Modes of LC-NMR and their application

There are four general modes of operation for LC-NMR on-flow, direct stop-flow, time-sliced and loop collection/transfer. The mode selected will depend on the level and complexity of the analyte and also on the NMR information required. All modes of LC-NMR can be run under full automation for LC peak-picking, LC peak transfer to storage loops or NMR flow cell, and NMR detection [46], 

In practice, if the NMR acquisition times are longer than 30 min then on-column diffusion dilutes subsequent peaks, thus reducing the sensitivity [63], Typically, LC peaks will be broadened by 30% and 50% after the flow is stopped for 5 and 10 h, respectively [74], significantly reducing the LC-NMR sensitivity. Such peaks are more efficiently analysed by repeating the chromatography. 

Carry-over can be problematic for closely eluting peaks in stop-flow mode [46], and these are better analysed using the loop collection mode (see below). 

In addition, carry-over from the main peak is very often problematic for low-level late-running impurities. One way of overcoming this problem is to divert the flow to waste at the PSU for the early-running analytes, bypassing the probe and then switching the flow to the probe to analyse the minor peak(s) of interest. 

Time-shcing is a variation of the stop-flow mode where the flow is stopped in a time-dependent manner (e.g. every 15 s) for the whole chromatographic run, in a sense the ultimate approach in slow-flow. When the flow is stopped, sufficient scans can be made to give the desired level of detection before moving on to the next time-slice. The whole process can be automated through software control. There is no requirement for an UV detector, and the approach has been used to identify non-UV-active components in drug substances [48]. The peak purity of 

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