Back to the new basics: Part 1 | Making the leap from GC-MS to LC-MS

Feb 10, 2022 | Biopharma, Blogs, Clinical, Environmental / Industrial, Food / Beverage, Forensic, Life Science Research, Pharma | 0 comments

Read time: 5 minutes

Producing accurate results quickly in a demanding environment is no easy feat for analytical scientists. What’s more, many of us are constantly questioning ourselves—I certainly am—about whether we are employing the best technique for the analysis at hand.

It’s an overwhelming thought, considering the wide range of tools that are available to choose from, each of which offers varying levels of capacity, sensitivity, selectivity, specificity and cost. How do you meet the unique needs of your organization without breaking the bank? I get it, and I’m not here to convince you it’s easy. My aim is to guide you through the process to help you make the right decision for you.

When faced with this challenge, the fundamental question is this: “Am I achieving all I can with my gas chromatography mass spectrometry (GC-MS) system, or should I move to a liquid chromatography mass spectrometry (LC-MS) system?”

Defining the two methods

Let’s start with some chromatography fundamentals. Chromatography is a method used to separate samples in time, and it is the most important procedure for isolating and analyzing chemicals. It can be classified into 2 types, depending on the carrier or the mobile phase used: GC or LC. Table 1 summarizes the key capabilities of each type.

With GC, the mobile phase used is usually a gas insert such as helium or argon (a carrier gas), and the technique itself is performed in a capillary or packed column. Although capillary columns are more expensive than packed columns, they provide greater resolution. Traditionally, GC with electron impact ionization is the preferred technique for analyzing volatile compounds (e.g., benzene and trihalomethanes), as well as organochlorine pesticides and environmental contaminants such as dioxins and polychlorinated biphenyls. It is a technique best used for thermally stable analytes, since the GC inlet temperatures are generally high to facilitate the transfer of the injected sample into the gas phase, where chromatographic separation occurs before detection at the mass spectrometer.

With LC, on the other hand, a liquid mobile phase is used. With this method, several factors—including size, charge and hydrophobicity—influence the interactions between sample molecules and the chromatography medium or phase. The strength of this technique is in the ability of LC to separate a wide range of compounds, and these compounds do not have to be volatile. An advancement in the LC technique is high-performance liquid chromatography (HPLC), which uses higher pressures to force the sample through a column and is currently the most routinely used technique in the pharmaceutical industry.

Table 1. An overview of LC and GC characteristics.

Using GC vs. LC

Both GC and LC are often coupled with a mass spectrometer to enable specific detection and identification of separated analytes. This is the reason you often see the terms GC-MS and LC-MS.

While GC-MS can offer good separation, the high temperatures used for vaporization during GC analysis can alter or degrade many analytes. This is a concern for life science researchers who deal with relatively labile biological molecules that break down easily at high temperatures. GC-MS can also be challenging because it can involve labor-intensive sample preparation and long chromatographic run times. While they are not yet widely adopted, there are newer technologies such as LCMS that can reduce these long run times.

As described in Table 1, LC is a liquid phase separation technique typically used for larger, more polar molecules that are incompatible with GC. It does not require a high temperature, enabling the analysis of more labile molecules, and in turn allowing the analysis of a wider range of compound classes using LC. When coupled with a mass spectrometer for LC-MS detection, you can confirm the compound identity and quantify it with good specificity.

Another appealing characteristic of LC-MS is dramatically reduced signal-to-noise levels. In most cases, depending on the application, this enables you to achieve lower limits of quantification (LLOQs) than you can with GC-MS. There are also a wide range of mass spectrometers to which you can directly couple LC, from a low-cost workhorse instrument to a high-end, high-sensitivity powerhouse instrument. The sensitivity and speed of an LC-MS system enables you to monitor multiple fragment ions for each target compound. This can help you be confident that you have detected the right compound (based on the ion ratio comparison to knowns), even for analytes that are present at low levels. This can sometimes be difficult with GC-MS, where some lower abundant ion fragments cannot be observed in most cases.

All this talk about the power of LC-MS may make me seem biased, so I think it’s important to point out a weak point of LC-MS in comparison to GC-MS. When analyzing complex matrices, LC-MS can suffer from matrix effects or background interferences. These effects or interferences can alter ionization efficiency by either suppressing or enhancing the ionization properties of target analytes in the presence of co-eluting compounds in the same matrix. Both ion suppression and enhancement can dramatically affect the analytical performance of a method. To mitigate this issue, LC-MS users often adopt stable isotope dilution assays by adding known amounts of stable isotope-labeled standards to the analyzed sample, or they adjust the chromatographic strategy to resolve the target compounds from the confounding background.

So, what’s the right choice?

Let’s go back to the question we started with: Am I achieving all I can with my GC-MS system, or should I move to an LC-MS system? My vote is for LC-MS, because I believe that GC-MS cannot provide adequate performance across a broad range of applications, including those that deal with biological fluids. For this reason, while LC-MS systems can be more complex than GC-MS systems, they are worth the investment.

If you are new to LC-MS or thinking about making the leap, check out the SCIEX Triple Quad 3500 system. It has the potential to expand your operation beyond the restrictions of GC, and it is a great way to enter the world of LC-MS and its power, speed and accuracy. Download the SCIEX Triple Quad 3500 system compendium to learn more about what it can do for your laboratory.

If you require additional training, check out the online and in-person courses available in the SCIEX Now Learning Hub to help get your lab up to speed. And be sure to take advantage of our new digital tool, the SCIEX Now Learning Manager, which provides a centralized digital platform that enables lab directors to spend less time and resources tracking the training competencies of their staff and offers access to current content from leading industry experts at SCIEX. Browse and enroll now!

This is part 1 of a 3-part “Back to the new basics” series on mass spectrometry. Look for the next installment soon.


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Alex Liu is the Product Manager for the entry-level nominal mass MS product line at SCIEX (the SCIEX Triple Quad 3500 and 4500 systems). Alex came from the market management team, where he was previously responsible for driving the strategic growth of food and environmental markets. Alex started his career as an Application Scientist supporting pre- and post-sales activities related to food safety testing. He then moved on to working as an Account Manager responsible for selling microbiology monitoring portfolio products to national food and beverage accounts in the US before joining SCIEX in August 2016, based in Framingham, MA. Alex holds an MBA in Marketing from the University of Massachusetts Amherst, an MSc in Food Science from the University of Missouri and a BSc in Plant Science from Zhejiang University in China.


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