A Perspective on the Analytical Challenges Encountered in High-Throughput Experimentation
- Rachel Grainger* and
- Stuart Whibley*
High-throughput experimentation (HTE) is a well-established technique used in the pharmaceutical industry to accelerate compound synthesis and route optimization through automated chemical processes. A key part of any HTE workflow is the analytical component, through which the reaction outcome can be determined. The development of new analytical techniques capable of high-throughput data generation from nanoscale chemical reactions has been required to streamline the HTE process and address challenges generated through the recent move to miniaturize synthesis. In this Perspective, we review the currently available state-of-the-art analytical methods, discuss the challenges encountered in high-throughput analysis—with a particular focus on the analysis of nanoscale reactions, and provide a future outlook on potential developments in the field.
It is worth noting that the level of spectral information obtainable through LC–MS analysis is in part dictated by the mass analyzer(s) employed. For relatively little expense, a single-quadrupole instrument is sufficient to quantify a limited number of ions, while an ion trap may provide structural information through fragmentation, although quantitative power will be limited. High-resolution MS analyzers such as time-of-flight (TOF) can predict the empirical formulas of unknown compounds, while tandem mass spectrometers, such as quadrupole time-of-flight (Q-TOF) excel at overall sensitivity, albeit at a much higher price point.
In relation to experimental information disclosed in Table 1 and Figure 9, MISER acquisition LC–MS experiments were performed on an Agilent 1290 Infinity II system. The Agilent stack comprised a G7120A binary pump, a G7167B multisampler, a G7116B column compartment, a G7117B diode array detector, and a G6135B quadrupole LC–MS detector with multimode (simultaneous ESI and APCI) ionization in the positive mode. The system was controlled by OpenLab Chemstation Edition software with the FIA mode enabled. Separations were carried out on a 2.0 mm i.d. × 30 mm length, 1.9 μm YMC-Triart C18 column by isocratic elution at a flow rate of 1.5 mL/min. The LC eluents were 16% solvent A (0.1% formic acid in H2O) and 84% solvent B (acetonitrile). The column was maintained at a temperature of 40 °C. The MISERgrams were obtained from continuous sample injections (0.5 μL) every 13 s. The positive ion multimode parameters were as follows: fragmentor, 60 V; drying gas flow, 12 L/min; nebulizer pressure, 35 psig; drying gas temperature, 350 °C; vaporizer temperature, 250 °C; capillary voltage, 3000 V; corona current, 1 μA; charging voltage, 2000 V.
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