Process Flow Spectroscopy
The ABCRF Process Flow Spectroscopy (ProSpect) facility offers state-of-the-art reaction analysis, allowing the direct observation of pharmaceutical process reactions as they occur. The suite of equipment consists of specially designed, integrated instrumentation adapted for direct real-time analysis of both batch and continuous reaction processes. Used together, these complementary techniques provide an unprecedented level of mechanistic insight. The facility, located in the ABCRF, the Pharmacy Building, UCC, operates within the SSPC and provides academic researchers and the pharmaceutical industry with a platform for enhancing their understanding of chemical transformations and pharmaceutical processes – where improvements can lead to yield enhancements, shorter reaction times and reduced costs for the manufacturer.
The suite of instrumentation available within the ProSpect facility includes:
- Bruker Avance III 600 MHz NMR (ABCRF NMR Services) spectrometer in conjunction with a Bruker InsightMR flow tube, to enable direct analysis of reaction mixtures by NMR.
- Mettler–Toledo ReactIR 15 and FlowIR for in situ/inline IR analysis.
- Agilent 6530 Series Q-TOF LC/MS System.
- Agilent 1290 series UPLC.
- Perkin–Elmer Lambda 265 UV/Vis spectrophotometer, including a flow cell for reaction monitoring.
- Mettler–Toledo EasyMax workstation for batch chemistry.
- Vapourtec R-Series flow chemistry system for continuous flow processing.
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Chemical processes can be directly analysed by a Bruker Avance III 600 MHz NMR spectrometer incorporating Bruker’s InsightMR flow tube, which carries reaction mixtures between the instrument and the reaction vessel via a temperature-controlled transfer line. The system allows for reactions to be conducted in non-deuterated solvents and thus can mimic conditions for the synthesis of pharmaceutical compounds. NMR active reaction components can be detected, quantitated and characterised using a range of available CryoProbes and room temperature probes, which have multinuclear and variable temperature capability. Data is captured and analysed using Bruker proprietary Topspin 4.0 and InsightMR software.
In Situ & In-Line IR Analysis
Real-time process analysis by infrared spectroscopy is provided using either a Mettler–Toledo ReactIR 15 (for batch systems) or a Mettler–Toledo FlowIR (for continuous flow systems). Both diamond and silicon probes are available for each instrument, allowing the full spectral range to be observed, depending on chemical compatibility with the experimental conditions. Data is collected using and processed using iC IR 7.0 software. The ReactIR 15 can be used for in situ reaction monitoring alongside the Flow NMR system, enabling simultaneous collection of IR and NMR data for a given experiment.
Off-line analysis of chemical processes by mass spectrometry is available using an Agilent 6530 Accurate-Mass Quadrupole Time-of-Flight (Q-TOF) LC/MS system, which delivers exceptional sensitivity, excellent mass accuracy, fast data acquisition and streamlined qualitative and quantitative analyses. MassHunter Workstation software offers data mining and analysis capabilities. HPLC/UPLC capability is provided by an Agilent 1290 Infinity II LC, system which includes Agilent’s Intelligent System Emulation Technology (ISET) – allowing transfer of methods between LCs, regardless of the brand with unchanged retention time and peak resolution.
Reaction monitoring by UV/Vis profile can be conducted using a Perkin–Elmer UV/Vis spectrophotometer in conjunction with a flow cell – through which the reaction mixture can be carried, in a loop with the reaction vessel. The instrument uses a photodiode array (PDA) detector to enable data to be acquired simultaneously across the full wavelength range, from 190 nm to 1100 nm.
- Preparative scale batch chemistry can be run using a mettler–toledo easymax 102 advanced synthesis workstation, with working volumes between 0.5 mL–100 mL. precise control is afforded over reaction parameters such as temperature (–40 °C to 180 °C), pH, stirrer rate (rpm), and reagent addition with high quality data and key information recorded throughout an experiment.
- Chemistry in continuous flow can be conducted using a vapourtec r-series flow chemistry system. the system consists of four pumps and has an operating temperature range of –70 °C to 250 °C, depending on the reactor(s) in use. the system uses flow commander software to design and run experiments, and to log and store data on measured reaction parameters during the course of an experiment.
The facility’s suite of equipment also includes a Rudolph Autopol V Plus digital polarimeter, for accurate determination of optical purity of compounds. The system is also equipped with a flow cell which enables real-time monitoring of experiments by measurement of the optical rotation of a reaction mixture. A Gilson GX-241 Liquid Handler is also available for automatic sampling of reaction mixtures. The GX-241 has an injection volume range of 1 µL to 5 mL using a minimal dead volume direct injection design and features two transfer ports for delivering sample to off-bed detection devices, with the ability to hold hundreds of samples ranging from 2 mL vials to 100 mm test tubes.
In addition to each instrument’s own software capabilities, the facility also has access to Mestrelab’s latest Mnova suite of analytical software which can be used for advanced processing of NMR and MS data sets.
External Projects & Enquiries
The ProSpect facility is open to projects from external users, both in industry and academia. Requests for information should be directed to Dr Lorraine Bateman.