Method development detector considerations

In summary, LC-MS offers excellent sensitivity for many classes of pharmaceutical compounds. Due to the fact that MS is becoming more routine (i.e., it is essentially another detector), LC-MS should be the first consideration for all cleaning verification assays that are less than 0.1 pg/swab. In the citations outlined above, LC-MS has been shown to offer excellent sensitivity and specificity for the analytes of interest. The mass spectrometric conditions can be optimized in a flow injection mode to allow for rapid method development. All LC-MS analytical methods were validated in a way consistent with the requirements outlined in Table 15.3. The applications cited utilized LC-MS because of the sensitivity requirements of the safety acceptance limits however, if the molecule of interest poses unique detection challenges such as a poor chromophote, LC-MS should be considered for assays at the level of 1.0 ig/unit area, or less. Above 1.0 xg/unit area there may be more attractive options for these swab determinations. 

The ultimate in selectivity in HPLC detection is seen with the use of mass-spectrometric detection, and for many applications this could be seen as the ideal detection method. However, more mundane considerations such as size of the instrumentation and limited budgets combine to reduce HPLC-MS to a relatively small number of applications which most effectively exploit its unique properties. When such practical constraints are taken into account, the real detector coimected to the HPLC system usually turns out to be a device that is a compromise, and its performance characteristics need to be taken into account during the development of many analyses just as much as the performance of the column or any other component of the HPLC system. For example, lack of detection selectivity may require extra method development to completely resolve an interfering peak, or lack of sensitivity could force the inclusion of an extraction-concentration step in an analytical method to achieve detectable levels of analyte. 

Despite the considerable amount of information that has been garnered from more traditional methods of study it is clearly desirable to be able to generate, spectroscopically characterize and follow the reaction kinetics of coordinatively unsaturated species in real time. Since desired timescales for reaction will typically be in the microsecond to sub-microsecond range, a system with a rapid time response will be required. Transient absorption systems employing a visible or UV probe which meet this criterion have been developed and have provided valuable information for metal carbonyl systems [14,15,27]. However, since metal carbonyls are extremely photolabile and their UV-visible absorption spectra are not very structure sensitive, the preferred choice for a spectroscopic probe is time resolved infrared spectroscopy. Unfortunately, infrared detectors are enormously less sensitive and significantly slower... 

Bond et al. [68] have described a method for the simultaneous determination of down to lmg L 1 free sulphide and cyanide by ion chromatography, with electrochemical detection. These workers carried out considerable exploratory work on the development of ion chromatographic conditions for separating sulphide and cyanide in a basic medium (to avoid losses of toxic hydrogen cyanide and hydrogen sulphide) and on the development of a suitable amperometric detector. 

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