Process development using oscillatory baffled mesoreactors

PhD ThesisThe mesoscale oscillatory baffled reactor (meso-OBR) is a flow chemistry platform whose niche is the ability to convert long residence time batch processes to continuous processes. This reactor can rapidly screen reaction kinetics or optimise a reaction in flow with minimal waste. In this work, several areas were identified that could be addressed to broaden the applicability of this platform. Four main research themes were subsequently formulated and explored: (I) development of deeper understanding of the fluid mechanics in meso-OBRs, (II) development of a new hybrid heat pipe meso-OBR for improved thermal management, (III) further improvement of continuous screening using meso-OBRs by removing the solvent and employing better experiment design methodologies, and (IV) exploration of 3D printing for rapid reactor development. I. The flow structures in a meso-OBR containing different helical baffle geometries were studied using computational fluid dynamics simulations, validated by particle image velocimetry (PIV) experiments for the first time. It was demonstrated, using new quantification methods for the meso-OBR, that when using helical baffles swirling is responsible for providing a wider operating window for plug flow than other baffle designs. Further, a new flow regime resembling a Taylor-Couette flow was discovered that further improved the plug flow response. This new double vortex regime could conceivably improve multiphase mixing and enable flow measurements (e.g. using thermocouples inside the reactor) to be conducted without degrading the mixing condition. This work also provides a new framework for validating simulated OBR flows using PIV, by quantitatively comparing turbulent flow features instead of qualitatively comparing average velocity fields. II. A new hybrid heat pipe meso-OBR (HPOBR) was prototyped to provide better thermal control of the meso-OBR by exploiting the rapid and isothermal properties of the heat pipe. This new HPOBR was compared with a jacketed meso-OBR (JOBR) for the thermal control of an exothermic imination reaction conducted without a solvent. Without a solvent or thermal control scheme, this reaction exceeded the boiling point of one of the reactants. A central composite experiment design explored the effects of reactant net flow rate, oscillation intensity and cooling capacity on the thermal and chemical response of the reaction. The HPOBR was able to passively control the temperature below the boiling point of the reactant at all conditions through heat spreading. Overall, a combined 260-fold improvement in throughput was demonstrated compared to a reactor requiring the use of a solvent. Thus, this ii wholly new reactor design provides a new approach to achieving green chemistry that could be theoretically easily adapted to other reactions. III. Analysis of in situ Fourier transform infrared (FTIR) spectroscopic data also suggested that the reaction kinetics of this solventless imination case study could be screened for the first time using the HPOBR and JOBR. This was tested by applying flow-screening protocols that adjusted the reactant molar ratio, residence time, and temperature in a single flow experiment. Both reactor configurations were able to screen the Arrhenius kinetics parameters (pre-exponential factors, activation energies, and equilibrium constants) of both steps of the imination reaction. By defining experiment conditions using design of experiments (DoE) methodologies, a theoretical 70+% reduction in material usage/time requirement for screening was achieved compared to the previous state-of-the-art screening using meso-OBRs in the literature. Additionally, it was discovered that thermal effects on the reaction could be inferred by changing other operating conditions such as molar ratio and residence time. This further simplifies the screening protocols by eliminating the need for active temperature control strategies (such as a jacket). IV. Finally, potential application areas for further development of the meso-OBR platform using 3D printing were devised. These areas conformed to different “hierarchies” of complexity, from new baffle structures (simplest) to entirely new methods for achieving mixing (most complex). This latter option was adopted as a case study, where the passively generated pulsatile flows of fluidic oscillators were tested for the first time as a means for improving plug flow. Improved plug flow behaviour was indeed demonstrated in three different standard reactor geometries (plain, baffled and coiled tubes), where it could be inferred that axial dispersion was decoupled from the secondary flows in an analogous manner to the OBR. The results indicate that these devices could be the basis for a new flow chemistry platform that requires no moving parts, which would be appealing for various industrial applications. It is concluded that, for the meso-OBR platform to remain relevant in the next era of tailor-made reactors (with rapid uptake of 3D printing), the identified areas where 3D printing could benefit the meso-OBR should be further explored

Continuous direct compression as manufacturing platform for sustained release tablets

This study presents a framework for process and product development on a continuous direct compression manufacturing platform. A challenging sustained release formulation with high content of a poorly flowing low density drug was selected. Two HPMC grades were evaluated as matrix former: standard Methocel CR and directly compressible Methocel DC2. The feeding behavior of each formulation component was investigated by deriving feed factor profiles. The maximum feed factor was used to estimate the drive command and depended strongly upon the density of the material. Furthermore, the shape of the feed factor profile allowed definition of a customized refill regime for each material. Inline NIRs was used to estimate the residence time distribution (RTD) in the mixer and monitor blend uniformity. Tablet content and weight variability were determined as additional measures of mixing performance. For Methocel CR, the best axial mixing (i.e. feeder fluctuation dampening) was achieved when an impeller with high number of radial mixing blades operated at low speed. However, the variability in tablet weight and content uniformity deteriorated under this condition. One can therefore conclude that balancing axial mixing with tablet quality is critical for Methocel CR. However, reformulating with the direct compressible Methocel DC2 as matrix former improved tablet quality vastly. Furthermore, both process and product were significantly more robust to changes in process and design variables. This observation underpins the importance of flowability during continuous blending and die-filling. At the compaction stage, blends with Methocel CR showed better tabletability driven by a higher compressibility as the smaller CR particles have a higher bonding area. However, tablets of similar strength were achieved using Methocel DC2 by targeting equal porosity. Compaction pressure impacted tablet properties and dissolution. Hence controlling thickness during continuous manufacturing of sustained release tablets was crucial to ensure reproducible dissolution. (C) 2017 Elsevier B.V. All rights reserved

Closed-Loop Model-Based Design of Experiments for Kinetic Model Discrimination and Parameter Estimation: Benzoic Acid Esterification on a Heterogeneous Catalyst

An autonomous reactor platform was developed to rapidly identify a kinetic model for the esterification of benzoic acid with ethanol with the heterogeneous Amberlyst-15 catalyst. A five-step methodology for kinetic studies was employed to systematically reduce the number of experiments required to identify a practical kinetic model. This included (i) initial screening using traditional factorial designed steady-state experiments, (ii) proposing and testing candidate kinetic models, (iii) performing an identifiability analysis to reject models whose model parameters cannot be estimated for a given experimental budget, (iv) performing online Model-Based Design of Experiments (MBDoE) for model discrimination to identify the best model from a list of candidates, and (v) performing online MBDoE for improving parameter precision for the chosen model. This methodology combined with the reactor platform, which conducted all kinetic experiments unattended, reduces the number of experiments and time required to identify kinetic models, significantly increasing lab productivity

Mathematical modeling of anaerobic digestion in plug-flow reactors

Anaerobic digestion is one of the most used technology for the treatment of organic compounds contained in a great variety of waste through which the production of a renewable energy is obtained, the biogas. Mathematical modelling plays a key role in providing tools supporting the designing and managing of plants performing this kind of process. The vast majority of mathematical models describing the anaerobic digestion process focus their attention on systems in wet conditions, whose mathematical problem consists in non-linear systems of ordinary differential equations. Dry anaerobic digestion modelling, due to the reactors where it is performed, needs more complex systems of partial differential equations to describe properly the dynamics of the process. The lack of scientific literature on this topic drove the interests and the efforts of the research activities of the three years of Ph.D, concretized in the scientific articles that are presented in this work of thesis. Research activities were aimed to the development of a mathematical model describing the dynamics of the main compounds involved in a dry anaerobic digestion process in plug-flow reactors. The thesis is divided in 6 chapters. In chapter 1 the main topic is introduced. Chapter 2 presents the calibration and validation of an ADM1-based model, performed using the results of experimental campaigns of anaerobic digestion of potato waste having the characteristic dimension of the particles varying in a wide range. Chapter 3 describe the derived mathematical model of anaerobic digestion in plug-flow reactors: model equations and hypothesis are presented and model consistency with experimental observations is shown through numerical simulations. The model considers the variation of compounds concentrations in both space and time and takes into account the mass/volume variation of the treated matrix along the reactor. Moreover, a new equation describing the gas-transfer phenomenon is presented in this chapter. A global aensitivity analysis and uncertainty quantification for the model of dry anaerobic digestion in plug-flow reactors is performed in Chapter 4. These activities revealed the most important model parameters influencing the methane production, the main output of the model. In Chapter 5, based on the global sensitivity analysis and uncertainty quantification results, model parameters have been calibrated and validated. Results of two experimental campaigns of dry anaerobic digestion in a plug-flow reactor have been used to this purpose. Lastly, in Chapter 6 a general discussion for future research developments is given

The Development of Microreactor Technology for the Study of Multistep Catalytic Systems and Rapid Kinetic Modelling

Microreactor technology was applied to the study of catalytic systems because their high rates of heat and mass transport, improved safety and ease of automation makes them particularly effective research tools in this area. A multistep flow system for the synthesis of benzylacetone from benzyl alcohol via oxidation, aldol condensation and reduction reactions was developed by utilising three micropacked bed reactors and a gas liquid membrane separator. This reaction had previously been conducted in batch cascade, however, the multistep flow system enabled the achievement of higher yields with lower catalyst contact times because separating each reaction into its own reactor allowed greater freedom to tailor the operating conditions for each reaction. The multistep system also allowed the catalysts to be studied in a process wide environment, leading to the identification of significant catalyst inhibition due to by and co-products from upstream reactions. An automated closed loop microreactor platform was developed which utilised Model-Based Design of Experiments (MBDoE) algorithms for rapid kinetic modelling of catalytic reactions. The automated platform was first applied to the homogenous esterification of benzoic acid with ethanol using a sulfuric acid catalyst, where a campaign of steady-state experiments designed by online MBDoE led to the estimation of kinetic parameters with much higher precision than a factorial campaign of experiments. This reaction was then conducted with MBDoE designed transient experiments, which dramatically reduced the experimental time required. The same reaction was studied using a heterogeneous Amberlyst-15 catalyst, and by combining factorial designs, practical identifiability tests and MBDoE for model discrimination and parameter precision, a practical kinetic model was identified in just 3 days. The automated platform was applied to the oxidation of 5-hydroxymethylfurfural in a micropacked bed reactor with gas-liquid flow using AuPd/TiO2 catalysts, however due to poor experimental reproducibility, a kinetic model was not identified

The kinetics of biodegradation of trans-4-methyl-1-cyclohexane carboxylic acid

This thesis presents the study of biodegradation factors of a candidate naphthenic acid compound, the trans isomer of 4-methyl-1-cyclohexane carboxylic acid (trans-4MCHCA). Low molecular weight components of naphthenic acids such as trans-4MCHCA are known to be toxic in aquatic environments and there is a need to better understand the factors controlling the kinetics of their biodegradation. In this study, a relatively low molecular weight naphthenic acid compound and a microbial culture developed in our laboratory (primarily Alcaligenes paradoxus and Pseudomonas aeruginosa) were used to study the biodegradation of this candidate naphthenic acid. The purpose of the research was to evaluate the kinetic parameters and model the biodegradation of this compound in three bioreactor systems: batch reactors, a continuously stirred tank reactor and immobilized cell reactors. In batch reactors, the maximum specific growth rate (0.52±0.04 d-1) of the consortium at 23oC and neutral pH was not highly variable over various initial substrate concentrations (50 to 750 mg/L). Batch experiments indicated that biodegradation can be achieved at low temperatures; however, the biodegradation rate at 4oC was only 22% of that at room temperature (23oC). Biodegradation at various pH values indicated a maximum specific growth rate of 1.69±0.40 d-1 and yield (0.41±0.06 mg/mg) at a pH of 10. Study of the candidate substrate using a continuously stirred tank reactor and the microbial culture developed in the batch experimentations revealed that the kinetics of the candidate naphthenic acid are best described by the Monod expression with a maximum specific growth rate of 1.74±0.004 d-1 and a half saturation constant of 363±17 mg/L. The continuously stirred tank reactor achieved a maximum reaction rate of 230 mg/(L∙d) at a residence time of 1.6 d-1 (39 h).Two high porosity immobilized cell reactors operating continuously over three months were found to consume trans-4MCHCA at a rate almost two orders of magnitude higher than a continuously stirred tank reactor. The immobilized cell systems attained a maximum reaction rate of 22,000 mg/(L∙d) at a residence time of 16 minutes. High porosity immobilized cell reactors were shown to effectively remove a single naphthenic acid substrate in continuously fed operation to dilution rates of 90 d-1. A plug flow model best represented the degradation in the immobilized cell systems and was demonstrated to be a useful tool for studying the effects of parameter variation and prediction of reactor performance. This work highlights the potential of augmented bioremediation systems for the degradation of naphthenic acids

Investigating approaches to continuous crystallisation using process-analytical technology: establishment of a steady-state cooling crystallisation process

In this work, two approaches to continuous crystallisation are investigated. The first approach is the mesoscale continuous oscillatory flow crystalliser which possesses a smooth periodic constriction design (herein known as the SPC mesoscale crystalliser) and is a tubular device operating at turbulent flow conditions. The second of these approaches is the popular mixed suspension mixed product removal (MSMPR) crystalliser based on stirred tank technology. The investigation of both approaches is aided by integrated process analytical technology (PAT), newly developed characterisation methods, and offline solid-state analytical tools. The SPC mesoscale crystalliser is a type of continuous oscillatory baffled crystalliser (COBC), which unlike the plug flow crystalliser (PFC), decouples mixing from net flow by combining oscillatory flow with steady flow. This enables significantly longer residence times to be achieved in practical lengths of the crystalliser for crystallisation purposes. In the past few years, COBCs have gained increasing attention as promising platforms for developing robust continuous crystallisation processes and transforming already existing commercial batch processes in industry. This small-diameter SPC mesoscale crystalliser, however, has had very little application to crystallisation despite possessing superior capabilities for efficient mixing and solids suspension, and small volume requirements for process development. The MSMPR crystalliser is an idealised crystalliser model that assumes steady-state operation of a well-mixed suspension with no product classification, and uniform supersaturation throughout, leading to constant nucleation and growth rates. The investigation of both approaches in this work involves the characterisation of the mixing and heat transfer performance, and the development of processes for the continuous cooling crystallisation of glycine (GLY) from water in both platforms. A characterisation of the mixing performance of the SPC mesoscale crystalliser is performed using a newly developed RTD measurement technique. The technique known as non-invasive dual backlit imaging involves the use of two high-definition (HD) cameras and light sources to simultaneously and precisely capture the concentration of a tracer in the crystalliser as a function of grayscale intensity. The new technique is benchmarked against the more traditional invasive conductivity measurements to determine the reliability of both techniques. Using the dual backlit imaging technique, the liquid and solid phase axial dispersion performance the SPC mesoscale crystalliser is determined, and the optimum conditions for solid-liquid plug flow are identified for crystallisation. A series of heat transfer experiments are performed to characterise the heat transfer performance of the SPC mesoscale crystalliser and its suitability for tight control of temperature and local supersaturation. Based on these experiments, an empirical correlation is developed to predict the tube-side Nusselt number and enable spatial temperature profile predictions in the SPC mesoscale crystalliser for cooling crystallisation. A seeded continuous cooling crystallisation process is then carried out based on metastable zone width (MSZW) measurements in a batch version of the SPC mesoscale crystalliser. A rapid intermittent vacuum transfer technique is applied to the single- and two-stage configurations of the MSMPR crystalliser to successfully mitigate transfer line blockage issues and obtain uninterrupted steady-state operation. The RTD performance of the MSMPR crystalliser is characterised and benchmarked against the SPC mesoscale crystalliser, confirming the contrasting RTD profiles offered by each platform. Solid suspension performance and determination of critical residence time for heat transfer is also carried out for the MSMPR platform to aid crystallisation process development. Subsequently, using a complete recycle operation, the unseeded cooling crystallisation of GLY from water is investigated systematically to understand the effect of mean residence time, MSMPR operating temperature, and number of MSMPR stages on the GLY product mean size, crystal size distribution (CSD), and yield. The systematic study of GLY-water seeded continuous cooling crystallisation in the SPC mesoscale crystalliser identified an operating strategy for obtaining desired product attributes. Specifically, seeding with small-sized seeds, running at longer mean residence times (by extending the crystalliser length), operating at near plug flow conditions, and implementing a spatial cubic temperature profile will lead to larger product mean sizes, with narrower CSDs, and higher yields. In the MSMPR crystalliser, experimental investigations showcased the higher degree of operational capability offered by cascade operation, whereby a two-stage MSMPR configuration enabled operation at much lower MSMPR temperature than possible in the single-stage MSMPR and provided higher yield. Results particularly highlighted the importance of controlling supersaturation distribution in the MSMPR system by manipulating operating variables such as mean residence time and MSMPR stage temperatures to achieve desired product quality. Overall, the investigations carried out in this body of work demonstrate the potential of the SPC mesoscale crystalliser for application to continuous crystallisation process development of small-volume active pharmaceutical ingredients (APIs). Both platforms are therefore equally feasible for process development and manufacturing