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High-Resolution Mass Spectrometry: Instruments and Technology

The upper range of MS resolving power comes ever closer to real-world laboratory budgets

by
Brandoch Cook, PhD

Brandoch Cook, PhD, is a freelance scientific writer. He can be reached at: brandoch.cook@gmail.com.

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Although mass spectrometry (MS) is a mature technology, it is ever-evolving, particularly by offering higher accuracy and data analysis capabilities for a broader pool of users. At its cutting edge is high-resolution mass spectrometry (HRMS), with instruments that offer the highest resolution while preserving the sensitivity to resolve the most informative mass spectra. 

In its simplest form, an MS instrument triggers ionization of a sample, often with nebulizing and desolvation gases flowing in parallel. The resulting particulate plasma segregates through a vacuum-enclosed chamber, across an applied electrical potential or magnetic field. The rate or frequency of ion movement is dependent on mass. A detector registers a mass-to-charge ratio (m/z) accurate enough to identify thousands of known organic and inorganic compounds and narrow down the identity of unknown compounds. 

Low-resolution mass spectrometers (LRMS): time-of-flight and quadrupole 

The original MS instruments used time-of-flight (TOF), in which samples are laser-ionized and the ions accelerate and then drift down a single flight tube. Because heavier ions move more slowly, time elapsed before an ion flies into a detector serves as the surrogate measure of its mass. With fast acquisition and wide dynamic range, TOF is still popular, and has expanded in variety and capability. Pulsed ionization via matrix-assisted laser desorption/ionization (MALDI-TOF) has improved the accuracy of biomolecule characterization, with the ability to desorb ions of molecular weights up to 300 kilodaltons. Continuous electrospray ionization or MALDI, combined with orthogonal acceleration and collisional cooling, produces a focused ion beam that can achieve high resolving power (usually held to be anything above about 50,000). In quadrupole instruments, voltage travels across four parallel rods with alternating potentials, creating separate filters for oscillating ions in the resulting electric field. Because ions with only one m/z ratio at a time can traverse the field without neutralizing against the quadrupole, the instrument must continuously scan the ratio of potentials. This necessitates longer acquisition times, although ion monitoring imparts an exquisite sensitivity. Quadrupole-TOF hybrid configurations can also achieve high resolution, although neither can match the capabilities of FT-ICR-MS. 

High-resolution mass spectrometry (HRMS)

When considering the purchase of a mass spectrometry instrument, it's crucial to understand the unique advantages of high-resolution mass spectrometry, especially the Fourier Transform Ion Cyclotron Resonance (FT-ICR-MS) technology. Unlike traditional mass spectrometers, HRMS offers unparalleled precision and sensitivity, making it an invaluable tool for advanced scientific research and complex analyses. Here are six key advantages of HRMS systems worth considering when in the market for a new MS system:

1. Ion cyclotron resonance cell precision: 

The ion cyclotron resonance (ICR) cell in FT-ICR-MS is crucial for its unmatched precision. This component is responsible for detecting minimal mass variations down to an extra electron or change in isotope ratio, based on the intrinsic frequencies at which ions oscillate in a magnetic field. Such precision, inherent to the ICR cell's design, is indispensable in fields like pharmaceuticals, environmental studies, and biochemical research.

2. Mass analyzer accuracy:  

The mass analyzer in HRMS is pivotal in measuring the mass-to-charge ratio (m/z) with exceptional accuracy. This component's high precision is essential when dealing with complex mixtures or identifying unknown compounds, allowing for differentiation between similar molecular structures.

Unlike traditional mass spectrometers, HRMS offers unparalleled precision and sensitivity . . .

3. High-precision detectors for varied mass measurement:  

The detectors in HRMS offer accurate readings of nominal, average, and monoisotopic mass. This precision is essential for applications requiring exact molecular formula determination, like in drug development and metabolomics.

4. Magnet system and resolving power:  

The superconducting magnet system in FT-ICR-MS is key to its superior resolving power, which is continually improved by higher-strength magnetic fields. This system enables differentiation between compounds with nearly identical masses, crucial for detailed molecular analysis in the study of complex organic molecules and trace elements.

5. Sophisticated data acquisition systems for complex samples:  

The data acquisition systems in HRMS are optimized for high resolution and accuracy, ideal for analyzing complex or unknown samples. These systems enable the identification and quantification of trace compounds in challenging matrices, a task difficult for lower-resolution technologies.

6. Comprehensive system design for long-term application:  

While FT-ICR-MS represents a significant initial investment, its comprehensive system design, including ICR cells, mass analyzers, detectors, and magnet systems, offers a broad application scope and in-depth information, ensuring long-term value. This design makes it suitable for leading-edge scientific research and analysis.

When considering an investment in HRMS technology, specifically FT-ICR-MS, it's important to evaluate the specific analytical needs, complexity of samples, and the required level of detail. The sophisticated components of HRMS, from the ICR cell to the mass analyzer and magnet system, make it an ideal choice for pushing the boundaries of molecular analysis and discovering new insights in various scientific fields.

The original MS instruments used time-of-flight, in which samples are laser-ionized and the ions accelerate and then drift down a single flight tube.

A final note on cost and maintenance

As one might imagine, HRMS instruments are costly. However, depending on configuration, ranges can overlap significantly between LRMS and HRMS, with TOF and quadrupole instruments anywhere between $50k and a million dollars, and FT-MS instruments typically from about $150k to two million and beyond. Purchasing a refurbished instrument can often drop the price by at least half, although lab managers may then be responsible for securing third-party warranties and maintenance/repair contracts. 

Routine maintenance is a boon to laboratory productivity, as it reduces overall instrument down-time and identifies potential problems before they become emergency repair issues. However, it requires additional detective work by the purchaser to determine which contractors are best qualified. You want one who can perform installation and calibration or operational and performance qualifications of MS instruments. But you also want one who can service instruments of different vendors equally well (or, alternatively, focus on just your vendor of interest), and maintain agreements to access OEM replacement parts and software updates. With an FT-ICR-MS instrument in particular, there are specialized parts such as superconducting magnets that require specialized skillsets. However, there is still a wealth of service options, including those provided by the major manufacturers for their own instruments, usually with three to five full packages of coverage and special options for older instrumentation.