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Date
2025-09-30
Abstract
Crystallisation is one of the key processes in the pharmaceutical industry for manufacturing active pharmaceutical ingredients (APIs), as it combines particle formation and purification in a single unit operation. The pharmaceutical industry has widely adopted batch crystallisation as the mode of 0peration due to its easy and flexible operation. However, batch or semi-batch manufacturing has issues like batch-to-batch inconsistency in the product critical quality attributes (CQAs) and scale-up limitations. Continuous crystallisation has emerged as a tool to ensure consistent CQAs with advantages like smaller process equipment, reduced capital and operation costs, and less impurity accumulation. Controlling CQAs during a continuous process is challenging, unlike batch or semi-batch, which offer many degrees of freedom. Various in-line devices like ultrasound, wet mill, hydrodynamic cavitation (HC), classifiers, etc., are used to tailor Particle Size Distribution (PSD), which is one of the key CQAs. Hydrodynamic cavitation leads to cavitation bubbles, which implode and cause particle breakage. This work investigates the application of a vortex-based HC device to enhance the performance of a continuous crystallisation (called as cavitation assisted or cavi-crystallisation). The goal is to investigate the role of hydrodynamic cavitation in crystallisation kinetics (nucleation and growth) and breakage of crystals. Anti-solvent crystallisation of paracetamol using methanol - water system was chosen as the model system.
The first part of the present work was focused on investigating the influence of HC on nucleation and breakage. Induction time measurements were conducted using a saturated solution of paracetamol in isothermal conditions. The use of VD was found to enhance nucleation, which led to a significant reduction in induction time in the presence of HC. The breakage of paracetamol particles in methanol-water solution was investigated in the absence of crystallisation. The influence of three in-line milling devices, namely vortex-based HC device (VD), wet mill (WM), and ultrasound horn (US), on particle breakage was studied. VD was found to provide control over the
dominant breakage mechanism, which, in turn, controls the formation of fines during milling. As the pressure drop increases, VD causes a shift in the dominant breakage mechanism from fracture resulting in coarse daughter fragments) to abrasion (resulting in fines). A particle breakage model within the framework of population balance modelling was developed to simulate particle breakage due to VD. A novel two-phenomena model was developed to identify the scale at which and the limits to which the particles break due to shear and cavitation. A parent-particle-size-dependent-shape-shifting daughter size distribution was developed to represent the dominant breakage mechanisms at different scales.
After investigating particle breakage, the second part of the work focused on continuous antisolvent crystallisation and cavi-crystallisation experiments. Three different configurations, namely, a reference configuration of a continuous stirred tank crystalliser, a base configuration comprising a stirred tank crystalliser augmented with an external loop where solvent and anti-solvent streams are introduced, and an augmented base configuration with an in-line VD in the loop (cavi-crystallisation). The results of the continuous crystallisation experiments conducted using these three configurations were compared and critically analysed to investigate the effect of VD on the PSD and crystallisation kinetics. A generalised population balance model (PBM) based on a tanks-in-series framework was developed to simulate continuous crystallisation or to estimate the nucleation, growth, and breakage kinetic parameters from the experiments. The total surface area or the second moment within the crystalliser increased due to breakage induced by cavitation, resulting in smaller crystals. The validated PBM was then used to simulate the effect of residence time on yield and productivity. This was followed by an investigation of the potential of harnessing enhanced nucleation by applying VD for enhancing the performance of a continuous crystalliser. The VD-induced enhanced nucleation was used as a pre-nucleator to a tubular crystalliser (COBC). This VD-assisted continuous antisolvent crystallisation process, where nucleation and growth are decoupled, was shown to achieve better control over PSD and improved overall performance. The approach, models, and experimental data presented in this work demonstrate the potential of using hydrodynamic cavitation for intensifying and optimising the continuous antisolvent crystallisation process.
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Description
Publisher
University of Limerick
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Funding code
Funding Information
Sustainable Development Goals
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Type
Thesis
Rights
http://creativecommons.org/licenses/by-nc-sa/4.0/