LC/MS Techniques Review: Molecular Identification & Quantitation

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MINI REVIEW ON LC/MS TECHNIQUES
Article · January 2016
DOI: 10.20959/wjpps20164-6581
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www.wjpps.com Vol 5, Issue 4, 2016. 2381
Saibaba et al. World Journal of Pharmacy and Pharmaceutical Sciences
MINI REVIEW ON LC/MS TECHNIQUES
S.V. Saibaba1
*, M. Sathish Kumar2
and P. Shanmuga Pandiyan3
1,2
Research Scholar, Mewar University, Rajasthan.
3
Supervisor, Mewar University, Rajsthan.
ABSTRACT
Liquid Chromatography/Mass Spectrometry (LC/MS) is fast becoming
the preferred tool of liquid chromatographers. It is a powerful
analytical technique that combines the resolving power of liquid
chromatography with the detection specificity of mass spectrometry.
Liquid chromatography (LC) separates the sample components and
then introduces them to the mass spectrometer (MS). The MS creates
and detects charged ions. The LC/MS data may be used to provide
information about the molecular weight, structure, identity and
quantity of specific sample components.
KEYWORD: Liquid Chromatography/Mass Spectrometry, mass spectrometer components.
INTRODUCTION
Liquid Chromatography/Mass Spectrometry (LC/MS) is fast becoming the preferred tool of
liquid chromatographers. It is a powerful analytical technique that combines the resolving
power of liquid chromatography with the detection specificity of mass spectrometry.[1-3]
Liquid chromatography (LC) separates the sample components and then introduces them to
the mass spectrometer (MS). The MS creates and detects charged ions. The LC/MS data may
be used to provide information about the molecular weight, structure, identity and quantity of
specific sample components.
Sample Types
LC/MS systems facilitate the analysis of samples that traditionally have been difficult to
analyze. Despite the power and usefulness of gas chromatography/mass spectrometry
(GC/MS), many compounds are impossible to analyze with GC/MS. LC/MS significantly
expands the effective analytical use of mass spectrometry to a much larger number of organic
compounds. Gas chromatography and GC/MS can be used to analyze a small percentage of
WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
SJIF Impact Factor 6.041
Volume 5, Issue 4, 2381-2395 Review Article ISSN 2278 – 4357
*Correspondence for
Author
S.V. Saibaba
Research Scholar, Mewar
University, Rajasthan.
Article Received on
20 Feb 2016,
Revised on 10 March 2016,
Accepted on 31 March 2016
DOI: 10.20959/wjpps20164-6581

the 9 million registered compounds. Because they impart little or no heat to the analyte
molecules, LC and LC/MS-based methods can be applied to most organic compounds.
Sample types range from small pharmaceutical compounds to large proteins. Because it is a
much more widely applicable method than GC/MS, LC/MS is suitable for the analysis of
large, polar, ionic, thermally unstable and involatile compounds. Some of these compounds
can be made amenable to GC/MS by derivatization, but LC/MS eliminates the need for time-
consuming chemical modifications. This permits MS analysis of non-volatile, thermally
labile, or charged molecules.[4,5]
Fig.1 applications of LC/MS techniques[6]
Selectivity and Sensitivity
A mass spectrometer combined with a liquid chromatograph can detect masses characteristic
of a compound or of a class of compounds. The system can selectively detect compounds of
interest in a complex matrix, thus making it easy to find and identify suspected impurities at
trace levels. When configured to simultaneously detect a range of masses (and depending on
the compound) LC/MS sensitivity can be comparable to that provided by a diode-array
detector (DAD). Far greater sensitivity is possible when the LC/MS is configured to detect
only those masses characteristic of the compounds being monitored.
Complementary Information
Using MS in combination with other LC detectors gives richer information. For example, a
DAD acquires data on selected ultraviolet (UV) and visible (Vis) wavelengths and spectra.
This information is useful for identifying unknown peaks and for determining peak purity or
for both.

An MS acquires mass information by detecting ions; it offers molecular-weight and structural
information. The LC/MS can be used with analytes that do not have chromophores. The two
orthogonal sets of data can be used to confidently identify, confirm, and quantitate
compounds. In addition, an LC/MS can be used as a highly selective and sensitive tunable
detector. An MS chromatogram for a single mass often produces an interference-free signal
that offers high precision and low minimum detection limits.
Using both a UV detector and a mass selective detector is more effective than using either
one alone. There are compounds (such as metabolites or degradents) for which the UV-Vis
spectra of two analytes will be very similar and it may be difficult to detect an impurity based
on UV spectra alone. It is also possible to have impurities that have the same mass, especially
at lower molecular weights. It is rare, however, for two components to have identical UV-Vis
spectra and mass. Figure 2 shows the ability to separate polymer components from an
unresolved peak using the information available in a mass spectrum. This separation would
not be possible using a conventional UV detector.
Figure: 2 Separation of isomers in a chromatographically unresolved peak[7]
Instrumentation
Interfacing LC and MS
There has been a major focus on improving the interface between the LC and the MS.
Liquid chromatography uses high pressure to separate a liquid phase and produces a high gas
load. Mass spectrometry requires a vacuum and a limited gas load. For example, common
flow from an LC is 1 ml/min of liquid which, when converted to the gas phase, is 1 l/min.
However, a typical mass spectrometer can accept only about 1 ml/min of gas. Furthermore,

an LC operates at near ambient temperature where as an MS requires an elevated
temperature. There is no mass range limitation for samples analyzed by the LC but there are
limitations for an MS analyzer. Finally, LC can use inorganic buffers and MS prefers volatile
buffers. Recent developments in atmospheric pressure ionization sources have expanded the
molecular weight, sample polarity, and flow-rate limitation of older LC/MS techniques. In
many cases, analysts are able to use unmodified high-pressure LC methods.
Atmospheric Pressure
Ionization
Atmospheric pressure ionization (API) techniques are soft ionization processes well suited
for the analysis of large and small, polar and nonpolar, labile compounds. These techniques
can be used to rapidly confirm the identity of a wide range of volatile and non-volatile
compounds by providing sensitive and accurate molecular-weight and fragmentation
information. API techniques can be used in metabolite confirmation analysis of most
pharmaceutical compounds, and other applications.
API-Electrospray
Application
API-electrospray (API-ES) is useful in analyzing samples that become multiply charged such
as proteins, peptides, and oligonucleotides, as well as in analyzing samples that are singly
charged, such as benzodiazepines and sulfated conjugates. API-ES can be used to measure
the molecular weights of most polymers, peptides, proteins, and oligonucleotides up to
150,000 Daltons quickly and with high mass accuracy. In biopharmaceutical applications,
chemists use API-ES to speed protein characterization, to accurately identify and characterize
post-translational modifications, and to quickly confirm the molecular weight of synthetic
peptides.
Process
API-ES is a process of ionization followed by evaporation. It occurs in three basic
steps: (1) nebulization and charging; (2) desolvation and; (3) ion evaporation.
Nebulization
The HPLC effluent is pumped through a nebulizing needle which is at ground potential. The
spray goes through a semi-cylindrical electrode which is at a high potential. The potential
difference between the needle and the electrode produces a strong electrical field.This field

charges the surface of the liquid and forms a spray of charged droplets. There is a concentric
flow of gas which assists in the nebulisation process.
Desolvation
The charged droplets are attracted toward the capillary sampling orifice. There is a
counterflow of heated nitrogen drying gas which shrinks the droplets and carries away the
uncharged material.
Ionization
As the droplets shrink, they approach a point where the electrostatic (coulombic) forces
exceed the cohesive forces. This process continues until the analyte ions are ultimately
desorbed into the gas phase. These gas-phase ions pass through the capillary sampling orifice
into the lowpressure region of the ion source and the mass analyzer, see Figure 3.
Figure: 3 API-electrospray ionization[8]
Atmospheric Pressure Chemical
Ionization
Application
Atmospheric pressure chemical ionization (APCI) is an ionization technique that is applicable
to a wide range of polar and nonpolar analytes that have moderate molecular weights.
Process
APCI, a process of evaporation followed by ionization, is complementary to API-ES.

Nebulization and Desolvation
APCI nebulization is similar to that in API-ES. However, APCI nebulisation occurs in a hot
(typically 250°C–400°C) vaporizer chamber. The heat rapidly evaporates the spray droplets,
resulting in gas-phase HPLC solvent and analyte molecules, see Figure 4.
Figure: 4 Atmospheric Pressure Chemical Ionization (APCI)
Ionization
The gas-phase solvent molecules are ionized by the discharge from a corona needle. In APCI
there is a charge transfer from the ionized solvent reagent ions to the analyte molecules in a
way that is similar to chemical ionization in GC/MS. These analyte ions then are transported
through the ion optics to the filter and detector.
Scan and SIM
Mass spectrometers can be operated in either a scan mode or a selected ion monitoring (SIM)
mode (Figure 5).
Figure: 5 Scan and SIM data acquisition[9]

Scan Mode
In the scan mode, the instrument detects signals over a mass range (e.g. from 50–2000 m/z)
during a short period of time (e.g. 2 sec). During this scan period, the MS electronics
sequentially read the signals detected within narrower mass intervals until the full mass range
is covered. The spectra that are stored represent the detected signal for the full mass range.
Since full mass spectra are recorded, this mode of operation is typically selected for
qualitative analysis, or for quantitation when all analyte masses are not known in advance.
Samples may be introduced into a mass spectrometer by infusion or through an HPLC. In the
latter, it is important to match the peak width and the scan range. The narrower the peaks, the
shorter the total scan time must be in order to get proper peak definition. In order to get a
short total scan time, it may be necessary to reduce the scan range.
SIM Mode
Mass spectrometers can also operate in the selected ion monitoring (SIM) mode. Rather than
scanning continuously, they can be set to only monitor a few massto- charge ratios (m/z). As
a result the quadrupole is able to spend significantly more time sampling each of the m/z
values, with a concomitant and large increase in sensitivity. Moreover, because the cycletime
between data points is often shorter than it is in scan mode, quantitative precision and
accuracy are improved through optimal peak-shape profiling. Since the m/z values to be
sampled must be set in advance, SIM is most often used for target compound analysis. For
analyses consisting of multiple target compounds, SIM ion sampling choices can be
timeprogrammed To match compound elution time windows. No data is collected at m/z
values other than those specifically sampled, so SIM is rarely used in qualitative analysis.
Collision-Induced Dissociation
MS/MS is accomplished by a process called collision-induced dissociation (CID) in which
ions break apart as a result of collisions with other molecules. Electrospray ionization can
also be used to produce CID spectra even with a single quadrupole system. In many
instances, a single quadrupole system can be used for work that has traditionally required
triple quadrupoles or ion traps. Electrospray is a soft ionization technique that produces a
large number of molecular adduct ions. Adduct ions are typically protonated parent ions
[M+H]+. These ions are guided into the vacuum region by applied voltages on lenses. By
changing the voltage, various degrees of fragmentation may be achieved. With a low voltage,
there is little fragmentation; with higher voltages, the parent ion is fragmented to a larger

degree. Electrospray CID has the advantage of more efficient transfer than in a triple
quadrupole. There are some limitations to using CID in a single quadrupole mass
spectrometer. In a triple quadrupole or ion trap, a single ion can be selected and fragmented.
In CID with a single quadrupole instrument, there will be multiple ions in the source that are
fragmented. These other ions may interfere with the analyte of interest by generating
additional fragments. In many cases, this problem can be solved by improving the
chromatography to isolate the analyte (Figure 6).
Figure: 6 CID with single quadrupole and triple quadrupole mass spectrometers
Adapting LC Methods[11-14]
Compared to previous LC/MS interfaces, the API-ES and APCI interfaces are relatively
rugged. In many cases, existing methods may be used with little or no adaptation. Some
instruments allow flow rates of 1 to 2 ml/min without splitting. One of the most critical
factors in adapting LC methods is the choice of buffer. Involatile buffers interfere with good
MS performance. For the best long-term perfomance, it is highly recommended that the
method be modified to use a volatile buffer. Modern mass spectrometer Designs incorporate a
number of features to increase their tolerance for involatile buffers. In the first-generation
systems, the spray from the LC was directed into the lens axis for quadrupole systems. In
newer designs, the flow is directed orthogonal to the lens axis and ions are focused into the
mass filter (Figure 7). The extraneous material is pumped away. Figure 8 shows a source that
had been subjected to 600 injections with a complex involatile salt solution (approximately 9
g/l). Even after this abuse, the performance was only slightly degraded. This ruggedness
makes this technique attractive for laboratories in which there are many users of the system

and in which large varieties of sample are commonly handled. The instrument does not need
to be finely adjusted for every sample.
Figure: 7. Orthogonal spray of APIelectrospray source
LC-MS/MS in drug metabolism & toxicology studies[15-18]
Studies of the metabolic fate of drugs and other xenobiotics in living systems may be divided
into three broad areas such as qualitative studies for elucidation of metabolic pathways
through identification of circulatory and excretory metabolites, quantitative studies for
determination of pharmacokinetics of the parent drug and/or its primary metabolites, and
mechanistic studies for identification of chemically-reactive metabolites, which play a key
role as mediators of drug-induced toxicities. The mass spectrometry has been regarded as one
of the most important analytical tools in studies of drug metabolism, pharmacokinetics and
biochemical toxicology. With the commercial introduction of new ionization methods such as
API techniques and the combination of LC-MS or LC-MS/MS, it has now become a truly
indispensable technique in pharmaceutical research. Triple stage quadrupole and ion trap
mass spectrometers are presently used for this purpose, because of their sensitivity and
selectivity. API-TOF mass spectrometry has also been very attractive due to its enhanced
full-scan sensitivity, scan speed, improved resolution and ability to measure the accurate
masses for protonated molecules and fragment ions. The study of the metabolic fate of drugs
is an essential and important part of the drug development process. The analysis of
metabolites is a challenging task and several different analytical methods have been used in
these studies. However, after the introduction of the API technique, ESI and APCI, LC-MS
has become an important and widely used method in the analysis of metabolites owing to its
superior specificity, sensitivity and efficiency. methods include product ion, precursor ion

and neutral loss scans . Metabolites are derivatives of the parent drug and as such it can be
assumed that many of the metabolites show the same fragment ions or neutral losses as the
parent drug. Therefore, the precursor ion and neutral loss scan modes with QQQ are
especially useful in group-specific detection of metabolites.[19,20]
To overcome the problems
in metabolic analysis, new technologies are continuously being developed. The recently
introduced LC-MS/NMR technology provides unambiguous structure characterization of
metabolites. Although the sensitivity of NMR does not suffice for the analysis of metabolites
in trace quantities, the sensitivity of the technology is continuously being improved. The use
of standards or radiolabeled compounds in quantitative analysis and thus the time-consuming
synthesis step of reference compounds can be avoided, when on-line coupling of LC-MS to
detection techniques that provide equimolar responses, such as ICP-MS or chemiluminescent
nitrogen detection, are used. Microfluidic systems offer possibilities to integrate all the
experimental steps of metabolite analysis on one microchip, providing complete analysis
steps (e.g. sample pretreatment, chemical reactions, analytical separation, and detection and
data processing steps) on a single device with a high level of automation. Progress in
microfluidics gives reason to assume that the metabolite analysis will be carried out by
miniaturized lab-on-achip techniques integrated with miniaturized mass spectrometers in the
near future.[21-23]
LC-MS/MS as quantification method for biogenic amines
The term biogenic amines refer to amine containing biogenic substrates such as
catecholamines, serotonin and histamine. Biogenic amines function throughout the body,
both in the central and peripheral nervous system. Disorders affecting their metabolism or
action can have devastating effects on homeostasis of the human body. In
www.intechopen.com 472 Tandem Mass Spectrometry – Applications and Principles clinical
chemistry quantification of biogenic amines is mainly used for diagnosis of neuroendocrine
tumors such as pheochromcytoma and carcinoids. HPLC coupled tandem MS is becoming an
indispensible technique in the special chemistry laboratories in clinical chemistry as it greatly
increases sensitivity and specificity of test results. Applying this technique will result in
improved biochemical diagnosis of endocrine disorders, and opens new roads to gain insight
in pathophysiological processes. For the measurement of biogenic amines in biological
matrices, LC-MS/MS needs to compete with conventional HPLC with UV, fluorescence or
ECD and to a lesser extend GC methods and immunoassay. In pharmaceutical industries and
toxicology laboratories, LC-MS/MS is the method of choice for the development and the

measurement of drugs. For clinical chemical analyses LC-MS/MS is rapidly emerging and is
applicable to a broad selection of compounds, especially for the diagnosis of aberrations
within the endocrine system, such as biogenic. Furthermore LC-MS/MS enable the use of
sophisticated sample pretreatment techniques and automation of the whole process by on-line
coupling of the separate techniques. To correct for losses during sample pretreatment, analyte
separation and detection, stable isotopes of analytes are used as internal standard with mass
spectrometry. LC-MS/MS combines the physical separation capabilities of HPLC with the
high analytical sensitivity, specificity and accuracy of mass spectrometric detection. In recent
years, LC-MS/MS equipment has been improved in performance. Due to its superior
specificity, shorter runtimes and less laborious sample preparation, LC-MS/MS methods
replace more and more of the conventional HPLC, GCMS and immunoassay techniques. LC-
MS/MS has, just as HPLC and GC-MS, the advantage that several compounds can be
measures simultaneously. Introduction of on-line solid-phase extraction coupled to LC-
MS/MS shortened chromatographic run times and allowed automation of sample
preparation.[24]
Urinary deconjugated metanephrines have been analyzed with LC-MS/MS for
many years. Since these markers occur in higher concentration ranges and require less
sensitive assays. Catecholamines assist in the diagnosis of neuroendocrine catecholamine-
producing tumors, such as pheochromocytoma and neuroblastoma, in addition to
metanephrine and HVA. Recently, an on-line SPE LC-MS/MS method has been described for
catecholamines in urine, especially improving specificity, sensitivity and run time compared
to the conventional HPLC-ECD method used on the same laboratory. Serotonin in blood is
mainly stored in platelets. Free serotonin occurs in low concentrations in plasma because of
active reuptake and fast metabolism which complicates detection with most conventional
techniques. Platelet serotonin is specifically measured for the detection of carcinoid tumors
that secrete little serotonin. With LCMS/MS, it is possible to measure accurate and
reproducible serotonin both in platelet-rich and plasma-poor plasma. For this purpose, protein
precipitation, using acetonitrile, combined with chromatography based on strong cation
exchange and reversed-phase interaction, was used with a total run time of 6 min and a
detection limit of 5 nmol/L. Solid phase www.intechopen.com Principles and Applications of
LC-MS/MS for the Quantitative Bioanalysis of Analytes in Various Biological Samples 473
extraction based on weak cation exchange and HILIC, comparable to the method described
for plasma metanephrines, resulted in the same run time with detection limits even below 1
nmol/L . Therefore, LC-MS/MS is becoming an indispensible tool for low-molecular weight
biomarker quantification also in the field of special clinical chemistry. It overcomes

drawbacks of conventional techniques, such as long analysis times and chance of
interferences, has a broad analyte compatibility and high analytical performance. It enables
more sensitive and specific measurement of biogenic amines and metabolites, and the routine
quantification of biomarkers in low concentration range0s.[25]
Usefulness of LC-MS/MS in doping control
LC-MS(/MS) has become an integral part of modern sports drug testing as it offers unique
capabilities complementing immunological and GC-MS(/MS)-based detection methods for
prohibited compounds. The improved options of fast and sensitive targeted analysis as well as
untargeted screening procedures utilizing high resolution/high accuracy MS have
considerably expanded the tools available to anti-doping laboratories for initial testing and
confirmation methods. One approach is to focus on preselected target analytes that are
measured with utmost specificity and sensitivity using diagnostic precursor–product ion pairs
in low resolution tandem mass spectrometers. The other scenario is to measure and plot
extracted ion chromatograms of protonated or deprotonated molecules as well as product ions
as recorded in the full scan mode with high resolution/high accuracy MS . For modern doping
control laboratories, the use of LC-MS(/MS) has become obligatory to meet the needs of fast,
robust, sensitive, and specific detection methods in sports drug testing. GC with or without
low or high resolution GC-MS held a superior position in routine doping controls until almost
the end of the last century, and various analytical challenges such as those presented by heavy
volatile or polar target analytes were successfully overcome, e.g., by means of sophisticated
derivatization strategies; a few aspects, however, remained unsolved by mass spectrometry,
particularly concerning high molecular weight analytes.[26,27]
LC-MS/MS in therapeutic drug monitoring for immunosuppressants
The outcome of post-transplantation patient care has been improved dramatically over the last
decades, primarily due to the availability of appropriate immunosuppressive regimens The
immunosuppressants present toxicity and have narrow therapeutic ranges. For example, CsA
showed numerous side effects including immunological, renal, hepatic and neurological
complications, requiring dose adjustments or discontinuations in a significant percentage of
patients. In addition, blood levels of the active drugs vary significantly in different
individuals and ethnicities as well as different combinations of immunosuppressants.
Therefore, the success of the post-transplant patient care largely depends on optimization of
immunosuppressive therapy based on routine therapeutic drug monitoring (TDM). The

available analytical methods for monitoring immunosuppressant levels in patient specimens
can be divided into two categories: immunoassays, such as microparticle enzyme
immunoassay (MEIA), enzyme multiplied immunoassay technique (EMIT), fluorescent
polarization immunoassay (FPIA), cloned enzyme donor immunoassay (CEDIA), and liquid
chromatography-based methods. Immunoassays are widely employed to measure
mycophenolic acid (MPA, active metabolite of MMF), CsA, tacrolimus, and sirolimus in
human blood or serum/plasma. Chromatography-based methods include high performance
liquid chromatography (HPLC) with ultraviolet detection, HPLC-MS, and HPLC-MS/MS.
HPLCMS/MS has gained increasing popularity in clinical laboratories due to the advantages
of the technology over other methods while the capital cost for instruments has been
decreased. HPLC-MS/MS provides high specificity and sensitivity for the above mentioned
immunosuppressants. In addition, HPLC-MS/MS is able to simultaneously measure several
drugs and/or their major metabolites in one single analytical run. The combination of HPLC
and MS has revolutionized the analytical society during the past decades. MS measures the
abundance of charged particles based on mass over charge ratio (m/z). MS/MS technique
utilizes multiple (two or more) MS with collision cell in between resulting in improved
specificity by providing characteristic molecular fragments (fingerprints) generated by
collision-induced dissociation. Because of high specificity of MS/MS detection, the baseline
separation of target compounds from their potential interferents by HPLC, which is a must
for many HPLC-UV or HPLC-MS assays, becomes unnecessary leading to significant
savings in analytical time, sample purification effort and chemical reagents.[28-32]
CONCLUSION
In this chapter, we reviewed basic principles and most recent advances of LC-MS/MS
methdology including sample preparation, seperation and MS/MS detection and appications
in the several areas such as quantification of biogenic amines, pharmacokinetic and TDM for
immunosuppresants and doping control. Until now, together with advancement including
automation in the LC-MS/MS instrumentations along with pararell sample processing,
column switching, and usage of more efficient supports for SPE, they drive the trend towards
less sample clean-up times and total run times–high-throughput
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