International Journal of Analytical Mass Spectrometry and Chromatography, 2013, 1, 31-47 Published Online September 2013 (
What Can Be Improved in GC-MS—When Multi Benefits
Can Be Transformed into a GC-MS Revolution
Aviv Amirav1,2*, Alexander B. Fialkov1, Tal Alon1,2,3
1School of Chemistry, Tel Aviv University, Tel Aviv, Israel
2Aviv Analytical Ltd, Tel Aviv, Israel
3Afeka College, Tel Aviv, Israel
Email: *
Received July 13, 2013; revised August 20, 2013; accepted September 15, 2013
Academic Editor: Ilia Brondz1,2
1Department of Biosciences, University of Oslo, Oslo, Norway; 2R&D Department, Jupiter Ltd.
Copyright © 2013 Aviv Amirav et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Gas chromatography mass spectrometry (GC-MS) is a widely used central analytical technology. Commercially avail-
able GC-MS systems use different types of mass analyzers such as Quadrupole, Ion Trap and/or Time of Flight, but
practically all systems utilize the same Nier type electron ionization (EI) ion source and the same standard GC-MS
transfer-line interface. Consequently, the various GC-MS vendors characterize their systems by a short list of specifica-
tions that relate to improvements in the technology of GC or of MS and not of the in terfacin g techn o logy and ion so ur ce.
This article presents a list of 62 ways in which the performance of GC-MS as a whole can be improved by an innovative
interface and ion source. Such an interface can possibly lead to a GC-MS revolution in a way that is similar to that
which is brought to Liquid Chromatography Mass Spectrometry (LC-MS) by the Electrospray ionization interface and
ion source and not by improvements to the technology of LC or MS. These 62 possible GC-MS improvements (grouped
into eight main categories) are not merely theoretical as they are provided by the Cold-EI GC-MS interface, which is
based on the ionization of vibrationally cold sample molecules in a Supersonic Molecular Beam (SMB) within a fly-
through ion source. An explanation and discussion is provided for each of these possible improvements.
Keywords: Gas Chromatography Mass Spectrometry (GC-MS); Supersonic Molecular Beams; Cold EI; Instrument
1. Introduction
GC-MS vendors typically describe and characterize their
systems using a small set of specifications that include
octafluoronap hthalene (OFN) signal to noise rat i o (SNR ) ,
mass range and scan speed. As a result, improvements in
GC-MS are often focused on the incremental increase of
these few specifications. However, GC-MS is character-
ized by many additional features and operational param-
eters that contribute to its performance, and their im-
provements can make a big impact on the GC-MS ana-
lytical capabilities. Many such GC-MS aspects are im-
proved by incorporating the new Cold-EI GC and MS
interface and ion source technology and by using “out of
the box” thinking. In LC-MS, the biggest revolution was
brought not by LC or MS improvements but rather by the
development of a new interface and ionization method
namely Electrospray. Similarly, Cold EI with its super-
son ic molecular beams interface and fly-through ion sour-
ce brings multiple benefits and improvements into GC-
MS which can initiate a new GC-MS revolution. This
manuscript lists 62 GC-MS improvements brought forth
by the Cold EI interface and ion source, encompassing
any and every important aspect of GC-MS, and explains
how the unique features of GC-MS with Cold EI enable
these benefits. When these multiple benefits come together,
they amount to a whole new GC-MS experience that we
believe is destined to ignite the next GC-MS revolution.
2. 5975-SMB GC-MS with Cold EI—The
Technology and System
GC-MS with Cold EI is b ased on the use of a Supersonic
Molecular Beam (SMB) as an interface between the GC
opyright © 2013 SciRes. IJAMSC
and MS and as a medium for the ionization of sample
compounds while they are cold in the SMB. Thus, the
Electron Ionization (EI) of cold molecules in SMB was
termed as “Cold EI”. Within this interface a supersonic
molecular beam is formed by the expansion of a gas
through a ~0.1 mm pinhole into a vacuum chamber.
During the expansion process the carrier gas (helium)
and heavier sample molecules obtain the same final ve-
locity so that the sample compounds are accelerated to
the carrier gas velocity, since it is the major gas mixture
component. This uniform velocity ensures slow intra-
beam relative motion, resulting in the cooling of the
sample compound internal vibrational degrees of free-
dom. SMB’s are characterized by the following features
of importance for mass spectrometry and GC-MS:
1) Super-cooling of the sample molecular vibrational-
rotational degrees of freedom.
2) Hyperthermal sample molecular kinetic energy (up
to 20 eV).
3) Unidirectional motion in space with heavy species
concentration along the beam axis (jet separation).
4) High column flow rate compatibility up to 100 ml/min.
These unique properties of SMB, which improve GC-
MS and GC-MS with Cold EI are explored by Amirav,
Gordin, Poliak, and Fialkov (2008) [1].
In Figure 1, a schematic diagram of GC-MS with
Cold EI is shown with its supersonic molecular beam
interface and fly-through ion source.
The basic standard GC-MS instrument modifications
for its conversion into GC-MS with Cold EI include:
a) The analytical column of a conventional GC with
unrestricted column type (ID), length and flow rate is
connected to a supersonic nozzle via a heated transfer
line and mixed with added helium make up gas (typically
60 ml/min).
b) Sampling to the MS vacuum system is in the form
of skimmed supersonic molecular beam, as the organic
sample compounds expand with the added make up he-
lium gas from the supersonic nozzle into a separately
(differentially) pumped nozzle vacuum chamber;
c) The electron ionization ion source is modified to
allow for unperturbed axial passage of the molecular
beam (fly-through) with a high (typically 8 mA) ionizing
electron emission current;
d) A suitable 90 degrees ion mirror is added to sup-
press mass spectral noise, keep the mass analyzer clean
and for minimizing the added bench space.
3. What Can Be Improved in GC-MS?
A list of 62 GC-MS improvements is presented below,
categorized into eight separate sections. The list includes
an explanation of the ways in which GC-MS with Cold
EI can provide these many benefits and improvements
via the unique properties of its interface and ion source.
One can clearly see that the list of possible GC-MS
improvements is far greater than commonly perceived
since most of these improvements are not mentioned in
any vendor specification or in any other type of publica-
tion or paper .
3.1. Improved Sample Identification
The coupling of Mass Spectrometry with Gas Chroma-
tography is aimed at improved samples identificatio n and
quantification versus GC-FID. While GC-MS excels in
sample identification its performance can be significantly
further improved in a few ways. These improvements,
when combined (as in the 5975-SMB GC-MS with Cold
EI) can provide significantly improved confidence level
in sample identification:
1) Enhanced molecular ions
The molecular ion is the single most important mass
spectral peak for sample identification. Standard EI pro-
duces molecular ions for about 70% of the samples and
as the sample compound gets bigger its molecular ion
relative abundan ce gets smaller . In Cold EI the molecu lar
cooling reduces the internal vibrational energy and thus
decreases the chance of fragmentation after the sample
compound impact with an ionizing electron and as a re-
sult the molecular ion abundance is enhanced. The de-
gree of Cold EI enhancement of the molecular ion is
small for small and rigid compounds (enhancement fac-
tor of near 1) while for large compounds it can be more
than 1000 times due to the large heat capacity of large
polyatomic compounds. The molecular ion enhancement
factor dependence on compound size was demonstrated
and discussed by Amirav, Keshet, and Alon (2012) [2].
The standard alternative to EI for the provision of mo-
lecular ions is chemical ionization (CI), however, while
CI (or APCI) provides molecular ions its response (ioni-
zation yield) is highly non uniform, certain compounds
are not properly ionized with it, its mass spectra are in-
compatible with library search, the closed CI ion source
induces peak tailing and sample decomposition even
more than standard EI ion source, and it adds cost and
requires venting for ion source replacement. Cold EI en-
hances the molecular ions which are provided for about
99% of the compounds combined with uniform ioniza-
tion yield and without any of the CI downsides as above.
2) Improved confidence in the identity of the molecu-
lar ions.
While the molecular ion can be found in standard EI
spectra, often it is weak and can not be trusted since it
can be suspected to be an impurity or matrix ion, vacuum
background or high mass sample fragment ion. In Cold
EI th e mo lec ula r io n c an b e tru st ed mo re than in s tand ard
EI. This is in part due to the enhancement of the relative
abundance of the molecular ion and in part due to the
elimination of vacuum background of ions with masses
above the molecular ion. Thus, the highest mass spectral
peak can be assumed with high confidence level to be the
Copyright © 2013 SciRes. IJAMSC
Copyright © 2013 SciRes. IJAMSC
Figure 1. A schematic diagram of the 5975-SMB GC-MS with Cold EI. It is based on the Aviv Analytical conversion of
Agilent 7890 GC + 5975 MSD (or 5977 MSD) into GC-MS with Cold EI. The various elements are indicated by their names.
molecular ion since it is fairly abundant and there is
nothing in the mass spectrum above it. In addition, the
use of low electron energy and or cluster CI (available
via a method change) can further serve to confirm the
molecular ion identity.
3) Improved library search and identification capabili-
One of the most important advantages of GC-MS and
its standard EI ion source is that EI mass spectra of about
600.000 compounds are available in extensive libraries
that enable easy to obtain, fast and automated identifica-
tion. Cold EI mass spectra, with their enhanced molecu-
lar ions, retain the lower mass fragments and are thus
fully compatible with library based sample identification.
Furthermore, while the enhancement of the molecular
ions reduces the library (such as NIST) matching factors
it often improves the library identification probability
factors since the matching to competing candidates is
largely reduced via the enhancement of the molecular ion,
as described by Amirav, and Alon (2012) [3]. Addition-
ally, the availability of the molecular ions provides a
good “manual” confirmation (or rejection) of the library
identification via the identity of the molecular ion and
enables its further automated confirmation or rejection
via isotope abundance analysis, such as with the TAMI
sof tw are (Alon, and Amirav, 2006 and also the Aviv Ana-
lyti c al Website-TA MI page ) [4,5], as des cribed be low.
4) Provision of accurate isotope distributions of the
molecular ions.
Cold EI provides abundant molecular ions with accu-
rate isotope distributions without any ion source related
self chemical ionization or vacuum background interfer-
ence, and thereby with unperturbed isotope distributions.
Isotope Abundance Analysis (IAA) provides important
information by itself (as used with isotope ratio MS and
for isotope labeling experiments) and enables the eluci-
dation of elemental formula of an analyte (Alon, &
Amirav, 2006) [4]. The Tal-Aviv Molecule Identifier
(TAMI) software [5] was developed in order to provide a
new method for identification, and even though it works
well with standard EI sources, it truly excels when a Cold
EI source is used. TAMI automatically converts the mo-
lecular ion group of isotopomers into elemental formulas
and automatically (zero clicks) confirms or rejects the
identification results of the NIST library. As a result,
Cold EI with TAMI provides the ideal and u ltimate sam-
ple identification technology for low cost unit resolution
quadrupole MS.
5) Provision of elemental formulas with unit resolution
quadrupole MS.
Clearly, it is highly desirable to be able to obtain ele-
mental formula from unit resolution quadrupole based
GC-MS systems. Along with the isotopomeric informa-
tion of the molecular ion which enables IAA as described
above, an identification procedure can and should con-
sider the exact mass of the molecular ion, even though a
quadrupole based ±0.1 amu mass accuracy is used (an
extended explanation is provided by Alon, and Amirav,
2013 [6]). GC-MS with Cold EI is superior to GC-MS
with high resolution TOF in the provision of elemental
formula since without trustworthy molecular ions
HR-TOF can not provide elemental formula, while Cold
EI provides it for extended range of compounds that are
amenable for analysis (The topic of extended range is
discussed in B below). The combin ation of library id enti-
fication which provides sample compound name and
isomeric structure with the TAMI software which pro-
vides automated library confirmation or rejection as well
as sample elemental formula (based on both IAA and
quadrupole based medium accuracy masses) plus the
Cold EI interface which provides those much needed
enhanced molecular ions, is superior to LC-MS based
sample identification as further discussed by Amirav
(2012) [7].
6) Increased isomer and structural MS information.
Standard EI mass spectra excel in the provision of in-
formative structurally related fragments (unlike with CI
or ESI) that can serve for structure elucidation as dis-
cussed in a few books. Cold EI further enhances high
mass fragments MS peaks and as a result provides even
more structural and isomer MS information as shown in
the analysis of drugs with the same elemental formula
but different structures (Amirav, 2012) [7] and in the
analysis of hydrocarbon isomers (Amirav, 2012) [8].
Clearly Cold EI is much closer to the ideal ion source in
the provision of abundant and informative high mass
spectral fragment peaks as these MS peaks can be related
to the molecular ion which is often absent in standard EI.
7) Fragmentation Tun ability.
Tunable fragmentation enab les the elucidation of order
of fragmentation hence helps to obtain the molecular
structure. In Cold EI in view of the elimination of intra-
ion thermal energy (which is controllable by itself, see
point 8 below), the electron energy is the only remaining
parameter that controls the intra ion energy, and the re-
duction of the electron energy allows better control and
reduction of the degree of molecular ion fragmentation.
While Cold EI does not provide full fragmentation con-
trol (in many cases the effect is small), it still clearly im-
proves on this feature in comparison with standard EI.
8) Classical EI mass spectra with the Fly-through ion
While Cold EI outperforms standard EI, some users
feel uncomfortable without the ability to obtain “classical
EI” mass spectra. Such mass spectra can be beneficial if
the need arises to distinguish between certain isomers via
the library. Cold EI, unlike CI, enables method based
(software controlled) easy and fast switching to “stan-
dard” EI for the provision of classical EI mass spectra.
This conversion is simply performed via lowering the
Cold EI make up gas flow rate to 5 ml/min without any
need to physically replace an ion source or open the
vacuum chamber (Gordin, Amirav, and Fialkov, 2008)
[9]. Furthermore, one can use slightly higher flow rate
and obtain slight enhancement of the molecular ions
which results in having the best matching factors with the
NIST library since the NIST search algorithm emphasis
the molecular ions (Gordin et al., 2008) [9].
9) Cluster chemical ionization (CCI).
Cluster CI mode of ionization is provided with the
fly-through ion source via a simple method based addi-
tion of methanol vapor from a methanol vial into the He-
lium make up gas (Fialkov, & Amirav, 2003 and also
Dagan, & Amirav, 1996) [10,11]. Cluster CI further en-
hances the molecular ions and results in having proto-
nated molecular ions and methanol satellite (M + 32
and/or M + 33) ions that serve to en sure the id en tification
of the molecular ions masses. This is possible as frag-
ments do not show such satellite peaks since the cluster
is the first to fragment. Cluster CI was found by us as
useful especially for the full confirmation of molecular
ions in the monitoring of synthetic organic chemical re-
10) Deut e rium Exc hange
Cold EI enables a unique mode of intra-nozzle deute-
rium exchange that helps in OH, NH and SH groups
identification for further improved structural and iso-
meric elucidation (Dagan et al. 1996) [11]. While deute-
rium exchange gains popularity in LC-MS due to its pro-
vision of valuable structural information, it is not used in
standard GC-MS. Probably this is since in standard
GC-MS costly deuterated solvents should be used while
the sample can re-exchange hydrogen in the column and
ion source. With Cold EI a small amount of deuterated
methanol or heavy water is used for many samples and
back exchange can not occur in the column or at the ion
source since the deuterated solvent is added after the
sample elution and the ion source is fly- through type.
11) Isomer Dist ri but i o n A nal y s is
As often the case, new instrument concepts leads to
the development of new and powerful methods of analy-
sis. The enhancement of the molecular ions obtained with
Cold EI and the unique availability of these important
ions for branched hydrocarbons and other types of iso-
mers led to the development of isomer distribution
(abundance) analysis. This type of analysis is an impor-
tant new method for fuel and hydrocarbon mixture char-
acterization via their origin unique isomer distribution
pattern. This important new method is discussed by
Fialkov, Gordin, and Amirav (2008) [12] and several
applications are presented online (Advanced GC-MS
Blog Journal) [13].
3.2. Extending the Range of Compounds
Amenable for GC-MS Analysis
It is well recognized and known that the Achilles heel of
GC-MS is its limited range of volatile and thermally sta-
ble compounds that are amenable for analysis. This limi-
tation emerges from GC injector, column and ion source
induced sample degradation and/or lack of sufficient va-
porization. The limited range of compounds amenable
for GC-MS analysis is further exacerbated by the fact
that the relative abundance of the molecular ion is re-
duced with the sample compound size (mass) and for
large compounds even if they elute, without trustworthy
molecular ions there can not be properly analyzed. In CI
the ion source limitation is even greater than in EI in
view of its closed structure. GC-MS with Cold EI en-
Copyright © 2013 SciRes. IJAMSC
ables significant extension of the range of compounds
amenable for analysis via the use of short columns with
high column flow rates in combination with full elimina-
tion of intra-ion-source degradation and exhibition of
abundant molecular ions. GC-MS with Cold EI provides
the ultimate range of compounds amenable for GC-MS
analysis and effectively bridges the gap between standard
GC-MS and LC-MS. The key parameter for this unique
capability is the use of very high column flow rates
which in combination with the use of shorter columns
leads to significantly (up to 200˚C) lower elution tem-
peratures, while the provision of the enhanced molecular
ions compensates for the traded GC resolution. High
column flow rate further reduces intra injector liner deg-
radation (lower elution temperature from the liner to the
column and reduced liner residence time) and intra-
ion-source sample dissociation is inherently avoided due
to the Cold EI fly-through ion source geometry. Fialkov,
Gordin, and Amirav (2003) [14] provide more details of
this important feature and our perception of the range
extension is further illuminated in Figure 2 and its cap-
tion. Improved GC-MS range of compounds amenable
for analysis can be separated into three groups as below:
1) Significantly extended range of thermally labile
compounds that are amenable for analysis.
The significantly lower elution temperatures from the
GC column in combination with the use of temperature
programmable injector with high injection flow rates
enables a major increase in the range of thermally labile
compounds that can be analyzed which is complemented
and supplemented by the Cold EI enhanced molecular
ions that proves the elution of intact thermally labile
sample compound. In fact, GC-MS with Cold EI is equi-
valent and even superior to LC-MS with APCI or APPI
in its range of thermally labile compounds that are ame-
nable for analysis. In APCI and/or APPI the sample is
Figure 2. A cartoon that demonstrates our perception of the
average sensitivity gain of Cold EI with the 5975-SMB ver-
sus sample mass, which at some point is transformed into
extended range of compounds ame nable for analysis.
thermally vaporized at a very hot vaporization (liner like)
oven (400˚C - 500˚C) where the sample stays for a short
time while in GC-MS with Cold EI the sample is vapor-
ized at much lower injector temperatures and spends
much longer time at the column at much lower tempera-
tures. Since the effect of thermal degradation exponen-
tially depends on the temperature, Cold EI can be gentler
to thermally labile compounds than APCI/ APPI.
2) Significantly extended range of low volatility com-
pounds that are amenable for analysis.
The significantly lower elution temperatures from the
GC column with high short column flow rates enables a
major increase in the range of low volatility compounds
that can be analyzed. It was found that it is possible to
approximately double the molecu lar weight and size limit
of compounds that can be analyzed (in comparison with
standard GC-MS) to about 1200 amu for non polar com-
pounds and 800 amu for polar compounds. In fact,
GC-MS with Cold EI is equivalent in its range of com-
pounds to LC-MS with APCI or APPI.
3) Significantly extended range of polar compounds
that are amenable for analysis.
The elimination of ion source tailing and degradation
on its metallic surfaces enables the analysis of many po-
lar compounds without their derivatization. One example
is given in the work of Amirav, Seltzer and Hefetz (2013)
on the analysis of free fatty acids in ant heads [15].
3.3. Speed—Faster GC-MS Analysis
The reduction of analysis time is an obvious needed
GC-MS improvement. While there are few ways to re-
duce the analysis time they are all involved with trade-
offs and thus fast GC-MS is an art of finding the optimal
trade-off. GC-MS with Cold EI enables the highest capa-
bility fast GC-MS, from the reduction or elimination of
sample preparation to the final fast analysis results. Ba-
sically, fast GC-MS is achieved based on the trade-off of
GC resolution for speed of analysis and compensation for
the sacrificed GC separation with enhanced separation
(selectivity) power of the MS and/or MS-MS via the en-
hancement of the molecular ion. A few GC-MS aspects
can be improved for achieving faster analysis as dis-
cussed below:
1) Faster splitless injection
In standard GC-MS the splitless injectio n takes a min-
ute plus another minute or more for the temperature of
the GC oven to rise and start the separation process, plus
another minute or more for cooling down from that initial
separation temperature to about 50˚C that is needed for
the splitless injection cryo -focusing. While split injection
can be much faster via avoiding the above wasted time
problems, it often involves with unacceptable signal loss.
GC-MS with Cold EI uniquely enables simple syringe
based fast splitless injections. With Cold EI, very high
Copyright © 2013 SciRes. IJAMSC
injection column flow rates can be used such as 30 - 60
ml/min hence the splitless in jection tak es a second or two,
similarly to a split injection, and it can be performed at
higher initial GC oven temperature, th ereby saving a few
precious minutes from the injection time, temperature
program rise and cooling down time.
2) Freedom in choice of the most suitable column.
Standard GC-MS typically uses 30 m columns with
0.25 mm ID and 1 ml/min column flow rate which re-
stricts the analysis time. The use of a shorter 0.1 mm ID
microbore column can shorten the analysis time by a
factor of 2.5 while retaining the separation but with a
trade-off of on-column sample amount, column loadabil-
ity (sample capacity) and column lifetime. Fast GC-MS
with Cold EI is characterized by an unrestricted selection
of column type, ID, length and flow rate and in this as-
pect GC-MS with Cold EI is similar to LC-MS in which
the user can select any column length, diameter and par-
ticle size for optimal trade-off of separation with speed of
analysis. Note that with the reduction of the column
length and/or increase in its flow rate, every reduction by
a factor of two of the GC separation peak capacity en-
ables four times faster analysis. Furthermore, while the
use of short columns facilitates faster analysis, the use of
high column flow rates is preferable since it can be con-
trolled without any hardware change and time pro-
grammed with sub second response time (unlike GC
oven temperature). As a result, GC-MS with Cold EI
enables the optimization of the GC-MS analysis method
for achieving the shortest analysis time while delivering
the needed results via an optimized selection of column
ID, length and flow rate.
3) Ultra-fast ion source response time.
While the fast GC-MS literature is full of discussions
conducted by proponents of time of flight MS about the
need for fast scan speed, no one mentions the equally or
even more important role of fast ion source response time
and elimination of ion source p eak tailing. In th e analysis
of semi-volatile and/or polar compounds GC-MS peak
tailing originates in the ion source due to its slow re-
sponse time and hampers the GC separation particularly
in fast GC-MS and/or GCxGC-MS. Cold EI on the other
hand is characterized by ultra fast sub millisecond ion
source response time and full elimination of any ion
source tailing. A full discussion of this aspect is provided
by Amirav, Alon, and Fialkov (2013) [16].
4) Compatibility with the scanning speed of quadru-
pole MS.
Quadrupole is the most widely used mass analyzer in
GC-MS. However, it has a somewhat limited scan speed
which today is in the 10,000 - 20,000 amu/s range by
most vendors. The us e of fast GC-MS through the use of
high flow rate and short widebore (0.53 mm ID) or stan-
dard narrowbore (0.25 mm ID) columns provides fast
analysis with peak width in the order of 0.5s (or more)
that are fully compatible with the scan speed of quadru-
pole MS that can exceed 20 Hz scan rate for 50 - 550
amu mass scan range.
5) Extract-free dirty sample introduction without
lengthy sample preparation.
While the chromatographic separation could be fast,
for truly fast analysis the time devoted for sample han-
dling and preparation must be reduced as well. The use
of the ChromatoProbe for sample introduction for its
intra GC injector thermal desorption facilitates extract-
free sample introduction for broad range of solid and
sludge samples and thereby reduces the time devoted for
sample handling and clean up. The use of the Chromato-
Probe with GC-MS with Cold EI benefits from a higher
possible injector flow rate for easier and softer sample
thermal desorption with higher recoveries. More infor-
mation on the ChromatoProbe is p rovide by Amirav, and
Dagan (1997) [17] and in the product website [18]. In
addition, using short colu mns and high co lumn flow rates
combined with flow programming at the end of the
analysis guarantees that every compound that is intro-
duced from the injector into the column is eluted. Con-
sequently, faster and simpler forms of sample preparation
such as immersion and injection can be practiced as de-
scribed in the analysis of synthetic cannabis performed
by Amirav (2012) [19].
6) Improved compatibilit y with low thermal mass ultra
fast GC.
When the sample contains several compounds with
broad volatility range, fast analysis requires using a low
thermal mass (LTM) fast GC that can provide fast tem-
perature programming rate. An LTM Fast GC was de-
veloped, which enables full analysis cycle time of under
one minute with temperature programming rate of up to
2000˚C/min and cooling back time of under 10 seconds
(Fialkov, Morag, and Amirav, 2011) [20]. GC-MS with
Cold EI is fully compatible with the LTM Fast GC use of
short columns and high column flow rates (Fialkov et al.,
2011) [20]. High column flow rates are highly desirable
for fast temperature programmed fast GC-MS in order to
elute the late eluting compounds before the high tem-
perature plateau end of analysis where the peaks can be
broadened and delicate samples can decompose.
7) Shorter sample handling time - Open Probe Super-
sonic Fast GC-MS.
The recently developed Open Probe Fast GC-MS is
the latest and most advanced development in the field of
real time analysis. In addition to real time analysis, and
unlike any other real time analysis technique, it also pro-
vides separation and library identification. The Open
Probe (Poliak, Gordin, and Amirav, 2010) [21] further
reduces the time devoted for sample collection and
preparation. Amirav, and Alon (2013) [22] provide fur-
Copyright © 2013 SciRes. IJAMSC
ther information on the Open Probe Fast GC-MS in-
cluding its comparison with DART and DESI.
3.4. Sensitivity
GC-MS sensitivity is its prime sp ecification and although
not very important for qualitative applications it serves
for many users as a symbol of the system quality. How-
ever, the OFN specification that is used to measure GC-
MS sensitivity is inappropriately provided by all GC-MS
vendors and does not properly represents the GC-MS
sensitivity (or LOD) as discussed by Fialkov, Steiner,
Lehotay, and Amirav (2007) [23] and further discussed
by Amirav (2012) [24]. The subject of GC-MS sensitiv-
ity is more involved than commonly perceived and GC-
MS sensitivity depends on several parameters and per-
formance features that can be improved as explained by
Fialkov et al. (2007) [23], by Amirav et al. (2008) [1]
and in the points listed below. As discussed below, Cold
EI improves the GC-MS sensitivity (lowers its LOD), the
5975-SMB GC-MS with Cold EI is the most sensitive
GC-MS and the harder the compound for analysis the
greater is the Cold EI gain in sensitivity.
1) Ion source signa l strength.
Standard EI ion source is operated with 30-100 µA
emission current and with few spiral paths of electron
motion that are magnetically confined. This ion source
provides good ionization efficiency which nowadays
approaches 0.1% at the ion detector (~600 OFN molecu-
lar ions per femtogram in SIM mode). The Cold EI fly-
through ion source is operated with 8 - 12 mA emission
current and with about three cycles for each ionizing
electron thus it is more sensitive th an standard EI despite
the ×10 faster motion velocity of sample compounds in
the SMB. However, SMB skimmer collimation losses
(×4 - 5) and ion mirror losses (×3) reduce the Cold EI
overall ion signal which is similar to that of standard EI.
The TIC signal of Cold EI is slightly (up to ×1.5) lower
than that of the Agilent 5975 EI ion source for small
molecules and higher (without limitation s) for large com-
pounds. Naturally, these numbers are time dependent as
improvements are steadily introduced and Cold EI as a
younger technology has a lot of potential for future im-
2) Ion source noise – The elimination of vacuum back-
ground noise.
Standard EI ion sources have two major noise sources,
vacuum background and helium metastable (neutral)
related mass independent noise. While the mass inde-
pendent no ise was recently su ppressed in stand ard EI ion
sources via the use of improved ion detector and ion op-
tics designs (such as the Agilent triple axis ion detector),
vacuum background still remains and is the most promi-
nent source of noise. While OFN specifications are ob-
tained in a mass spectral region that has a minimal vac-
uum background noise, with a new and clean vacuum
system and with electro-polished ion source surfaces
(that are scratched and become rough after the first ion
source cleaning), in real world applications vacuum
background could be high and severely limit the obtained
S/N. In Cold EI, vacuum background is filtered out in the
dual-cage fly-through ion source. This filtration is en-
abled due to the fact that sample compounds in the su-
personic molecular beam have a few eV directional ki-
netic energy, while vacuum background species have
non-directional <0.1 eV kinetic energy at the ion source.
Thus, the combination of directional SMB compound
motion and a small electrostatic repulsion potential in
one of the fly-through ion source lenses fully eliminates
vacuum background noise. This improved reduction of
noise level improves the obtained S/N in Cold EI which
are superior to any standard EI ion source and can lead to
noise free OFN mass chromatograms which allows OFN
1 pg RSIM S/N specification of any desirable value in-
cluding >10+6.
3) Elimination of mass independent noise.
Helium related mass independent noise is a one type of
noise that exists in all GC-MS systems. It emerges from
the co-formation of metastable helium atoms during the
electron ionization process, and these metastable atoms
can either directly ionize molecules upon collisions or
generate free electrons upon there scattering from sur-
faces that can directly contribute to noise or ionize sam-
ple and/or vacuum background compounds after the mass
analyzer. Recently, curved pre quadruple ion optics and
improved ion detectors with multiple axis ion paths sig-
nificantly reduced this type of mass independent noise.
However, the effect of such mass independent noise re-
duction on the overall sensitivity is limited since the most
important type of noise caused by vacuum background
still remained. In Cold EI vacuum background is fully
eliminated as above, making the elimination of mass in-
dependent noise a relatively more important task. In the
5975-SMB GC-MS with Cold EI a 90º ion mirror is used
in order to obtain further significant suppression of mass
independent noise, and as a result its mass independent
noise count rate is very low, below 5 ions/s.
4) Reduced column bleed and ghost peaks noise.
Column bleed with its multiple mass peaks of m/z =
73, 147, 207, 281, 355, 429, 503 etc. is a known major
source of noise that hampers the detection and identifica-
tion of low volatility compounds. In addition, ghost
peaks which belong to previous runs (sample compounds
that elute in the next few runs) further complicate and
increase the apparent column bleed noise. Cold EI en-
ables the use of shorter columns with higher column flow
rates and column flow programming at the end of the run.
As a result, the sample compounds elute at significantly
lower temperatures (Fialkov et al., 2003) [14] so that
Copyright © 2013 SciRes. IJAMSC
column bleed and ghost peaks noise can be eliminated
altogether. The lower elution temperatures and flow pro-
gramming column cleaning significantly reduce any
ghost peak. In addition, the use of transfer-line tempera-
ture programming further reduces PDMS related bleed
noise to a minimum and thus Cold EI is characterized by
exceptionally low no ise.
5) Enhanced molecular ions for improved sensitivity.
The molecular ion is by far the most informative and
selective ion. Thus, for the sensitive and selective detec-
tion of any compound it is advised to monitor it via its
molecular ion either in SIM or full scan RSIM modes.
Thus, the enhancement of the molecular ion directly im-
proves the sensitivity (lower LOD). In Cold EI the mo-
lecular ion is enhanced while keeping the total ion count.
The degree of enhancement can be small or modest for
small and rigid compounds such as benzene or OFN but
large, more than three orders of magnitude, for large ali-
phatic compounds as demonstrated and discussed by
Fialkov et al. (2007) [23], by Amirav et al. (2008) [1]
and by Amirav et al. (2012) [2]. As a resu lt, Cold EI par-
ticularly excels in the sensitive detection of large and
difficult to analyze compounds.
6) Reduced ion source peak tailing.
One of the adverse GC-MS EI ion source effects that
limits its sensitivity is ion source peak tailing. A small
chromatographic peak tail hides, like an iceberg, a sig-
nificant loss of TIC signal. Ion source peak tailing can be
reduced at increased EI ion source temperature but as the
ion source temperature is increased the molecular ions
are exponentially reduced for many classes of com-
pounds and intra-ion-source degradation is promoted. Ion
source peak tailing reduces the chromatographic separa-
tion, increases the signal RSD, lowers the sample signal
and increases its MS noise. With Cold EI, ion source
related peak tailing is fully eliminated in view of the use
of a contact-free fly-through ion source. Thus, as the
sample size and/or polarity are increased and its volatility
is reduced the gain in S/N with cold EI is significantly
increased. The tailing-free ultra fast ion source response
time is provided with Cold EI, regard less of the sample’s
volatility. Peak tailing, its consequences and the way to
eliminate it, are discussed by Amirav et al. (2013) [16].
7) Improved ion source inertness for increased range
of thermally labile compounds that are amenable for
Regardless of the selection of ion source materials and
the various claims made by vendors, standard EI ion
sources are active due to unavoidable contact of sample
compounds with metal surfaces, and since all metals act
as catalysts to degrade many types of organic compounds.
The use of electrically conductive materials such as met-
als is essential at the ion source to create optimal electric
fields in it. As a result, standard EI ion sources are not
inert and induce sample decomposition for many com-
pounds. Cold EI is an inherently inert ion source since it
uses a contact-free fly-through ion source configuration.
No sample contact inherently means no sample degrada-
tion at the ion source. This feature of ultimate ion source
inertness leads to enhanced sensitivity particularly when
it is most needed in the analysis of sample compounds
that are difficult to analyze such as thermally labile
8) Improved compatibility with large volume injec-
Large volume injection (LVI) is a known technique
that can improve the concentration sensitivity and pro-
vide lower detected concentration. It is usually per-
formed via the injection of larger than the standard 1 µL
sample volume with a temperature programmable GC
injector. However, at some point the injection of further
larger volume leads to increased column, liner and ion
source contamination while the increased signal is offset
by similarly increased matrix noise. With Cold EI the
matrix interference on the molecular ion is minimal
(Kochman, Gordin, Goldshlag, Lehotay, and Amirav,
2002) [25] thus Cold EI can further benefit from LVI.
Furthermore, with the use of short column and flow pro-
gramming at the end of the run, practically everything
that entered from the liner into the colu mn elutes, thereb y
keeping the column clean. Cold EI enables another con-
venient mode of “Larger Volume Injection” that utilizes
standard splitless injections with very high pulsed split-
less flow rates that are possible with short columns (such
as 30 - 60 ml/min). In such injections conditions, the
sample is vaporized and swept into the column at a rate
of >1 µL per second hence injection volume in the range
of 2 - 10 µL can be employed with standard injectors
without injector temperature programmin g and its related
loss of volatile sample compounds.
9) Reduced matrix interferences.
Matrix interference is the most important source of
noise that limits the LOD in the analysis of samples in
complex matrices such as drugs in urine or blood and/or
pesticides in agricultural products. However, it was
found that matrix interference is exponentially reduced
with mass by a factor of ~20 every 100 amu (Kochman et
al., 2002) [25] as also discussed in the work of Amirav
(2013) [26]. Thus, the enhancement of the molecular ions
in Cold EI enables the detection of the sample com-
pounds with significantly less matrix interference hence
with much lower LOD. In fact, the detection of pesticid es
in agricultural products via the molecular ions in Cold
EI is as selective and sensitive as their detection by
MS-MS on a fragment parent ion in standard EI. When
MS-MS is employed on the molecular ion the selectivity
is further increased and both first and third quad resolu-
tion can be opened fo r higher signal and sensitivity.
Copyright © 2013 SciRes. IJAMSC
10) Lower level impurities analysis.
Another type of “sensitivity” which is not often dis-
cussed regards low level impurities analysis in a given
material and the most known such requirement is in the
analysis of impurities in active pharmaceutical ingredi-
ents (API) or in simple terms the analysis of impurities in
drugs. This topic is separately discussed with examples
in the work of Amirav (2013) [27]. While initially such
analysis seems simple as the required detection limits are
typically 0.1%, in fact it is a challenging ap plication. The
challenge begins with the fact that uniform response is
needed in order to know the concentration of the impu-
rity without knowing its identity and without requiring a
lengthy procedure of impurity sample calibration. Two
factors are most detrimental for this type of analysis; a)
Drugs are typically polar compounds and so are most of
their impurities and even if they are thermally stable th ey
tend to saturate the column at <10 ng amount via the
formation of peak fronting. When the GC peak starts to
exhibit fronting it means that any additional on-column
sample amount will not increase the peak height but it
will only broaden the peak via its increased front hence
hamper the analysis of nearly co-eluting impurities. It
was found that most drug impurities are either isomers or
homologous and related compounds that elute near the
main API compound in GC-MS. b) Ion source related
peak tailing reduces the total ion count signal for polar
drug like compounds. When the column capacity is be-
low 10 ng and the TIC sign al to noise ratio is below 100
(peak to peak) for 1 ng impurities, at the 0.1% concentra-
tion level they are barely or not detected and certainly
can not be identifies. With Cold EI the peak tailing losses
are eliminated thus it provides better TIC sensitivity. In
addition, the use of high column flow rates increases the
column capacity which depends on the separation plate
film volume that linearly increases with the flow rate. As
a result, Cold EI excels in the analysis of impurities and
can detect 0.1% impurities with S/N >100 (peak to peak
noise) [27]. Recently, the need for genotoxic impurities
analysis is growing and in such analysis much lower
concentration detection limits are required.
11) Reduced limit of identification.
Often detection must includ e trustworthy iden tification.
While the subject of what is meant by identification is
not trivial it is easy to agree that improved identification
relates to improved total ion count signal to noise ratio
plus having more abundant sample compound character-
istic ions such as the molecular ions and high mass frag-
ment ions. Cold EI enhances the molecular ions and high
mass fragments and provides improved total ion count
signal to noise ratio that can be > 1000/ng.
12) More representative sensitivity specifications.
Clearly, the current use of OFN full scan RSIM speci-
fication is inappropriate and misleading (Amirav, 2012)
[24]. GC-MS sensitivity should be characterized by sev-
eral specifications given for a range of compounds that
include OFN (as the easiest to analyze compound) plus a
few other compounds that are gradually more difficult to
analyze. The test mixture of the Aviv Analytical 5975-
SMB GC-MS with Cold EI includes OFN, Hexadecane
(n-C16H34), Methylstearate, Cholesterol and n-C32H66.
Representative specifications can include: a) RSIM S/N
on all the mixture compounds; b) SIM S/N; c) OFN sig-
nal in number of molecular ions per femtogram; d) Total
ion count (TIC) S/N for all the test mixture compounds,
which in our opinion is the most representative sensitiv-
ity specification as it includes both signal and square root
of the background noise lev el; e) TIC ov er baseline ratios
which relate to the identification limits.
3.5. Uniform, Compound Independent Ion
Source Response
Uniform compound independent response is a highly
needed f eatur e which is ab sent in LC-UV and/or LC-MS.
GC with FID is well known to be a semi-quantitative
analytical tool while GC-MS is similar to GC-FID for
volatile sample compounds but its response uniformity is
eroded for semi volatile compounds due to ion source
related peak tailing. Uniform response provides the abil-
ity to know the relative amount of any unknown com-
pound or impurity without its separation, identification,
synthesis and the performance of compound specific cali-
bration curves. Thus, uniform response is of particular
importance in the areas of drug impurities analysis and
for the elucidation of chemical reaction yields as dis-
cussed in the work of Amirav on drug impurities analysis
(2013) [27] in the work of Amirav, Gordin, Belgorodsky,
Seeman, Gozin and Fialkov (2013) on the measurement
and optimization of organic chemical reaction yields [28]
and in the work of Amirav, Gordin, Hagooly, Rozen,
Belgorodsky, Seemann, Marom, Gozin, and Fialkov,
(2012) [29].
1) Uniform, compound independent ion source re-
The electron ionization cross section approximately
depends on the number of electrons in the sample com-
pounds hence on its molecular weight thus sample
weight. As a result, for volatile compounds the EI TIC
mass chromatograms provide uniform compound-inde-
pendent peak area responses, similar to those of GC-FID.
However, as the sample compound becomes bigger,
more polar and/or less volatile, ion source peak tailing
becomes more and more pronounced and consequently
the standard EI ion source response uniformity is eroded
and lost. Cold EI provides uniform response regardless
the sample volatility and provide it for about doubled
range of compounds amenable for analysis. This feature
is translated into a unique Cold EI capab ility—the provi-
Copyright © 2013 SciRes. IJAMSC
sion of chemical reaction yields, something that is miss-
ing in ESI LC-MS or standard GC-MS sys tems.
3.6. Improved GC-MS Compatibility with
Enhancement Technologies
Enhancement technologies are important add-on tech-
niques, devices and software that serve to further im-
prove the performance of GC-MS. Usually they are of-
fered as options to the basic GC-MS systems. Known
enhancements are the CI ion source, MS Probe, bigger
Turbo molecular pump, MS libraries, auto-samplers and
thermal desorption units. Clearly, improved compatibility
with enhancement technologies can further improve GC-
MS as descri b ed below .
1) MS Probe, ChromatoProbe and Intra Injector Ther-
mal Desorption Devices.
GC-MS can benefit from having MS probe. One type
of such MS probe is the ChromatoProbe sample intro-
duction device that provides fast probe sampling and
instant ChromatoProbe/GC-MS switching (Amirav et al.,
1997) [17]. The ChromatoProbe is based on the conver-
sion of a GC injector into an MS probe that accepts sam-
ples in micro-vials when the injector is connected to the
ion source via a short 1 m micro bore transfer-line. The
ChromatoProbe also uniquely enables the injection of
very “dirty” samples without any sample preparation
(Amirav et al., 1997) [17] when it serves as a thermal
desorption unit behind a standard analytical column. The
use of high flow rate with short transfer-line capillary
enables significantly extended range of compounds am-
enable for analysis with Cold EI and combined with the
fully inert Cold EI ion source and the provision of en-
hanced molecular ions the ChromatoProbe operation as
an MS probe excels and is more effective and informa-
tive with Cold EI than a standard Probe is with a standard
EI ion source. Similarly, intra injector thermal desorp tion
is more effective and can be performed at lower injector
temperatures when operated with higher column flow
rates that are possible with Cold EI.
2) Tal Aviv Molecule Identifier Software (TAMI).
The TAMI [5] provides automatic confirmation or re-
jection of NIST library search results and in case of a
rejection it performs an independent search for the ana-
lyte's elemental formula, providing a table of possible
elemental formula with a declinin g probability of match-
ing to the experimental isotope abundances and molecu-
lar ion measured mass even with unit resolution single
quad GC-MS. TAMI requires the provision of accurate
isotope abundances and thus, for proper compatibility
with it, the sample must exhibit abund ant molecular ions
free from vacuum background and/or residual ion source
self chemical ionization. Cold EI, unlike standard EI,
excels in the provision of such analysis conditions, and
provides trustworthy data for extended range of com-
pounds. Thus, a quadrupole based GC-MS system, cou-
pled with Cold EI, is more effective in the provision of
elemental formulae than expensive GC-MS with high
resolution TOF and standard EI.
3) Pulsed Flow Modulation GCxG C-MS.
An effective type of GCxGC modulation method
named pulsed flow modulation (PFM) was developed for
its combination with GC-MS (Poliak, Kochman, and
Amirav, 2008) [30] and also Poliak, Fialkov, and Amirav,
2008) [31]. It is a simple and low cost type of GCxGC
modulation method and device that does not require any
cryogenic gas or liquid. However, it requires compatibil-
ity with second GCxGC column flow rates of ~20
ml/min which is not a problem with FID, FPD or other
types of GC detectors but is incompatible with standard
GC-MS flow acceptance that requires significant flow
splitting. However, Cold EI is seamlessly compatible
with the pulsed flow modulation GCxGC flow rate re-
quirements, providing the ultimate in both sensitiv ity and
sample information.
4) Low Thermal Mass Fast GC for ultr a fast G C-M S.
Currently, a few low thermal mass fast GC systems are
available. The most widely used is of Agilent (prev iously
RVM). Recently, a unique LTM Fast GC was developed
with full analysis cycle times of under one minute (50 –
350 - 50˚C) with temperature programming rates of up to
2000˚C/min and cooling back time of under 10 seconds
(Fialkov et al. 2011) [20]. This “Supersonic Fast GC”
(possible future name) is fully compatible with the use of
any fused silica short column and high column flow rate
(Fialkov et al. 2011) [20]. However, one other feature
that needs to be improv ed in fast GC-MS is the ability to
perform fast splittless injections which require high
column flow rate. Furthermore, fast GC-MS analysis of
compounds in complex mixture requires the ability to
periodically trim the column due to matrix contamination
buildup at the front segment of the column near the liner,
and to be able to replace the column at low cost. All the
above mentioned improvements are uniquely met with
the combination of the LTM Supersonic Fast GC and
GC-MS with Cold EI (Fialkov et al. 2011) [20].
5) Open Probe Fast GC-MS.
The ultimate goal in fast analysis is to combine fast
separation with fast or no sample preparation in order to
approach the ultimate goal of real time analysis with
separation. Recently, a few types of real time analysis
techniques such as DART and DESI gained popularity,
but these methods suffer from several deficiencies and do
not provide separation and/or library based easy and
trustworthy identificatio n. As described in previous work
by Amirav et al. (2013) [22 ] and Po liak et al. (2010 ) [21 ],
the unique low thermal mass fast GC-MS was combined
with Cold EI and with a novel Open Probe inlet for
achieving fast sampling without sample preparation. The
Copyright © 2013 SciRes. IJAMSC
Open Probe is a probe-oven that is mounted onto the fast
GC and which is open to room air with helium purge
flow protection to eliminate air leakage. Thus, sample
handling and introduction is as simple and fast as touch-
ing the sample (with a swab or melting point glass tube)
and pushing it into the open probe. The Op en Probe Fast
GC-MS provides direct analysis in real time (DART) but
in comparison with other types of DART it uniquely
provides the following features:
a) Fast chromatography separation for improved mix-
tures analysis.
b) Library based sample identification is enabled co m-
bined with isotope abundance analysis software for best
c) Cold EI uniquely provides uniform compound in-
dependent response for improved quantitation. Further-
more, quantitation by Cold EI does suffer as ESI or APCI
from any ion suppression effects.
d) Extended range of thermally labile and low volatil-
ity compounds are amenable for analysis.
e) Swabs can be used to bring samples from remote
surfaces combined with full thermal desorption.
f) An in-vacuum ion source is used hence the instru-
ment cost less and the broad install base of Agilent
5975/7 GC-MS can serve for the accommodation of
Open Probe Fast GC-MS.
g) The same system can be operated with a second in-
jector as GC-MS.
h) No solvent is used unlike with DESI while the he-
lium gas consumption is about 50 times lower than in
In short, Open Probe Fast GC-MS with Cold EI estab-
lishes the ideal goal of achieving real time analysis with
separation and library based identification.
6) Electron Ionization LC-MS in GC-MS.
LC-MS can significantly benefit from having electron
ionization as it provides automated library identification
and extensiv e fragment information for imp roved sample
identification. In addition, EI does not suffer from ion
suppression effects that plague ESI or APCI and it
uniquely exhibits uniform compound independent ioni-
zation yield (in contrast to ESI) for improved quantita-
tion. Thus, bringing back EI to LC-MS is highly valuable
if a reliable and robust EI interface can be developed.
Furthermore, yet another highly desirable goal is to have
both GC-MS and EI-LC-MS in a one system with easy
method based switching between these two modes of
operation. A novel EI-LC-MS approach was developed,
based on interfacing LC and MS with supersonic mo-
lecular beams (SMB) and sample ionization with elec-
trons as vibrationally cold compounds in the SMB (Cold
EI) (Granot, and Amirav, 2005) [32]. The output of an
LC was vaporized behind a supersonic nozzle at about
0.1 Bar to suppress cluster formation yet to obtain effi-
cient vibrational cooling, and the sample compounds
expended into the vacuum system. Sample vaporization
is based on spray formation followed by fast, thermal
vaporization of the sample compounds prior to their ex-
pansion from the supersonic nozzle. It was demonstrated
that the stage of spray formation and vaporization can be
performed in a modified GC-MS injector that is coupled
to the nozzle via a short heated transfer-line. Conse-
quently, in a GC-MS with Cold EI one injector can serve
for GC-MS analysis and a modified second injector for
EI-LC-MS (Amirav et al., 2008 ) [1] .
7) Backflush.
Backflush is a known effective technique to maintain
clean GC columns when used in the analysis of complex
matrices. In backflush, at the end of the analysis, when
the GC oven is at its highest temperature or after the elu-
tion of the last to elute sample compound of interest, the
flow in the column is inverted via the provision of high
pressure at the end (or middle) of the column and low
pressure at the injector. As a result, heavy compounds
with low volatility that coat the early portion of the col-
umn migrate back the short distance to the injector and
are eliminated from the column. However, it was found
that some of the backflush devices are active and in-time
develop major peak tailing. Several backflush devices are
based on a metal structure that it deactivated by Silcos-
teel (Restek) thin fused silica film. This film can deterio-
rate after several heating and cooling cycles due to large
differences in the thermal expansion coefficients of fused
silica and stainless steel. Thus, while in sales demonstra-
tions backflush is very effective, after short usage some
devices become faulty and induce major peak tailing. A
unique ultimate inert backflush device was developed,
utilizing a simple 1/16” Swagelok T union that includes
in its straight path a glass tube with 1.2 mm OD and 0.7
mm ID. The column and transfer line ends are brought
inside this glass tube to a distance of ~1-2 mm while the
third (middle) input serves to bring about 1 - 2 ml/min
make-up helium gas from an EFC. This way, the added
gas flow rate dynamically focuses the output of the col-
umn into the transfer-line and the sample compounds do
not adsorb on any surface except the column and trans-
fer-line hence tailing is eliminated. This novel concep t of
gas dynamic flow focusing into a column was described
and demonstrated in our papers on pulsed flow modula-
tion GCxGC (both papers by Poliak et al. 2008) [30, 31].
While this backflush device is inert it requires the addi-
tion of some flow rate which is not an issue with GC-MS
with Cold EI but could be a downside in standard
8) Thermal Desorption and Purge and Trap.
While these known devices are effective their com-
patibility with GC-MS can be improved via the increase
of splitless column flow rate acceptance as provided with
Copyright © 2013 SciRes. IJAMSC
GC-MS with Cold EI.
9) Improved GC -MS-MS Per formanc e.
MS-MS is a powerful GC-MS enhancement technol-
ogy which helps particularly in the reduction of matrix
interference in the analysis of target sample compounds
in complex matrices. The major use of GC-MS-MS is in
pesticide analysis in agricultural products and drug
analysis in biological fluids. Cold EI can improve GC-
MS-MS performance in a few important aspects includ-
ing: A) Improved selectivity. Cold EI enhances the
abundance of the molecular ion which is the most selec-
tive ion in the mass spectrum. Furthermore, when the
molecular ion serves in MS-MS as the parent ion the
daughter ion mass is typically higher than when a frag-
ment is used as the parent ion. Consequently, the MS-MS
selectivity is significantly improved by an estimated two
orders of magnitude in the use of molecular ion instead
of a fragment ion as the MS-MS parent ion. B) Improved
instrument sensitivity. While MS-MS on the molecular
ion further reduces matrix interference it also serves to
increase the number of daughter ions signal hence the
instrument sensitivity. This improved MS-MS sensitivity
emerges in two ways of: 1) Molecular ions as parent
MS-MS ions require lower CID voltage and they disso-
ciate in the CID process into lower number of fragment
ions which are better retained by the RF only Q2. The
molecular ion is easier to dissociate than a stable frag-
ment ion that was formed in the EI process since abun-
dant fragments are abundant as they are typically stable
fragments and thus are harder to break. The higher typi-
cal CID voltage used with fragments creates more ener-
getic lower mass daughter ions that are harder to retain in
Q2. 2) The increased selectivity of MS-MS on the mo-
lecular ion can be translated into up to an order of mag-
nitude higher signal via the use of lower Q1 and Q3
resolution. C) Extended range of compounds amenable
for GC-MS-MS analysis. GC-MS-MS is mostly used
with groups of target compounds such as pesticides and
drugs, which include significant portion of thermally
labile compounds. As a result, GC-MS-MS suffers from
growing competition with LC-MS-MS on those types of
analyses. Cold EI enables the analysis of much greater
range of those pesticides and drugs and can even serve
for the analysis of pesticides that are difficult to analysis
by both GC-MS-MS and LC-MS-MS such as captan,
captafol and folpet. Furthermore, GC-MS-MS with Cold
EI can uniquely serve for the confirmation of LC-MS-
MS labile samples.
3.7. Improved GC-MS Flexibility, Ease of Use
and Price
While not often discussed, flexibility, ease of use and
price are all GC-MS parameters that can be improved
and this section describes several areas of their possible
1) Unlimited selection of column parameters.
In LC-MS unlike in GC-MS users can select broad
range of columns with various lengths, diameters, solvent
types and solvent flow rates while GC-MS is practically
restricted to 30 m columns with 1 ml/min helium flow
rate. In GC-MS with Cold EI, any column can be used
without restrictions on its diameter, length and flow rate.
This feature allows optimal trade off of GC resolution,
speed, sensitivity and range of compounds amenable for
analysis and it significantly simplifies analysis method
2) Number of columns that can be simultaneously con-
In GC-MS with Cold EI two columns can be simulta-
neously conn ected with the nozzle transfer line from two
different injectors. Even three columns can be simulta-
neously connected in GC-MS with Cold EI with an addi-
tional third injecto r such as the Optic of ATAS-GL. This
feature improves the GC-MS flexibility in a few ways
such as enabling fast screening with a short column fol-
lowed by confirmation with a longer column. Similarly,
it enables the use of one injecto r with th e ChromatoProbe
either as an MS probe or behind a separation column for
intra injector thermal desorption of solids or sludge sam-
ples while a second injector can serve for standard sy-
ringe based injections. In addition, one injector and col-
umn can serve for GC-MS analysis while the second in-
jector can be modified and serve for EI-LC-MS or flow
injection analysis as described in 40 above. Another
utilization of the possibility of using two columns that
are connected together to the Cold EI nozzle is to have
one injector devoted for standard GC-MS analysis while
the second column can be connected with an Open Prob e
Fast GC-MS as briefly described in 39 above. In short,
the ability of having two simultaneously connected col-
umns with the nozzle and Cold EI ion source is highly
desirable as it improves the system's flexibility.
3) Columns replacement and injector service without
breaking vacuu m.
One further aspect in which GC-MS can be improved
is to make its service easier via enabling the replacement
of its GC column and injector liner or septum without
venting the MS vacuum chamber and/or full injector and
transfer line cooling. For GC-MS with standard EI a few
“no-vent” devices were developed which require the ad-
dition of another EFC. In GC-MS with Cold EI the col-
umn output is design ed to be able to to lerate atmospheric
pressure and the make up gas EFC is already available.
Thus, during column replacement the nozzle flow rate is
increased to form nozzle pressure of 1100 mBar while
the injector flow rate is off (1 Bar pressure). As a result,
the column flow is reversed and thus liner or septa can be
replaced while the column is protected from air penetra-
Copyright © 2013 SciRes. IJAMSC
tion. Similarly, when the tran sfer-line is open for column
replacement helium flows out and purge protects the
transfer line from the penetration of air although small
amount of air flow is actually harmless to the fly-through
ion source when its filament is off.
4) Column flow programming and reduced column
flow rate effects on ion source response.
In standard EI the ion source is designed to maximize
the sample ionization yield at about 1 ml/min helium
flow rate. Above this flow rate the ion source response
begins to decline, so that a new tune is required, and
above a few ml/min the ion source response begins to
sharply reduce due to extended intra-ion space-charge
effects. In contrast, Cold EI has no ion source flow rate
effects. In Cold EI the nozzle back pressure is stabilized
at values of about 1 Bar (usually at 700 mBar) and as the
column flow rate is modified, the added helium make up
gas flow rate is automatically changed to maintain and
stabilize the set nozzle back pressure. Thus, the super-
sonic molecular beam pressure and effective helium flow
rate at the ion source is independent on the column flow
rate and consequently the Cold EI ion source response is
column flow rate independent. This feature opens new
and unique opportunities with column flow programming
to improve the range of compounds amenable for analy-
sis, keep the column clean from matrix compound depos-
its and speed-up the analysis (Amirav, 2012) [33].
5) Multiple ion sources operation modes and their fast
In most standard GC-MS (excluding ion traps) systems
the replacement of standard EI with CI ion source is
lengthy and requires venting and hardware change plus
added price. In GC-MS with Cold EI the same fly-
through ion source can serve in four modes of operation
that are interchangeable via a method change which takes
a few seconds or minutes, without any hardware change
and without added cost. The fly-through ion source can
be operated in th e following fo ur modes of Cold EI, Low
Electron Energy Cold EI, Classical EI-SMB and Cluster
CI. However, the best situation is to be ab le to work with
only one ion source and the fly-through ion source in its
Cold EI mode of operation is close to the id eal ion sou rce
that outperforms standard EI and CI combined as elabo-
rated throughou t this blog post.
6) Temperature programmable transfer line.
GC-MS transfer-lines are currently provided by all
vendors without temperature prog ramming cap ab ility and
thus are typically maintained at the upper GC oven tem-
perature specified in the method such as 300˚C. The
Aviv Analytical 5975-SMB GC-MS with Cold EI is
uniquely provided with transfer-line temperature pro-
gramming capability to improve the GC-MS perform-
ance in several aspects: A) In the analysis of a mixture of
compounds that includes a relatively volatile thermally
labile compound the transfer line is maintained at a rela-
tively low initial temperature such as 180˚C and only
after the elution of the thermally labile compound(s) its
temperature is increased to prevent peak broadening for
the late eluters. A typical example is the analysis of pes-
ticides that include the relatively vo latile thermally labile
carbamate pesticides (aldicarb, methomyl etc.) as well as
less volatile pesticides, and similarly explo sives mixtures
that include TATP; B) Lower initial transfer-line tem-
perature results in lower PDMS transfer line bleed hence
provide lower MS noise and increased sensitivity; C)
Every syringe injection includes about 0.5 - 1 µL air in
the empty portion of the syringe needle. Consequently,
even if the column is cooled during the injection, the
pure air that is inevitably injected interacts with the col-
umn at its transfer line section, induces PFMS bleeding
noise and makes this portion of transfer-line column ac-
tive with exposed silanol g roups. The use of temperature
programmable transfer-line significantly reduces this
7) Transfer-line temperature uniformity.
While not specified by any vendor, transfer-lines in-
herently suffer from having non–uniform temperature
along their axis which requires their extra heating to
prevent peak broadening which can induce delicate sam-
ple decomposition. While the GC side is actively cooled
by the GC oven, the ion source side is not fully heated by
the transfer-line heater due to limited heat transfer that
depends on the design. In fact, since the ion source tem-
perature is insulated from the transfer-line temperature a
local cold spot between them is inevitably formed. The
transfer-line of the Aviv Analytical 5975-SMB GC-MS
with Cold EI is designed with thick aluminum block
heater with 28 mm diameter for effective heat transfer to
both sides. In add ition, once the sample elutes behind the
nozzle it is mixed with 60 ml/min make-up gas, thereby
eliminating peak broadening at the inevitably cooler noz-
zle even if its temperature is 30˚C lower. Furthermore,
unlike in standard GC-MS transfer-lines, in GC-MS with
Cold EI the nozzle is more effectively thermally coupled
with the transfer line heater, thereby reducing any cold
spot between them. At the GC side, an aluminum jacket
transfers the heat from the transfer line heater block up to
the column entrance point to minimize any “dynamic
cold spot” that can be formed during fast GC oven tem-
perature programs.
8) High temperature GC operation in GC-MS.
In GC-MS with standard EI the current industry stan-
dard for upper transfer-line and ion source temperatures
is 350˚C. This upper limit restricts the range of low vola-
tility compounds that can be analyzed and in addition, as
the ion source temperature is increased, the relative
abundances of the molecular ions are exponentially re-
duced. In the 5975-SMB GC-MS with Cold EI the ion
Copyright © 2013 SciRes. IJAMSC
source is of a fly-through design hence its temperature
(typically 400˚C) is irrelevant for the analysis. The
transfer-line temperature is limited to 350˚C although a
higher temperature version is offered. On the other hand,
the use of short column with increased column flow rate
enables the analysis of low volatility sample compounds
up to and beyond the mass limit of the 5975 MSD of
1050 amu. However, the penalty for using shorter col-
umns with high column flow rates is in having somewhat
reduced chromatographic separating by about a factor of
2 peak capacity per 40˚C lower elution temperature. As a
result, it is beneficial to analyze complex mixtures of
stable low volatility compounds using high temperature
standard length columns (15 - 60 m) with GC oven tem-
peratures up to 420˚C. The 5975-SMB GC-MS with Cold
EI enables such high temperature analysis with a back-
flush T union device that adds flow rate to the transfer
line, and thus with the use of 1 ml/min column flow rate
and 16 ml/min added make up gas at the transfer line, the
GC oven can be heated up to 420˚C without transfer-line
induced peak broadening even if the transfer line is at
350˚C. As a result, low volatility compounds can be
analyzed with improved separation.
9) Compatibility with hydrogen or nitrogen carrier
In certain cases the helium supply could be interrupted
and one might wish to consider working with hydrogen
or nitrogen as the carrier gas. The use of hydrogen with
standard EI could lead to the chemical activation of the
GC liner and ion source, while the use of nitrogen sig-
nificantly reduces the ion source ionization yield due to
significantly (x7) increased ion source space charge
(Amirav, & Alon, 2012) [34]. Cold EI can uniquely op-
erate with nitrogen as the column carrier gas and hydro-
gen as make up gas with minimal loss in sensitivity
(Amirav, 2013) [35].
10) Ion source robustness.
Ion source robustness is an important feature of any
ion source. In standard EI the ion source requires peri-
odic cleaning with an abrasive material to remove po-
lymerized insulating material from its metal surfaces.
The Cold EI fly-through ion source is highly robust and
requires very little maintenance since ~75% of the sam-
ple compounds are eliminated by the entrance skimmer
and from the rest 90% fly through the ion source thus
only 2% of the sample compounds scatter from the hot
(400˚C) and large ion source surface area. In addition,
the quadrupole also remains clean as the ion source is
separated from the quadrupole mass analyzer by a 90˚
ion mirror.
11) Ion source temperature-independent mass spectra.
Obviously users want their GC-MS to provide repro-
ducible mass spectra regardless of the ion source condi-
tions and temperatures. However, the ion source tem-
perature strongly affects the obtained standard EI mass
spectra. For example, as demonstrated and explained
(Amirav et al., 2013) [16], the relative abundance of the
molecular ion is exponentially reduced with the ion
source temperature. In Cold EI the ion source tempera-
ture is irrelevant to the Cold EI mass spectra which are
reproducibly obtained. In addition, the Cold EI fly-
through ion source is self-cleaned and provides Cold EI
MS with little effect of extended use.
12) Bigger GC-MS system pump.
Currently there is a trend of increasing the size of the
GC-MS vacuum system pump and older systems with 70
L/s turbo molecular pumps are being replaced by new
GC-MS systems that are offered o nly with bigger 250 L/s
pumps or split turbo molecular pumps for having differ-
ential pumping. In fact, currently all GC-MS vendors sell
their systems either with big (performance) turbo mo-
lecular pump or with split (differentially pumped) turbo
molecular pump. Clearly, with a bigger vacuum pump,
pump down time is faster, vacuum background noise is
lower and the maximum allowed input flow rate is higher.
Thus, the competition on increased OFN specification
leads to increased vacuum pump pumping speed despite
the added cost. GC-MS with Cold EI includes an addi-
tional differentially pumped vacuum chamber with 250
L/s turbo molecular pump, allowing a record high col-
umn flow rate (up to 100 ml/min) and fully eliminates
vacuum background, thus achieving the most from the
addition of a differential pumping stage. This trend of
using “big” or dual stage pumps reduces the added cost
gap between standard GC-MS and GC-MS with Cold EI.
13) Easier and more flexible method development.
For optimal GC-MS operation its method of operation
should be tailored to the analysis task. For example, in
service GC-MS samples significantly vary in terms of
sample types, volatility, thermal stability, and the need
for side products identification. As a result, an improved
GC-MS system should enable flexible and easy method
development, particularly in terms of flow programming
and the use of short co lumns as provided by G C-MS with
Cold EI.
14) Demonstration of benefits in challenging applica-
tions and new analy s i s methods.
Every GC-MS vendor praises its system with all the
buzzwords and superlatives. All the GC-MS vendors
further provide application notes, but these notes mostly
demonstrate their system use in standard applications and
thus are mostly a “me too” type of statement. However,
GC-MS systems should be further evaluated via the
availability of application notes and demonstrations of
the claimed benefits in the analysis of challenging appli-
cations. A large amount of demonstrations of unique and
challenging applications are published in the Advanced
GC-MS Blog Journal [36]. Furthermore, with Cold EI
Copyright © 2013 SciRes. IJAMSC
multiple benefits are sometimes combined into the de-
velopment of unique new analysis methods such as iso-
mer distribution [13], universal pesticide analysis method
(Amirav, January 2013) [37], the determination of
chemical reaction yields (Amirav et al. 2012) [29] and
(Amirav et al., 2013) [28] and a few other methods as
described in several blog posts. Finally, the ultimate sys-
tem test is in its applicability to user's specific applica-
tions and goals based on user samples that may serve as
the ultimate system performance test and demonstration.
15) Price.
This is the bottom line for many users. The price of
GC-MS with standard EI ion source is moderate. The
price of GC-MS with Cold EI ion source can be similar
to that of standard EI if a fully integrated ion sour ce will
be available as can be achieved by a company that will
produce a full GC-MS with Cold EI system. The Aviv
Analytical 5975-SMB GC-MS with Cold EI serves as an
add-on system and thus it about doubles the price of sin-
gle quad GC-MS but this high price emerges not from
the technology itself but rather from the fact that all its
components are doubled (vacuum chamber, turbo pump,
ion source, transfer line etc).
3.8. Improved Utilization of Mass Analyzer
The mass analyzer specifications clearly belong to “what
can be improved in GC-MS”. Initially, even though these
mass analyzer specifications are not affected by the in-
terface and ion source performance, they are coupled and
the improvement of an interface’s characteristics can aid
or increase the benefits provided by the mass analyzer.
Thus, a close examination of these aspects reveals that in
fact Cold EI enhances th e benefits from and utilizatio n o f
all the mass analyzer specifications.
1) Improved benefit from extended mass range.
The mass range is a parameter that is specified by all
GC-MS vendors. Typically it is from low mass up to and
over 1050 amu. While such mass range is sufficient for
standard GC-MS operation since very few compounds
with molecular mass of over 1050 amu can elute from
standard GC-MS column, GC-MS with Cold EI can
serve for the analysis of much bigger compounds (about
doubled mass range) and thus can benefit from improved
higher mass range specification. Such large compounds
with mass over 1050 amu not only can elute but they also
provide useful molecular ions in Cold EI.
2) Improved benefit from higher mass resolution.
Higher mass resolution serves mostly for the reduction
of matrix interference. However, in order to benefit from
the reduction of matrix interference the sample com-
pound must first elute and as described above (points 12
- 14) the Cold-EI interface enables the analysis of a
greater range of compounds. Furthermore, Cold EI also
improves the rejection of matrix interference via the en-
hancement of the molecular ion (Amirav, 2013) [26]. As
a result, the effect of high resolution is amplified with
Cold EI and the combination of high resolution and en-
hanced molecular ions can provide the ultimate selectiv-
ity and matrix interference rejection.
3) Improved benefit from higher mass accuracy.
High mass accuracy serves for the elucidation of ele-
mental formulas. However, for such service, the sample
compound must first elute and than it must exhibit a
trustworthy molecular ion. Cold EI excels in comparison
with standard EI in both of these aspects thus amplifies
the benefits of high mass accuracy. In addition, the
TAMI software [5] can combine the high mass accuracy
with isotope abundance analysis for obtaining highly
improved provision of elemental formula (Alon et al.,
March 2013) [6].
4) Improved benefit from faster scan speed.
Scan speed is a typical specification highlighted by
those vendors who sell GC-MS with time of flight MS.
However, the reality is that for fast GC-MS there is no
need for scan speeds that are faster than that which is
provided by current modern quadrupoles, which is
20,000 amu/s (40 Hz for mass range of 50 - 550 amu).
Only for GCxGC-MS with thermal modulation, in some
cases it is desirable to have higher scan speed. However,
fast scan speed alone is insufficient for GCxGC-MS
since for semi-volatile, low volatility and polar com-
pounds ion source related peek tailing broadens the GC
peaks and hampers the GCxGC resolution. As a result,
the ion source temperature must be increased to reduce
this ion source peak tailing in order to benefit from the
fast scan speed and narrow peaks. However, one must
remember that an order of magnitude narrower peaks (as
claimed for GCxGC-MS by the TOF companies) requires
70˚C higher ion source temperature than what is needed
for standard GC-MS and this 70˚C higher ion source
temperature exponentially reduces the molecular ions
and mass spectral information content plus induces ion
source degradation for many labile compounds. Cold EI
eliminates these problems, provides sub millisecond ion
source response time regardless of the sample com-
pounds’ volatility or polarity (due to its fly-through op-
eration) and also provides enhanced molecular ions with-
out ion source temperature issues. Thus, since GCxGC-
MS is all about information, faster scan speed shines
brighter with Cold EI as their combination uniquely en-
ables the analysis of very narrow GCxGC peaks of semi-
volatile compounds.
4. Discussion
This post article elaborates on the subject of “what can
be improved in GC-MS” and describes sixty two areas of
improvements and how they can be obtained via the use
Copyright © 2013 SciRes. IJAMSC
of the GC-MS with Cold EI with its supersonic molecu-
lar beams interface, fly-through ion source and other
supporting compatible technologies. Naturally, some im-
provements are more important than others and for ex-
ample the extension of the range of compounds amenable
for analysis is arguably the most important advantage of
GC-MS with Cold EI since it bridges the gap between
GC-MS and LC-MS and opens up new areas of analysis
and applications. As a result, GC-MS with Cold EI can
induce total GC-MS market growth. Quoting Aristotle
“The whole is greater than the sum of its parts” and
similarly, the combination of so many improvements
creates a new and qualitatively superior technology that
actually improves every type of analysis. While GC-MS
with Cold EI improves challenging analyses it does not
impede on any simple method of analysis (compared
with standard EI) and its added cost could be negligible
in a fully integrated GC-MS with Cold EI. Consequ ently,
GC-MS with Cold EI is destined to become the future
GC-MS rev oluti on.
As a good closure of this article, we quote Freeman
Dyson fr om his book “Imagine d Worlds”:
New directions in science are launched by new tools
much more often than by new concepts. The effect of a
concept-driven revolution is to explain old things in new
ways. The effect of a tool-driven revo lution is to discover
new things that have to be explained.”
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