Chromatography Focus The Fascinating History of the Development of LC-MS; a Personal Perspective


Today LC-MS is considered as a commonplace analytical tool that has been around for years. Most users do not give a second thought to the history of the development of this fascinating technique. It is twenty years since the first commercial instrument dedicated to atmospheric pressure ionisation (API) was produced by a small and then unknown company called Sciex, and so now is probably a good time to review some of the significant challenges that were faced to develop the technique. I would like to take you through some of the pioneering work that was carried out in this area, and discuss some of the exotic approaches that were taken by the pioneers of LC-MS prior to the API breakthrough.


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I have been working in mass spectrometry for nearly 40 years, and I consider myself fortunate to have grown up during the various stages in the development of LC-MS. What I have attempted to do in this article is give you a personal view of what I consider some of the landmarks on the road to achieving the perfect interface between LC and MS and how that technique plays a major part in the analytical chemists daily life.


They wanted to remove the solvent before the sample entered the mass spectrometer, and designed a moving belt interface which comprised of a stainless steel belt, onto which the LC eluent was deposited


Author Details:


Frank Pullen University of Greenwich at Medway, School of Science, Central Avenue, Chatham Maritime, Kent, ME4 4TB, UK frank.pullen@gre.ac.uk


Let me take you back to 1968 when the first ever attempt to interface these two apparently incompatible techniques together was published in the Russian Journal of Physical Chemistry by Victor Tal’rose [1]. This was a landmark publication for its time, because it was the first attempt connect LC to MS. They managed to spray a very small amount of liquid into a conventional high voltage electron impact mass spectrometer. This was no mean feat, as the ionisation source in the mass spectrometer needed to be at high vacuum (10-7 torr). Liquid produces a lot of gas as the pressure is reduced, and so this was seen by the mass spectrometry community as an incredible feat, and lots of excitement was generated around this direct liquid introduction (DLI) approach.


However, it was soon realised that electron impact, due to its inability to deal pressures in excess of 10-6 Torr, was not going to be a practical approach and interest waned. In 1973 Baldwin and McLafferty recognised that this approach could be viable if the liquid was sprayed into a chemical ionisation source as the amount of liquid entering the mass spectrometer could be increased [2]. They developed a DLI LC-MS interface (Figure 1), which was more robust and was capable of generating a stable ion beam in the mass spectrometer; but the liquid flow rate was still very low.


In the USA, McFadden et. al. [7] were approaching the solvent issue in a completely different way. They wanted to remove the solvent before the sample entered the mass spectrometer, and designed a moving belt interface which comprised of a stainless steel belt, onto which the LC eluent was deposited. The belt then passed under some infra red heaters to evaporate the solvent and then through a complex series of vacuum locks prior to the belt entering a conventional EI/CI mass spectrometer source (Figure 3).


Figure 3. Moving Belt Interface McFadden et. al. 1976 [7]


This approach was also developed as a commercial system. The first was developed commercially by Finnigan as an LC-MS interface to their quadrupole instruments, and this was followed by a variation developed by Vacuum Generators who used a polyimide belt instead of the stainless one, so that this approach could be used on high voltage double focussing mass spectrometers [8]. This was later further modified to be used in conjunction with Fast Atom Bombardment ion sources [9]. Around this time some interesting research was being carried out by Thomson and Iribarne [10] who were looking into the fate of charges in evaporating cloud droplets, but, just like Hornings work, this was not viewed with great interest, especially because Vestal had just published his early work on a new and exciting LC-MS interface called Thermospray [11].


Figure 1. Direct Liquid Introduction Probe - McLafferty et. al. 1973 [2]


Even with its limitations, this approach gained enough interest that Hewlett Packard actually developed a commercial interface that was launched at the Pittsburgh Conference in 1979 [3]. Some ground breaking work applying this technique to real problems were published by some eminent chromatographers such as Patrick Arpino and Jack Henion [4,5].


At the same time other research groups were approaching this interfacing problem from different directions, Horning with Dziric and Carrol in 1975 [6], were the first people to develop an atmospheric pressure source, firstly using radioactive Nickel and then subsequently corona discharge interfaced to a mass spectrometer (Figure 2). This interface showed promise, but the spectra were complex due to the presence of cluster ions and so this concept was not really pursued seriously at the time.


Figure 4. Thermospray source design; Vestal et. al. [11]


Figure 2. Schematic Diagram of a Corona Discharge Source - Horning et. al. 1975 [6]


This interface took the LC-MS community by storm. For the first time the MS and chromatography communities had an interface that could accommodate reversed phase solvent systems. It did have some significant limitations, in that you could not use phosphate buffer, and for ionisation to occur you needed to have ammonium acetate present, but it was the first real LC-MS approach which addressed many of the desires of the chromatographer. This was approach commercialised by all the main mass spectrometry manufacturers of the time, and the technique was fully embraced by the pharmaceutical industry. Everyone within the mass spectrometry and the chromatography communities were ‘over the moon’ because, for the first time, we had a working LC-MS approach which was capable of dealing with reversed phase solvent systems and which was complimentary with LC-UV detection (although the sensitivity was not as good). Other interfaces also popped up around this time; one was the particle beam interface [12] in 1984, and the other was flowing FAB [13] in 1985, but they only had limited impact on the


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