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Date
2025-12
Abstract
The pharmaceutical industry is witnessing a transition from batch to continuous mode of operation owing to the advantages of better control over product quality and productivity. Antisolvent crystallization, one of the key unit operations used for purification of solids and generation of crystals used in pharmaceutical formulations, is also undergoing the said transition. Continuous antisolvent crystallization is usually carried out in stirred tank crystallizers, known as the single stage mixed-suspension-mixed-product-removal (MSMPR) crystallizers. In recent years, various fluidic devices such as helical coils, coiled flow inverters, Taylor flow crystallizers, fluidic oscillators etc. are used for conducting continuous crystallization. These devices may offer improved control over mixing of the solution of active pharmaceutical ingredient (API) and the antisolvent stream and thereby improved control on the local supersaturation and overall crystallizer performance. In this work, we have investigated the application of the fluidic oscillator (FO) for continuous antisolvent crystallization. The goal was to evaluate the performance of FO for crystallisation of irregularly shaped particles having aspect ratio larger than one. Carbamazepine dihydrate, an anti-epileptic drug, which crystallizes in the form of acicular particles from aqueous ethanolic solutions, was selected as the model API.
In the first part of the thesis, the research work undertaken to establish basic data, experimental set-up, characterisation techniques and population balance models needed for investigating continuous antisolvent crystallization is presented. This includes the methodology for online measurement of particle size distribution using the focused beam reflectance measurement (FBRM). An appropriate model and a tool for conversion of the chord length distributions (CLD) of the non-uniform particles obtained using the FBRM was developed and validated for particles having aspect ratio larger than one. The solubility of carbamazepine dihydrate in the solvent and antisolvent pair of ethanol and water at different temperatures was measured and modelled. Equipped with these basics, the second part of the thesis presents the research focused on the continuous antisolvent crystallization. Initially experiments were performed in a single-stage MSMPR, referred to as the continuous stirred tank crystallizer (CSTC) to provide a basis for comparison of the other crystallizers. The particle size and concentration profiles were used to estimate the kinetic parameters for crystallization. Similar experiments performed in the FO augmented by a helical coil (HC) were used for comparison of the performance of the device as a crystallizer. A loop configuration was used to decouple residence time in the crystallizer and mixing in the FO. A generalised one-dimensional population balance model based on the tanks-in-series framework was developed. The model was used to simulate the continuous antisolvent crystallization experiments. The simulated results of particle size distribution (PSD) and ii transient profiles of supersaturation were in good agreement with the experimental results. The experimental and simulated results were used to develop guidelines on improving productivity while retaining control on PSD.
Noting the non-uniform shapes of the crystals, further work was performed to account for the shortcomings of the 1D PBM model, by exploring variable growth rate. Along with the studies on the crystallization devices and models, a short investigation was carried out to study the effect the additives on the morphology of the carbamazepine dihydrate crystals. While the experimental data reported in this work will be helpful for the development of processes involving the antisolvent crystallization of carbamazepine dihdyrate, the scientific approach and different models proposed will be useful to the wider crystallization community for the design and modelling of novel crystallizers.
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University of Limerick
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Sustainable Development Goals
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Attribution-NonCommercial-ShareAlike 4.0 International