analysis algorithms were developed and tested on glass sphere standards, illustrating the ability of these techniques to monitor size-shape features in situ. Lysozyme and taurine crystals as well as thin and transparent crystals of benzoic acid were monitored. Overall, the system in conjunction with image analysis techniques tracked the crystallization progress and identified complex shape features. Future incorporation of fast, automated edge detection and segmentation procedures would help with higher particle concentrations.