Multi-sensor measurements of quantitative particle size and shape information in crystal slurries

Ferreira, Carla Sofia and Agimelen, Okpeafoh and Cardona, Javier and Sefcik, Jan and Chen, Yi-Chieh (2017) Multi-sensor measurements of quantitative particle size and shape information in crystal slurries. In: ISIC20, 2017-09-03 - 2017-09-06, University College Dublin.

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IntroductionParticle size and shape are critical quality attributes for active pharmaceutical ingredients (API) as they have direct impact on downstream processing, as well as on the performance behaviour of the finished product such as bioavailability, dissolution rate and toxicity. Obtaining a reliable and robust quantitative information of these particle attributes in real-time remains a great challenge across the multiple manufacturing steps. None of the current process analytical technologies (PAT), although capable of providing an indication on these key attributes, measures particle size directly. Particle sizing technologies are often misused due to a lack of understanding of their underlying principles and a single instrument cannot provide direct in-line measurement of particle size and shape quantitatively. We aim to establish a physical model-based approach which fuses multiple optical measurements for monitoring particle size and shape in crystallisation process. An innovative spatially and angularly-resolved diffuse reflectance measurement (SAR-DRM) system was developed for in-line monitoring in variety of chemical manufacturing applications [1]. The SAR-DRM technology relies on multiple scattering from suspended particles and collects multi-wavelength (UV-visible-NIR) diffuse reflectance spectra from optical fibres of multi-angle multi-space arrangements. The measured diffuse reflectance of the samples can then be used to obtain both bulk absorption coefficient and bulk scattering coefficient spectra by applying light propagation theory. Those optical properties are dependent on chemical composition, concentration and particle size and shape, which can be determined by developing an inversion algorithm. Current particle sizing technologies measure the optical response of single particle (single scattering) to a single wavelength light source or in case of in-line microscopy, measurable size ranges are limited by the optical resolution of the light source and the optics. The increase of turbidity in the medium leads to nonlinear scattering effects and absorption contributions. When photons encounter several particles, they undergo multiple scattering, changing the direction during each scattering event. In these cases, SAR-DRM becomes more advantageous, collecting information from multi-wavelengths & multiple collecting fibers and consequently, more detailed information about the particles attributes and system behaviour. Thus, SAR-DRM technology can be a potential complementary to other Process Analytical Technology (PAT) tools such as Focus Beam Reflectance Measurement (FBRM) and Particle Vision and Measurement (PVM).MethodologyThe investigation was carried on crystal slurries of glycine and benzoic acid of different particle sizes and solid loadings. The samples were monitored using FBRM, PVM and SAR-DRM. Mathematical algorithms were applied to FBRM and PVM data to extract particle size distribution (PSD) and aspect ratio [2, 3]. These results were compared with the PSD and aspect ratio obtained from off-line technologies (laser diffraction and imaging). Characterisation of the particles attributes served as an input to validate SAR-DRM sensitivity, accuracy and capability to track the differences in size, shape and solid in crystal slurries. Multivariate analysis was applied to establish a performance matrix for all probes and combined methods.The results show that SAR-DRM is capable of handling high solid loadings and relatively large particle sizes (over 500 µm) and is sensitivity to both particle size and solid concentrations, performing better than FBRM and PVM for such suspensions. Therefore, SAR-DRM can be a complementary technique to the current in-line particle analysis to achieve robust process monitoring and enable improved control & optimisation of crystallisation processes.Acknowledgments: The authors would like to thank EPSRC and the Doctoral Training Centre in Continuous Manufacturing and Crystallisation (Grant Ref: EP/K503289/1 and Intelligent Decision Support and Control Technologies for Continuous Manufacturing of Pharmaceuticals and Fine Chemicals (Grant ref EP/K014250/1) and Centre for Innovative Manufacturing in Continuous Manufacturing and Crystallisation (Grant Ref EP/I033459/1) for funding this work.The authors would like to acknowledge that this work was carried out in the CMAC National Facility supported by UKRPIF (UK Research Partnership Fund) award from the Higher Education Funding Council for England (HEFCE) (Grant ref HH13054).References:[1] Thennadil. Suresh and Yi-Chieh. Chen, Measurement apparatus and method, U.S. Patent EP2783199A1 (2014).[2] Agimelen. Okpeafoh, Hamilton. Peter, Haley. Ian, Nordon. Alison, Vasile. Massimiliano, Sefcik. Jan, Mulholland. Anthony, Estimation of particle size distribution and aspect ratio of non-spherical particles from chord length distribution, Chemical Engineering Science, 123, 629-640 (2015).[3] Agimelen. Okpeafoh, Jawor-Baczynska. Anna, McGinty. John, Dziewierz. Jerzy, Tachtatzis. Christos, Cleary. Alison, Haley. Ian, Michie. Craig, Andonovic. Ivan, Sefcik. Jan, Mulholland. Anthony, Integration of in situ imaging and chord length distribution measurements for estimation of particle size and shape, Chemical Engineering Science, 144, 87-100 (2016).