Search

A highly scalable combined modular and 3D-printed falling film crystallization device is developed and demonstrated herein; the device uses a small, complex, printed overflow-based film distribution part that ensures formation of a well-distributed heated liquid film around a modular, tubular residence time/crystallizer section, enabling extended residence times to be achieved. A model API (ibuprofen) and impurity (ibuprofen ethyl ester) were used as a test system in the evaluation of the novel crystallizer design. The proposed crystallizer was run using three operational configurations: batch, cyclical batch, and continuous feed, all with intermittent removal of product. Results were suitable for intermediate purification requirements, and stable operation was demonstrated over multiple cycles, indicating that this approach should be compatible with parallel semicontinuous operation for intermediate purification and solvent swap applications in the manufacture of drugs.

Additive Manufacturing is transforming how researchers and industrialists look to design and manufacture chemical devices to meet their specific needs. In this work, we report the first example of a flow reactor formed via the solid-state metal sheet lamination technique, Ultrasonic Additive Manufacturing (UAM), and featuring directly integrated catalytic sections and sensing elements. The UAM technology not only overcomes many of the current limitations associated with the additive manufacturing of chemical reactionware but it also significantly increases the functionality of such devices. A range of biologically important 1, 4-disubstituted 1, 2, 3-triazole compounds were successfully synthesised and optimised inflow through a Cu mediated Huisgen 1, 3-dipolar cycloaddition using the UAM chemical device. By exploiting the unique properties of UAM and continuous flow processing, the device was able to catalyse the proceeding reactions whilst also providing real-time feedback for reaction monitoring and optimisation.

A low-cost, modular, robust, and easily customisable continuous liquid-liquid phase separator has been developed that uses a tubular membrane and annular channels to allow high fluidic throughputs while maintaining rapid, surface wetting dominated, phase separation. The system is constructed from standard fluidic tube fittings and allows leak tight connections to be made without the need for adhesives, or O-rings. The units tested in this work have been shown to operate at flow rates of 0.1 – 300 mL/min, with equivalent residence times from 80 to 4 seconds, demonstrating the simplicity of scale-up with these units. Further scale-up to litre per minute scales of operation for single units and tens of litres/minute through limited numbering up should allow these low cost concentric annular tubular membrane separators to be used at continuous production scales for pharmaceutical applications for many solvent systems. In principle this approach may be sufficiently scalable to be utilized in-line, in batch pharmaceutical manufacturing also, through further scale-up and numbering up of units. Several solvent systems with varying interfacial tensions have been investigated, and the critical process parameters affecting successful separation have been identified. An additively manufactured diaphragm based back pressure regulator was also developed and printed in PEEK, allowing highly accurate, adjustable, and chemically compatible pressure control to be accessed at low cost. Enterprise Ireland European Commission - European Regional Development Fund Science Foundation Ireland

Chemically resistant parts for flow chemistry, with integrated mixing elements have been produced using the 3D printing process of fused filament fabrication, from poly(etheretherketone). Poly(etheretherketone) has greater chemical resistance than common fused filament fabrication materials such as acrylonitrile butadiene styrene, polypropylene, or even high-performance plastics like poly(etherimide), in addition to having superior thermal resistance and excellent mechanical strength. Printed reactors were demonstrated to be suitable for liquid–liquid extraction and flow chemistry and to be capable of withstanding pressures of at least 30 bar allowing superheated solvents to be used. Burst tests in simple geometries of 20 minute duration have indicated that increased operating pressures of up to 60 bar could be accommodated in future reactor designs. The ability to use fused filament fabrication for these reactors allows highly customisable, cost effective flow reactors and equipment to be fabricated on relatively inexpensive benchtop scale printers. X-ray microcomputed tomography was utilised to non-invasively image and verify the internal structure of the prints to ensure fidelity in reactor fabrication. This non-invasive method of equipment validation shows potential in helping to demonstrate regulatory compliance for bespoke additively manufactured components, for example in continuous pharmaceutical manufacturing where the methods and printer used in this work should be sufficient to produce, (continuous) manufacturing scale equipment. Enterprise Ireland Science Foundation Ireland Pfizer Inc.

Additive manufacturing or ‘3D printing’ is being developed as a novel manufacturing process for the production of bespoke micro- and milliscale fluidic devices. When coupled with online monitoring and optimisation software, this offers an advanced, customised method for performing automated chemical synthesis. This paper reports the use of two additive manufacturing processes, stereolithography and selective laser melting, to create multifunctional fluidic devices with embedded reaction monitoring capability. The selectively laser melted parts are the first published examples of multifunctional 3D printed metal fluidic devices. These devices allow high temperature and pressure chemistry to be performed in solvent systems destructive to the majority of devices manufactured via stereolithography, polymer jetting and fused deposition modelling processes previously utilised for this application. These devices were integrated with commercially available flow chemistry, chromatographic and spectroscopic analysis equipment, allowing automated online and inline optimisation of the reaction medium. This set-up allowed the optimisation of two reactions, a ketone functional group interconversion and a fused polycyclic heterocycle formation, via spectroscopic and chromatographic analysis.

IntroductionMicrofluidic reactionware allows small volumes of reagents to be utilized for highly controlled flow chemistry applications. By integrating these microreactors with onboard analytical systems, the devices change from passive ones to active ones, increasing their functionality and usefulness. A pressing application for these active microreactors is the monitoring of reaction progress and intermediaries with respect to time, shedding light on important information about these real-time synthetic processes.ObjectiveIn this multi-disciplinary study the objective was to utilise advanced digital fabrication to research metallic, active microreactors with integrated fibre optics for reaction progress monitoring of solvent based liquids, incompatible with previously researched polymer devices, in combination with on-board Ultraviolet-visible spectroscopy for real-time reaction monitoring.MethodA solid-state, metal-based additive manufactured system (Ultrasonic Additive Manufacturing) combined with focussed ion beam milling, that permitted the accurate embedment of delicate sensory elements directly at the point of need within aluminium layers, was researched as a method to create active, metallic, flow reactors with on-board sensing. This outcome was then used to characterise and correctly identify concentrations of UV-active water-soluble B-vitamin nicotinamide and fluorescein. A dilution series was formed from 0.01-1.75 mM; which was pumped through the research device and monitored using UV-vis spectroscopy.ResultsThe results uniquely showed the in-situ ion milling of ultrasonically embedded optical fibres resulted in a metallic microfluidic reaction and monitoring device capable of measuring solvent solutions from 18 μM to 18 mM of nicotinamide and fluorescein, in real time. This level of accuracy highlights that the researched device and methods are capable of real-time spectrographic analysis of a range of chemical reactions outside of those possible with polymer devices.

The formation of smart Lab-on-a-Chip (LOC) devices featuring integrated sensing optics is currently hindered by convoluted and expensive manufacturing procedures. In this work, a series of 3D-printed LOC devices were designed and manufactured via stereolithography (SL) in a matter of hours. The spectroscopic performance of a variety of optical fibre combinations were tested, and the optimum path length for performing Ultraviolet-visible (UV-vis) spectroscopy determined. The information gained in these trials was then used in a reaction optimisation for the formation of carvone semicarbazone. The production of high resolution surface channels (100-500 μm) means that these devices were capable of handling a wide range of concentrations (9 μM-38 mM), and are ideally suited to both analyte detection and process optimisation. This ability to tailor the chip design and its integrated features as a direct result of the reaction being assessed, at such a low time and cost penalty greatly increases the user's ability to optimise both their device and reaction. As a result of the information gained in this investigation, we are able to report the first instance of a 3D-printed LOC device with fully integrated, in-line monitoring capabilities via the use of embedded optical fibres capable of performing UV-vis spectroscopy directly inside micro channels.