Two-dimensional chromatography

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Two-dimensional chromatograph GCxGC-TOFMS at Chemical Faculty of GUT Gdansk, Poland, 2016 GCxGC-TOFMS Analytical Dept Chemical Faculty GUT Gdansk.jpg
Two-dimensional chromatograph GCxGC-TOFMS at Chemical Faculty of GUT Gdańsk, Poland, 2016

Two-dimensional chromatography is a type of chromatographic technique in which the injected sample is separated by passing through two different separation stages. Two different chromatographic columns are connected in sequence, and the effluent from the first system is transferred onto the second column. [1] Typically the second column has a different separation mechanism, so that bands that are poorly resolved from the first column may be completely separated in the second column. (For instance, a C18 reversed-phase chromatography column may be followed by a phenyl column.) Alternately, the two columns might run at different temperatures. During the second stage of separation the rate at which the separation occurs must be faster than the first stage, since there is still only a single detector. The plane surface is amenable to sequential development in two directions using two different solvents.

Contents

History

Modern two-dimensional chromatographic techniques are based on the results of the early developments of paper chromatography and thin-layer chromatography (TLC) which involved liquid mobile phases and solid stationary phases. These techniques would later generate modern gas chromatography (GC) and liquid chromatography (LC) analysis. Different combinations of one-dimensional GC and LC produced the analytical chromatographic technique that is known as two-dimensional chromatography.

The earliest form of 2D-chromatography came in the form of a multi-step TLC separation in which a thin sheet of cellulose is used first with one solvent in one direction, then, after the paper has been dried, another solvent is run in a direction at right angles to the first. This methodology first appeared in the literature with a 1944 publication by A. J. P. Martin and coworkers detailing an efficient method for separating amino acids – "...but the two-dimensional chromatogram is especially convenient, in that it shows at a glance information that can be gained otherwise only as the result of numerous experiments" (Biochem J., 1944, 38, 224).

Examples

Two-dimensional separations can be carried out in gas chromatography or liquid chromatography. Various different coupling strategies have been developed to "resample" from the first column into the second. Some important hardware for two-dimensional separations are Deans' switch and Modulator, which selectively transfer the first dimension eluent to second dimension column. [2]

The chief advantage of two-dimensional techniques is that they offer a large increase in peak capacity, without requiring extremely efficient separations in either column. (For instance, if the first column offers a peak capacity (k1)of 100 for a 10-minute separation, and the second column offers a peak capacity of 5 (k2) in a 5-second separation, then the combined peak capacity may approach k1 × k2=500, with the total separation time still ~ 10 minutes). 2D separations have been applied to the analysis of gasoline and other petroleum mixtures, and more recently to protein mixtures. [3] [4]

Tandem mass spectrometry

Diagram of a triple quadrupole (QQQ) mass analyzer QQQ Mass Analyzer.png
Diagram of a triple quadrupole (QQQ) mass analyzer

Tandem mass spectrometry (Tandem MS or MS/MS) uses two mass analyzers in sequence to separate more complex mixtures of analytes. The advantage of tandem MS is that it can be much faster than other two-dimensional methods, with times ranging from milliseconds to seconds. [5] Because there is no dilution with solvents in MS, there is less probability of interference, so tandem MS can be more sensitive and have a higher signal-to-noise ratio compared to other two-dimensional methods. The main disadvantage associated with tandem MS is the high cost of the instrumentation needed. Prices can range from $500,000 to over $1 million. [6] Many form of tandem MS involve a mass selection step and a fragmentation step. The first mass analyzer can be programmed to only pass molecules of a specific mass-to-charge ratio. Then the second mass analyzer can fragment the molecule to determine its identity. This can be especially useful for separating molecules of the same mass (i.e. proteins of the same mass or molecular isomers). Different types of mass analyzers can be coupled to achieve varying effects. One example would be a TOF-Quadrupole system. Ions can be sequentially fragmented and/or analyzed in a quadrupole as they leave the TOF in order of increasing m/z. Another prevalent tandem mass spectrometer is the quadrupole-quadrupole-quadrupole (Q-Q-Q) analyzer. The first quadrupole separates by mass, collisions take place in the second quadrupole, and the fragments are separated by mass in the third quadrupole.

Diagram of a quadrupole/time of flight mass analyzer. The ionized source sample first enters the quadrupole mass analyzer, then enters the time of flight analyzer. QuadToF.png
Diagram of a quadrupole/time of flight mass analyzer. The ionized source sample first enters the quadrupole mass analyzer, then enters the time of flight analyzer.

Gas chromatography-mass spectrometry

Diagram of GCMS. The diagram shows the pathway of the analyte. The analyte first passes through the gas chromatographer and then the separated analytes are subjected to mass analysis. Different types of mass analyzers, ToF, qudrupole, etc., can by used in the MS. GCMS Block.png
Diagram of GCMS. The diagram shows the pathway of the analyte. The analyte first passes through the gas chromatographer and then the separated analytes are subjected to mass analysis. Different types of mass analyzers, ToF, qudrupole, etc., can by used in the MS.

Gas chromatography-mass spectrometry (GC-MS) is a two-dimensional chromatography technique that combines the separation technique of gas chromatography with the identification technique of mass spectrometry. GC-MS is the single most important analytical tool for the analysis of volatile and semi-volatile organic compounds in complex mixtures. [7] It works by first injecting the sample into the GC inlet where it is vaporized and pushed through a column by a carrier gas, typically helium. The analytes in the sample are separated based upon their interaction with the coating of the column, or the stationary phase, and the carrier gas, or the mobile phase. [8] The compounds eluted from the column are converted into ions via electron impact (EI) or chemical ionization (CI) before traveling through the mass analyzer. [9] The mass analyzer serves to separate the ions on a mass-to-charge basis. Popular choices perform the same function but differ in the way that they accomplish the separation. [10] The analyzers typically used with GC-MS are the time-of-flight mass analyzer and the quadrupole mass analyzer. [8] After leaving the mass analyzer, the analytes reach the detector and produce a signal that is read by a computer and used to create a gas chromatogram and mass spectrum. Sometimes GC-MS utilizes two gas chromatographers in particularly complex samples to obtain considerable separation power and be able to unambiguously assign the specific species to the appropriate peaks in a technique known as GCxGC-(MS). [11] Ultimately, GC-MS is a technique utilized in many analytical laboratories and is a very effective and adaptable analytical tool.

Liquid chromatography-mass spectrometry

Liquid chromatography-mass spectrometry (LC/MS) couples high resolution chromatographic separation with MS detection.  As the system adopts the high separation of HPLC, analytes which are in the liquid mobile phase are often ionized by various soft ionization methods including atmospheric pressure chemical ionization (APCI), electrospray ionization (ESI) or matrix-assisted laser desorption/ionization (MALDI), which attains the gas phase ionization required for the coupling with MS.[ citation needed ] These ionization methods allow the analysis of a wider range of biological molecules, including those with larger masses, thermally unstable or nonvolatile compounds where GC-MS is typically incapable of analyzing.

LC-MS provides high selectivity as unresolved peaks can be isolated by selecting a specific mass. Furthermore, better identification is also attained by mass spectra and the user does not have to rely solely on the retention time of analytes. As a result, molecular mass and structural information as well as quantitative data can all be obtained via LC-MS. [9] LC-MS can therefore be applied to various fields, such as impurity identification and profiling in drug development and pharmaceutical manufacturing, since LC provides efficient separation of impurities and MS provides structural characterization for impurity profiling. [12]

Diagram of LCMS. The sample is first subjected to analysis by HPLC and then is subjected to mass analysis. Different types of mass analyzers, ToF, qudrupole, etc., can be used in the MS. LCMS.png
Diagram of LCMS. The sample is first subjected to analysis by HPLC and then is subjected to mass analysis. Different types of mass analyzers, ToF, qudrupole, etc., can be used in the MS.

Common solvents used in normal or reversed phase LC such as water, acetonitrile, and methanol are all compatible with ESI, yet a LC grade solvent may not be suitable for MS. Furthermore, buffers containing inorganic ions should be avoided as they may contaminate the ion source. [13] Nonetheless, the problem can be resolved by 2D LC-MS, as well as other various issues including analyte coelution and UV detection responses. [14]

Liquid chromatography-liquid chromatography

Two-dimensional liquid chromatography (2D-LC) combines two separate analyses of liquid chromatography into one data analysis. Modern 2D liquid chromatography has its origins in the late 1970s to early 1980s. During this time, the hypothesized principles of 2D-LC were being proven via experiments conducted along with supplementary conceptual and theoretical work. It was shown that 2D-LC could offer quite a bit more resolving power compared to the conventional techniques of one-dimensional liquid chromatography. In the 1990s, the technique of 2D-LC played an important role in the separation of extremely complex substances and materials found in the proteomics and polymer fields of study. Unfortunately, the technique had been shown to have a significant disadvantage when it came to analysis time. Early work with 2D-LC was limited to small portion of liquid phase separations due to the long analysis time of the machinery. Modern 2D-LC techniques tackled that disadvantage head on, and have significantly reduced what was once a damaging feature. Modern 2D-LC has an instrumental capacity for high resolution separations to be completed in an hour or less. Due to the growing need for instrumentation to perform analysis on substances of growing complexity with better detection limits, the development of 2D-LC pushes forward. Instrumental parts have become a mainstream industry focus and are much easier to attain then before. Prior to this, 2D-LC was performed using components from 1D-LC instruments, and would lead to results of varying degrees in both accuracy and precision. The reduced stress on instrumental engineering has allowed for pioneering work in the field and technique of 2D-LC.

The purpose of employing this technique is to separate mixtures that one-dimensional liquid chromatography otherwise cannot separate effectively. Two-dimensional liquid chromatography is better suited to analyzing complex mixtures samples such as urine, environmental substances and forensic evidence such as blood.

Difficulties in separating mixtures can be attributed to the complexity of the mixture in the sense that separation cannot occur due to the number of different effluents in the compound. Another problem associated with one-dimensional liquid chromatography involves the difficulty associated to resolving closely related compounds. Closely related compounds have similar chemical properties that may prove difficult to separate based on polarity, charge, etc. [15] Two-dimensional liquid chromatography provides separation based on more than one chemical or physical property. Using an example from Nagy and Vekey, a mixture of peptides can be separated based on their basicity, but similar peptides may not elute well. Using a subsequent LC technique, the similar basicity between the peptides can be further separated by employing differences in apolar character. [16]

As a result, to be able to separate mixtures more efficiently, a subsequent LC analysis must employ very different separation selectivity relative to the first column. Another requirement to effectively use 2D liquid chromatography, according to Bushey and Jorgenson, is to employ highly orthogonal techniques which means that the two separation techniques must be as different as possible. [17]

Diagram of 1-dimensional LC. An example of the spectral results of this technique is also shown. 1D LC Chromatogram.png
Diagram of 1-dimensional LC. An example of the spectral results of this technique is also shown.
Diagram of 2-dimensional LC. An example of the spectral results of this specific technique is also shown. 2D LC Chromatogram.png
Diagram of 2-dimensional LC. An example of the spectral results of this specific technique is also shown.

There are two major classifications of 2D liquid chromatography. These include: Comprehensive 2D liquid chromatography (LCxLC) and Heart-cutting 2D liquid chromatography (LC-LC). [18] In comprehensive 2D-LC, all the peaks from a column elution are fully sampled, but it has been deemed unnecessary to transfer the entire sample from the first to the second column. A portion of the sample is sent to waste while the rest is sent to the sampling valve. In heart-cutting 2D-LC specific peaks are targeted with only a small portion of the peak being injected onto a second column. Heart-cutting 2D-LC has proven to be quite useful for sample analysis of substances that are not very complex provided they have similar retention behavior. Compared to comprehensive 2D-LC, heart-cutting 2D-LC provides an effective technique with much less system setup and a much lower operating cost. Multiple heart-cutting (mLC-LC) may be utilized to sample multiple peaks from first dimensional analysis without risking temporary overlap of second dimensional analysis. [18] Multiple heart-cutting (mLC-LC) utilizes a setup of multiple sampling loops.

For 2D-LC, peak capacity is a very important issue. This can be generated using gradient elution separation with much greater efficiency than an isocratic separation given a reasonable amount of time. While isocratic elution is much easier on a fast time scale, it is preferable to perform a gradient elution separation in the second dimension. The mobile phase strength is varied from a weak eluent composition to a stronger one. Based on linear solvent strength theory (LSST) of gradient elution for reversed phase chromatography, the relationship between retention time, instrumental variables and solute parameters is shown below. [18]

tR=t0 +tD + t0/b*ln(b*(k0-td/t0) + 1)

While a lot of pioneering work has been completed in the years since 2D-LC became a major analytical chromatographic technique, there are still many modern problems to be considered. Large amounts of experimental variables have yet to be decided on, and the technique is constantly in a state of development.

Gas chromatography – gas chromatography

Comprehensive two-dimensional gas chromatography is an analytical technique that separates and analyzes complex mixtures. It has been utilized in fields such as: flavor, fragrance, environmental studies, pharmaceuticals, petroleum products and forensic science. GCxGC provides a high range of sensitivity and produces a greater separation power due to the increased peak capacity.

See also

Related Research Articles

In chemical analysis, chromatography is a laboratory technique for the separation of a mixture into its components. The mixture is dissolved in a fluid solvent called the mobile phase, which carries it through a system on which a material called the stationary phase is fixed. Because the different constituents of the mixture tend to have different affinities for the stationary phase and are retained for different lengths of time depending on their interactions with its surface sites, the constituents travel at different apparent velocities in the mobile fluid, causing them to separate. The separation is based on the differential partitioning between the mobile and the stationary phases. Subtle differences in a compound's partition coefficient result in differential retention on the stationary phase and thus affect the separation.

<span class="mw-page-title-main">Inductively coupled plasma mass spectrometry</span> Type of mass spectrometry that uses an inductively coupled plasma to ionize the sample

Inductively coupled plasma mass spectrometry (ICP-MS) is a type of mass spectrometry that uses an inductively coupled plasma to ionize the sample. It atomizes the sample and creates atomic and small polyatomic ions, which are then detected. It is known and used for its ability to detect metals and several non-metals in liquid samples at very low concentrations. It can detect different isotopes of the same element, which makes it a versatile tool in isotopic labeling.

<span class="mw-page-title-main">High-performance liquid chromatography</span> Technique in analytical chemistry

High-performance liquid chromatography (HPLC), formerly referred to as high-pressure liquid chromatography, is a technique in analytical chemistry used to separate, identify, and quantify specific components in mixtures. The mixtures can originate from food, chemicals, pharmaceuticals, biological, environmental and agriculture, etc, which have been dissolved into liquid solutions.

<span class="mw-page-title-main">Mass spectrometry</span> Analytical technique based on determining mass to charge ratio of ions

A mass spectrum is a type of plot of the ion signal as a function of the mass-to-charge ratio. These spectra are used to determine the elemental or isotopic signature of a sample, the masses of particles and of molecules, and to elucidate the chemical identity or structure of molecules and other chemical compounds.

<span class="mw-page-title-main">Electron ionization</span> Ionization technique

Electron ionization is an ionization method in which energetic electrons interact with solid or gas phase atoms or molecules to produce ions. EI was one of the first ionization techniques developed for mass spectrometry. However, this method is still a popular ionization technique. This technique is considered a hard ionization method, since it uses highly energetic electrons to produce ions. This leads to extensive fragmentation, which can be helpful for structure determination of unknown compounds. EI is the most useful for organic compounds which have a molecular weight below 600. Also, several other thermally stable and volatile compounds in solid, liquid and gas states can be detected with the use of this technique when coupled with various separation methods.

<span class="mw-page-title-main">Gas chromatography</span> Type of chromatography

Gas chromatography (GC) is a common type of chromatography used in analytical chemistry for separating and analyzing compounds that can be vaporized without decomposition. Typical uses of GC include testing the purity of a particular substance, or separating the different components of a mixture. In preparative chromatography, GC can be used to prepare pure compounds from a mixture.

<span class="mw-page-title-main">Gas chromatography–mass spectrometry</span> Analytical method

Gas chromatography–mass spectrometry (GC–MS) is an analytical method that combines the features of gas-chromatography and mass spectrometry to identify different substances within a test sample. Applications of GC–MS include drug detection, fire investigation, environmental analysis, explosives investigation, food and flavor analysis, and identification of unknown samples, including that of material samples obtained from planet Mars during probe missions as early as the 1970s. GC–MS can also be used in airport security to detect substances in luggage or on human beings. Additionally, it can identify trace elements in materials that were previously thought to have disintegrated beyond identification. Like liquid chromatography–mass spectrometry, it allows analysis and detection even of tiny amounts of a substance.

<span class="mw-page-title-main">Liquid chromatography–mass spectrometry</span> Analytical chemistry technique

Liquid chromatography–mass spectrometry (LC–MS) is an analytical chemistry technique that combines the physical separation capabilities of liquid chromatography with the mass analysis capabilities of mass spectrometry (MS). Coupled chromatography – MS systems are popular in chemical analysis because the individual capabilities of each technique are enhanced synergistically. While liquid chromatography separates mixtures with multiple components, mass spectrometry provides spectral information that may help to identify each separated component. MS is not only sensitive, but provides selective detection, relieving the need for complete chromatographic separation. LC–MS is also appropriate for metabolomics because of its good coverage of a wide range of chemicals. This tandem technique can be used to analyze biochemical, organic, and inorganic compounds commonly found in complex samples of environmental and biological origin. Therefore, LC–MS may be applied in a wide range of sectors including biotechnology, environment monitoring, food processing, and pharmaceutical, agrochemical, and cosmetic industries. Since the early 2000s, LC–MS has also begun to be used in clinical applications.

<span class="mw-page-title-main">Atmospheric-pressure chemical ionization</span> Ionization method

Atmospheric pressure chemical ionization (APCI) is an ionization method used in mass spectrometry which utilizes gas-phase ion-molecule reactions at atmospheric pressure (105 Pa), commonly coupled with high-performance liquid chromatography (HPLC). APCI is a soft ionization method similar to chemical ionization where primary ions are produced on a solvent spray. The main usage of APCI is for polar and relatively less polar thermally stable compounds with molecular weight less than 1500 Da. The application of APCI with HPLC has gained a large popularity in trace analysis detection such as steroids, pesticides and also in pharmacology for drug metabolites.

<span class="mw-page-title-main">Thermospray</span>

Thermospray is a soft ionization source by which a solvent flow of liquid sample passes through a very thin heated column to become a spray of fine liquid droplets. As a form of atmospheric pressure ionization in mass spectrometry these droplets are then ionized via a low-current discharge electrode to create a solvent ion plasma. A repeller then directs these charged particles through the skimmer and acceleration region to introduce the aerosolized sample to a mass spectrometer. It is particularly useful in liquid chromatography-mass spectrometry (LC-MS).

<span class="mw-page-title-main">Desorption electrospray ionization</span>

Desorption electrospray ionization (DESI) is an ambient ionization technique that can be coupled to mass spectrometry (MS) for chemical analysis of samples at atmospheric conditions. Coupled ionization sources-MS systems are popular in chemical analysis because the individual capabilities of various sources combined with different MS systems allow for chemical determinations of samples. DESI employs a fast-moving charged solvent stream, at an angle relative to the sample surface, to extract analytes from the surfaces and propel the secondary ions toward the mass analyzer. This tandem technique can be used to analyze forensics analyses, pharmaceuticals, plant tissues, fruits, intact biological tissues, enzyme-substrate complexes, metabolites and polymers. Therefore, DESI-MS may be applied in a wide variety of sectors including food and drug administration, pharmaceuticals, environmental monitoring, and biotechnology.

Sample preparation for mass spectrometry is used for the optimization of a sample for analysis in a mass spectrometer (MS). Each ionization method has certain factors that must be considered for that method to be successful, such as volume, concentration, sample phase, and composition of the analyte solution. Quite possibly the most important consideration in sample preparation is knowing what phase the sample must be in for analysis to be successful. In some cases the analyte itself must be purified before entering the ion source. In other situations, the matrix, or everything in the solution surrounding the analyte, is the most important factor to consider and adjust. Often, sample preparation itself for mass spectrometry can be avoided by coupling mass spectrometry to a chromatography method, or some other form of separation before entering the mass spectrometer. In some cases, the analyte itself must be adjusted so that analysis is possible, such as in protein mass spectrometry, where usually the protein of interest is cleaved into peptides before analysis, either by in-gel digestion or by proteolysis in solution.

<span class="mw-page-title-main">Ion-mobility spectrometry–mass spectrometry</span>

Ion mobility spectrometry–mass spectrometry (IMS-MS) is an analytical chemistry method that separates gas phase ions based on their interaction with a collision gas and their masses. In the first step, the ions are separated according to their mobility through a buffer gas on a millisecond timescale using an ion mobility spectrometer. The separated ions are then introduced into a mass analyzer in a second step where their mass-to-charge ratios can be determined on a microsecond timescale. The effective separation of analytes achieved with this method makes it widely applicable in the analysis of complex samples such as in proteomics and metabolomics.

<span class="mw-page-title-main">Triple quadrupole mass spectrometer</span>

A triple quadrupole mass spectrometer (TQMS), is a tandem mass spectrometer consisting of two quadrupole mass analyzers in series, with a (non-mass-resolving) radio frequency (RF)–only quadrupole between them to act as a cell for collision-induced dissociation. This configuration is often abbreviated QqQ, here Q1q2Q3.

<span class="mw-page-title-main">Direct electron ionization liquid chromatography–mass spectrometry interface</span>

A direct electron ionization liquid chromatography–mass spectrometry interface is a technique for coupling liquid chromatography and mass spectrometry (LC-MS) based on the direct introduction of the liquid effluent into an electron ionization (EI) source. Library searchable mass spectra are generated. Gas-phase EI has many applications for the detection of HPLC amenable compounds showing minimal adverse matrix effects. The direct-EI LC-MS interface provides access to well-characterized electron ionization data for a variety of LC applications and readily interpretable spectra from electronic libraries for environmental, food safety, pharmaceutical, biomedical, and other applications.

<span class="mw-page-title-main">Instrumental chemistry</span> Study of analytes using scientific instruments

Instrumental analysis is a field of analytical chemistry that investigates analytes using scientific instruments.

Comprehensive two-dimensional gas chromatography, or GC×GC, is a multidimensional gas chromatography technique that was originally described in 1984 by J. Calvin Giddings and first successfully implemented in 1991 by John Phillips and his student Zaiyou Liu.

<span class="mw-page-title-main">Miniature mass spectrometer</span>

A miniature mass spectrometer (MMS) is a type of mass spectrometer (MS) which has small size and weight and can be understood as a portable or handheld device. Current lab-scale mass spectrometers however, usually weigh hundreds of pounds and can cost on the range from thousands to millions of dollars. One purpose of producing MMS is for in situ analysis. This in situ analysis can lead to much simpler mass spectrometer operation such that non-technical personnel like physicians at the bedside, firefighters in a burning factory, food safety inspectors in a warehouse, or airport security at airport checkpoints, etc. can analyze samples themselves saving the time, effort, and cost of having the sample run by a trained MS technician offsite. Although, reducing the size of MS can lead to a poorer performance of the instrument versus current analytical laboratory standards, MMS is designed to maintain sufficient resolutions, detection limits, accuracy, and especially the capability of automatic operation. These features are necessary for the specific in-situ applications of MMS mentioned above.

<span class="mw-page-title-main">Matrix-assisted ionization</span>

In mass spectrometry, matrix-assisted ionization is a low fragmentation (soft) ionization technique which involves the transfer of particles of the analyte and matrix sample from atmospheric pressure (AP) to the heated inlet tube connecting the AP region to the vacuum of the mass analyzer.

Gas chromatography–vacuum ultraviolet spectroscopy (GC-VUV) is a universal detection technique for gas chromatography. VUV detection provides both qualitative and quantitative spectral information for most gas phase compounds.

References

  1. ↑ Vékey, Károly; Vertes, Akos; Telekes, András (2008). Medical Applications of Mass Spectrometry. Elsevier B.V. ISBN   9780444519801.
  2. ↑ Sharif KM, Chin ST, Kulsing C, Marriott PJ (September 2016). "The microfluidic Deans switch: 50 years of progress, innovation and application". Trends in Analytical Chemistry. 82: 35–54. doi:10.1016/j.trac.2016.05.005.
  3. ↑ Blomberg J, Schoenmakers PJ, Beens J, Tijssen R (1997). "Comprehensive two-dimensional gas chromatography (GC×GC) and its applicability to the characterization of complex (petrochemical) mixtures". Journal of High Resolution Chromatography. 20 (10): 539–544. doi:10.1002/jhrc.1240201005.
  4. ↑ Stoll DR, Wang X, Carr PW (January 2008). "Comparison of the practical resolving power of one- and two-dimensional high-performance liquid chromatography analysis of metabolomic samples". Analytical Chemistry. 80 (1): 268–78. doi:10.1021/ac701676b. PMID   18052342.
  5. 1 2 3 Skoog DA, West DM (2014). Fundamentals of Analytical Chemistry. United States of America: Cengage Learning. p. 816. ISBN   978-0-495-55828-6.
  6. ↑ McLafferty, Fred W. (October 1981). "Tandem Mass Spectrometry". Science. 214 (4518): 280–287. Bibcode:1981Sci...214..280M. doi:10.1126/science.7280693. JSTOR   1686862. PMID   7280693.
  7. ↑ Hites, Ronald (1986). "Gas Chromatography Mass Spectrometry" (PDF). Analytical Chemistry. 58. doi:10.1021/ac00292a767. hdl: 2445/32139 . S2CID   42703412. Archived from the original (PDF) on 4 December 2018. Retrieved 3 December 2018.
  8. 1 2 "Gas Chromatography Mass Spectrometry (GC/MS)". University of Bristol. Retrieved 3 December 2018.
  9. 1 2 Skoog DA, West DM, Holler FJ, Crouch SR (2014). Fundamentals of Analytical Chemistry (9 ed.). Brooks/Cole Cengage Learning. pp. 895–920. ISBN   978-0-495-55828-6.
  10. ↑ Hussain SZ, Maqbool K (2014). "GS-MS: Principle, Technique and its application in Food Science". International Journal of Current Science. 13: 116–126.
  11. ↑ Ong RC, Marriott PJ (2002). "A Review of Basic Concepts in Comprehensive Two-Dimensional Gas Chromatography". Journal of Chromatographic Science. 40 (5): 276–291. doi: 10.1093/chromsci/40.5.276 . PMID   12049157.
  12. ↑ Gu GC, David R, Peter Y (2016). "Application of LCMS in small-molecule drug development". European Pharmaceutical Review. 21 (4).
  13. ↑ Pitt JJ (February 2009). "Principles and applications of liquid chromatography-mass spectrometry in clinical biochemistry". The Clinical Biochemist. Reviews. 30 (1): 19–34. PMC   2643089 . PMID   19224008.
  14. ↑ Catrain, Anicet; Delobel, Arnaud; Largy, Eric; Van Vyncht, Géry (May 2016). "2D-LC–MS for the Analysis of Monoclonal Antibodies and Antibody–Drug Conjugates in a Regulated Environment". www.spectroscopyonline.com. Special Issues-05-01-2016. 14 (2): 29–35. Retrieved 2018-12-03.
  15. 1 2 3 Stoll DR, Carr PW (January 2017). "Two-Dimensional Liquid Chromatography: A State of the Art Tutorial". Analytical Chemistry. 89 (1): 519–531. doi:10.1021/acs.analchem.6b03506. PMID   27935671.
  16. ↑ NAGY, KORNÉL; VÉKEY, KÁROLY (2008), "Separation methods", Medical Applications of Mass Spectrometry, Elsevier, pp. 61–92, doi:10.1016/b978-044451980-1.50007-0, ISBN   9780444519801
  17. ↑ Bushey MM, Jorgenson JW (1990-05-15). "Automated instrumentation for comprehensive two-dimensional high-performance liquid chromatography/capillary zone electrophoresis". Analytical Chemistry. 62 (10): 978–984. doi:10.1021/ac00209a002. ISSN   0003-2700.
  18. 1 2 3 Carr PW, Stoll DR (2016). Two Dimensional Liquid Chromatography: Principles, Practical Implementation and Applications. Germany: Agilent Technologies, Inc. p. 1.
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