(583b) Laser Speckle Probe for Monitoring Pharmaceutical Drying

The laser speckle is an interference pattern generated when a coherent light source backscatters from a surface. Features resulting from the laser speckle can be used to characterize surface roughness [1] and to visualize perfusion in biomedical applications [2]. Recently, we have shown that the laser speckle can also be used for the online measurement of particle size distribution during a particulate drying process [1]. Often during drying, soft agglomerates as indicated by an increase in the particle size distribution can form, which under certain conditions may result in the formation of harder agglomerates. These result from agitation of the wet cake in the ‘sticky point’ region which is the region of temperature, impeller speeds, and moisture/solvent combinations where harder agglomerates have a higher tendency to form [3]. These are held together by forces resulting from the presence of mobile liquid between the particles, that upon drying give rise to solid crystalline bridges [4]. Hard agglomerates could impact drug product manufacturability and performance and should therefore be minimized. Reliable real-time measurement of the size distribution of the intermediate soft agglomerates is not possible by conventional methods. The reported laser speckle is a cost-effective method for the online and in-situ monitoring of particle size distributions and for enabling key insights into the agglomeration mechanisms which were not previously possible. In the present work, the laser speckle is used to monitor the particle size distribution changes during the drying of different active pharmaceutical ingredients in an attempt to delineate the fundamental mechanisms of agglomeration.

The present study also shows that the speckle intensity can be correlated to the residual solvent content in the wet cake during drying. Through this correlation, the laser-based probe is demonstrated to be a reliable, in-situ, and online method for not only the end-point detection of drying but also for the detection of the sticky point region. The online and in-situ monitoring of the solvent content enabled by a laser probe also opens up the potential to intensify the drying operation: by suitably maximizing the drying temperature while still keeping it below the sticky point temperature for the current solvent content.

[1] Zhang, Q., Gamekkanda, J. C., Pandit, A., Tang, W., Papageorgiou, C., Mitchell, C., Yang, Y., Schwaerzler, M., Oyetunde, T., Braatz, R. D., Myerson, A. S., & Barbastathis, G. (2023). Extracting particle size distribution from laser speckle with a physics-enhanced autocorrelation-based estimator (PEACE). Nature Communications, 14(1), 1159. https://doi.org/10.1038/s41467-023-36816-2

[2] Senarathna, J., Rege, A., Li, N., & Thakor, N. v. (2013). Laser Speckle Contrast Imaging: Theory, Instrumentation and Applications. IEEE Reviews in Biomedical Engineering, 6, 99–110. https://doi.org/10.1109/RBME.2013.2243140

[3] Birch, M., & Marziano, I. (2013). Understanding and Avoidance of Agglomeration During Drying Processes: A Case Study. Organic Process Research & Development, 17(10), 1359–1366. https://doi.org/10.1021/op4000972

[4] Adamson, J., Faiber, N., Gottlieb, A., Hamsmith, L., Hicks, F., Mitchell, C., Mittal, B., Mukai, K., & Papageorgiou, C. D. (2016). Development of Suitable Plant-Scale Drying Conditions That Prevent API Agglomeration and Dehydration. Organic Process Research & Development, 20(1), 51–58. https://doi.org/10.1021/acs.oprd.5b00327