A large proportion of pharmaceutical crystallizations produce crystals with high aspect ratio, which can cause problems in operations downstream from the crystallizer, such as washing and filtration (e.g., see Refs. 1-24). This presentation describes the application of the Focused Beam Reflectance Measurement (FBRM) for the in-process estimation of the crystal characteristics and ReactIR Attenuated Total Reflection Fourier Transform Infrared Spectroscopy for solution concentration estimation during the nucleation, growth, and dissolution of crystals of varying shapes (e.g., see Refs. 3, 8, 12-13, 15, 18 and citations therein). The particle characterization includes the estimation of the mean crystal length and mean crystal width for rod-like crystals, which are commonplace in the pharmaceutical industry. Chord length distributions and their derived statistics are compared for the S- and G-Series FBRM probes for various types of systems, with additional particle characterization using Process Vision Measurement (PVM) and off-line optical microscopy. Experiments that cycle the temperature from conditions of positive and negative supersaturation are used to assess reproducibility of the estimated particle and solution properties while providing a wide range of changes in the aspect ratio in a single well-characterized experiment for assessing the different relative dependencies of growth and dissolution on supersaturation along the different crystal axes. The crystal size and solute concentration estimates are used to estimate kinetics in a multidimensional population balance model for prediction of the crystal size and shape distribution. In contrast to previous studies that have estimated kinetics along multiple crystal axes in mixed-tank crystallizers (e.g., Refs. 14 and 24), this study employs standardized commercial instrumentation that is readily available in pharmaceutical laboratories (FBRM) rather than using specialized instrumentation or excessive sampling. In contrast to Ref. 24, the size characterization in this work is of much higher quality. In contrast to past studies, this work characterizes the different dissolution kinetics along each crystal axis, and is able to collect enough experimental design for kinetics estimation in a single experiment (instead of multiple experiments). The subsequent model predictions are validated with experimental data.
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