Professional Documents
Culture Documents
Review
a r t i c l e
i n f o
Article history:
Received 20 February 2012
Received in revised form 17 April 2012
Accepted 18 April 2012
Available online 24 April 2012
Keywords:
Tandem mass spectrometry (MS/MS)
Gas-phase enantiomeric separation
Quantitative chiral analysis
Three-point interaction
Pharmaceutical and biological applications
Quality-by-design (QbD)
a b s t r a c t
Chirality has been of great interest in pharmaceutical and biological sciences. The capabilities of mass
spectrometry (MS) for rapid analysis of complex mixtures have encouraged its exploration for gas-phase
chiral differentiation. Although particular instances of successful discrimination between enantiomers
have been reported over the past three decades, a general method of quantitative chiral analysis by MS
has only been demonstrated recently. This review describes the current state of the chiral MS methods without chiral chromatographic separation, which fall into ve main categories: (1) the kinetic
method, (2) hostguest (HG) diastereomeric adduct formation, (3) ion/molecule (equilibrium) reactions, (4) collision-induced dissociation (CID) of diastereomeric adducts, and (5) the emerging technique
for gas-phase separation using ion mobility spectrometry (IMS). It emphasizes tandem mass spectrometry (MS/MS), which provides several unique analytical advantages for quantitative chiral analysis. These
include intrinsically high sensitivity, molecular specicity, and tolerance to impurities as well as the simplicity and speed of the mass spectrometric measurements. Practical prospects and current challenges
in quantitative chiral MS techniques for QbD (quality-by-design)-based pharmaceutical applications are
also discussed.
2012 Elsevier B.V. All rights reserved.
Contents
1.
2.
3.
4.
5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Fundamental interactions to achieve chiral recognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Advances in gas-phase mass spectrometric methods for chiral analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
The kinetic method formalism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.1.
Dissociation of cluster ions using the kinetic method formalism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.2.
Chiral analysis of binary mixtures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.3.
Improvements in the kinetic method for chiral analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Hostguest diastereomeric adduct formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.1.
Enantiomer labeled-host method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.2.
Determination of ee by the EL-host method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.3.
Types of host compounds used for the EL-host method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.
Ion/molecule (equilibrium) reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.
Collision-induced dissociation of diastereomeric complex ions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Recent advances in ion mobility spectrometry for chiral analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.
FAIMS technique. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.
DMS technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3.
Traveling-wave IMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pharmaceutical and biological applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.
Enantiomeric determination of L-nucleoside analogs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.
Enantiomeric quantication of generic chiral drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3.
Method development and validation for chiral purity determination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Corresponding author. Tel.: +1 610 270 4936; fax: +1 610 270 6185.
E-mail address: lianming.2.wu@gsk.com (L. Wu).
0731-7085/$ see front matter 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jpba.2012.04.022
134
134
137
138
138
138
139
139
139
140
140
140
141
141
141
141
142
142
142
142
142
134
L. Wu, F.G. Vogt / Journal of Pharmaceutical and Biomedical Analysis 69 (2012) 133147
5.4.
On-line LC-MS/MS chiral analysis by the kinetic method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.5.
Gas-phase chiral separation by ion mobility spectrometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Concluding remarks and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.
1. Introduction
Life itself has been under the constant inuence of chiral forces,
from the initial chemical processes that led to homochirality in
molecules right through the evolutionary processes that resulted
in the present diversity of biological forms [1,2]. Chirality is an
intrinsic property of the biomolecular building blocks of life, being
incorporated into the essential components that are necessary for
life such as amino acids, sugars, proteins, nucleic acids, and polysaccharides [3,4]. The use of enantiomerically pure compounds as
drugs has continuously attracted much interest in pharmaceutical industry. This is reected by the extensive investigation of
chiral bioactivity of drug molecules including their pharmacology and toxicology [59]. Individual enantiomeric forms of drugs
can produce different therapeutic (or adverse) effects and may be
metabolized at different rate or even by different pathways [10].
As a result, optically pure drugs account for more than 50% of the
total investigational new drugs (INDs) that have been approved by
the US Food and Drug Administration (FDA) since the year of 1999
(Fig. 1) [11]. In addition, among the top ten drugs in sale in the year
of 2010 eight are chiral drugs (Table 1).
Following the current FDA guidelines that recommend the study
of enantioselective identity and stability for the contributions of
individual enantiomers to pharmacological and toxicological activities, it is essential to develop quantitative analytical assays for
qualication of individual enantiomers in samples to support pharmacology and toxicology studies in drug development [79]. These
rules have encouraged pharmaceutical companies to explore new
technologies (in addition to chromatographic methods) for chiral
analysis that are not published in the United States Pharmacopeia
(USP) [12].
Quality-by-design (QbD) is a systematic approach to drug development, which begins with predened objectives, and uses science
and risk management approaches to gain product and process
understanding and ultimately process control [13]. The concept of
QbD has been extended to analytical methods [14]. QbD requires
the denition of a goal for the method, and emphasizes thorough
evaluation and scouting of alternative methods in a systematic
Racemate
Single enanomer
Achiral
80
70
Percentage (%)
60
50
40
30
20
10
0
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
Year
Fig. 1. Drugs approved by the US Food and Drug Administration (FDA) from year
1999 to 2008 (ref. [11]).
144
144
144
145
145
way to obtain optimal method performance. For chiral drug compounds, additional considerations are required for scientic and
regulatory aspects of quality control including (1) selection of a
candidate optical isomer to develop (e.g. a racemic mixture vs. a
single enantiomer); (2) prevention of racemization in vivo; and (3)
quantitation of the levels of stereoisomeric impurities (e.g. safety
assessment by toxicity qualication). The International Conference
on Harmonisation (ICH) guideline (ICH Q6A) requires the use of
robust chiral test methods to obtain proof of absolute chiral congurations and chiral purity. For single enantiomer drugs, chiral
identity is typically a part of the drug substance specication for
batch release. Minor enantiomers that are normally considered as
the critical quality attributes (CQAs) are required to be controlled
in drug substances [15]. In addition, chiral analysis is necessary to
determine if racemization occurs during drug product manufacture
and storage. Consequently, chiral analysis is vital to design space
in terms of (1) determination of critical process parameters (such
as enantiomeric excess (ee) of chiral auxiliary, temperature, crystallization parameters, etc.) that are required in order to control
the minor enantiomers in drug substances during manufacturing
process; and (2) scientic judgments about if enantiomeric quantitation of the upstream intermediates can be sufcient to correlate
with levels in nal drug substances [12].
2. Fundamental interactions to achieve chiral recognition
A well-accepted hypothetical three-point interaction [1618]
between a chiral drug and its binding sites is usually utilized to
elucidate different in vivo behaviors of two enantiomers of a chiral drug [19]. The difference between two enantiomers of a drug
is illustrated in Fig. 2, where one enantiomer is biologically active
while the other enantiomer is not. The portions of the drug labeled
A, B, and C must interact with the corresponding regions of the
binding sites labeled a, b, and c in order to have its pharmacologic
effects. The active enantiomer of the drug has a three-dimensional
structure that can be aligned with the binding sites to allow A to
interact with a, B to interact with b, and C to interact with c. In
contrast, the inactive enantiomer cannot bind in the same way no
matter how it is rotated in space, although the inactive enantiomer
possesses all of the same groups A, B, C, and D as the active enantiomer. Consequently, the inactive enantiomer is prevented from
having a desired biological effect at these binding sites.
The fundamental forces needed to achieve chiral recognition
are traditionally dealt with on a case-by-case basis with collections
of experimental ndings rationalized by qualitative explanations.
Despite the diversity of the interactions and the variety of explanations offered [2024], there are some commonalities that fall
into the concept of the three-point interaction that intrinsically
involves the use of a chiral selector and/or mediator to facilitate
chiral recognition [16]. This resembles the inherent interaction
between a chiral drug and the binding sites, as illustrated in Fig. 2.
The rationale for the three-point rule is that if at least three
active positions of a chiral selector simultaneously interact with
appropriate positions of at least one enantiomer of a chiral drug and
at least one of these interactions is stereochemically dependent,
then the enantiomers can be resolved [19]. This interaction will be
signicantly affected by replacing one enantiomer with the other.
For example, if the SS (S-selector and S-enantiomer) interaction
L. Wu, F.G. Vogt / Journal of Pharmaceutical and Biomedical Analysis 69 (2012) 133147
135
Table 1
Top 10 best-selling small-molecule therapeutics in US in 2010.a
Ranking
Product (Company)
Active Pharmaceutical
Ingredient(s)
Structureb
Form of Active
Ingredient(s)
Nexium (AstraZeneca
Pharmaceuticals)
N
N
H
Esomeprazole
..
O
Single enantiomer
O
N
OH
OH
H
N
2
Atorvastatin
OH
Single enantiomer
Cl
3
Plavix (Bristol-Myers
Squibb Company)
Clopidogrel
Single enantiomer
S
F
O
S
O
HO
H
F
O
4
Advair Diskus
(GlaxoSmithKline)
Fluticasone propionate
and salmeterol
xinafoate
+
OH
HO
N
H
OH
OxyContin (Purdue
Pharma LP)
OH
Oxycodone
Single enantiomer
H
O
Cl
Cl
N
6
Abilify (Bristol-Myers
Squibb Company)
aripiprazole
Achiral
H
N
136
L. Wu, F.G. Vogt / Journal of Pharmaceutical and Biomedical Analysis 69 (2012) 133147
Table 1 (Continued)
Ranking
Product (Company)
Structureb
Active Pharmaceutical
Ingredient(s)
Form of Active
Ingredient(s)
OH
O
7
S H
Montelukast
Cl
Single enantiomer
N
HO
HO
N
8
Seroquel (AstraZeneca
Pharmaceuticals)
Quetiapine
Achiral
OH
OH
O
OH
N
9
Crestor (AstraZeneca
Pharmaceuticals)
Rosuvastatin
Single enantiomer
O S
O
10
a
b
H
N
O
Duloxetine
Single enantiomer
Mirror Plane
Acve Enanomer
Inacve Enanomer
Inacve Enanomer
A
Rotaon
B
C
b
a
b
c
Fig. 2. Schematic diagram illustrates the hypothetical three-point interaction between two enantiomers of a chiral drug and its binding sites. The active enantiomer has a
three-dimensional structure that allows drug domain A to interact with binding site domain a, B to interact with b, and C to interact with c. In contrast, the inactive enantiomer
cannot be aligned to bind the same three sites simultaneously. The difference in the three-dimensional structure allows the active enantiomer to bind and have a desired
biological effect, whereas the inactive enantiomer cannot.
L. Wu, F.G. Vogt / Journal of Pharmaceutical and Biomedical Analysis 69 (2012) 133147
137
L. Wu, F.G. Vogt / Journal of Pharmaceutical and Biomedical Analysis 69 (2012) 133147
metal-bound trimeric cluster ions corresponding to two enantiomeric forms of an analyte [2951]. The trimeric cluster ions as
opposed to the dimeric cluster ions, as described in the introduction, are used to invoke more sterically hindered effects that have
the potential to magnify (G), thus improving the enantioselectivity. The kinetic method is related to two product ions, as a
result of the loss of either an analyte (An) or a reference (ref*) ligand from the isolated trimeric cluster ions in a MS/MS experiment
(Eq. (3.1.3)).
k1
M, ref*
An
[M(An)(ref*)2
[B 1 H+ B2 ]
k2
H+
(3.1.1)
B1 + B 2
(3.1.1)
k
1
k2
(G)
=
RTeff
(3.1.3)
k2
B 1H + + B 2
H]+ + ref*
H]+
ESI
k1
[M(An)(ref*)
(3.1.2)
In this equation, (G) is the difference in gas-phase basicities of B1 and B2 , R is the gas constant, and Teff is the effective
temperature (the parameter in the kinetic method which connects
the fragmentation of isolated ions to the mean internal energy of
fragmenting ions [138]). Note that this relationship applies when a
number of conditions are fullled.
As demonstrated by the early application of the kinetic method
using 2,3-butanediol for stereoisomeric identication [32], this system was examined by dissociating, in two separate experiments,
both positively and negatively charged proton-bound dimeric
cluster ions. The (G) between the set of diastereomeric complexes can be obtained through the competitive dissociation in
the non-reference channel of the cluster ion, and this represents the fundamental basis for chiral discrimination. Thus, energy
differences <1 kJ/mol for fragmentation result in large changes
in the respective rate constants [139]. This change can be corelated through the fragment ion abundance ratio in a MS/MS
experiment.
3.1.2. Chiral analysis of binary mixtures
The successful extension of the kinetic method for chiral analysis is achieved by examining the dissociation kinetics of the
[M(ref*)2
H]+ + An
(3.1.3)
In this equation, M represent a metal ion (either a divalent transition metal ion such as Mn2+ , Fe2+ , Co2+ , Ni2+ , Cu2+ , Zn2+ , or an
alkali metal ion such as Li+ , Na+ , K+ ). The branching ratio leading to
the formation of two fragment ions is given by Eq. (3.1.4).
R=
[M(An)(ref ) H]
[M(ref )2 H]
(3.1.4)
Rchiral =
RR
[M(AnR )(ref ) H] /[M(ref )2 H]
=
+
+
RS
[M(AnS )(ref ) H] /[M(ref )2 H]
(3.1.5)
The larger the difference between Rchiral and unity, the higher
the degree of chiral recognition. When Rchiral is equal to one, the
combination of a metal ion, a reference, and an analyte fails to create a stereochemically dependent interaction. In particular, when
choosing a central metal ion it should be coordinated by a reference
and an analyte simultaneously. The transition metal ions have the
advantage of easy formation of the trimeric cluster ions and large
chiral recognition, especially when aromatic references are used
to promote -cation interactions. There is a logarithmic relationship between the relative ion abundance ratio and the free energy
difference (Eq. (3.1.6)):
ln R =
(G)
RTeff
(3.1.6)
In Eq. (3.1.6), R is the gas constant, Teff is the effective temperature of the activated trimeric complex ion [M(An)(ref*)2 H]+ ,
and (G) is dened as the difference in free energies between
reactions (3.1.7) and (3.1.8) whose reverse barriers are considered
negligible or equal (Fig. 3).
+
[M(ref*) 2
H]+ + An Ror S
(3.1.7)
[M (AnS)(ref*)
H]+ + ref*
[M(An R)(ref*)
H]+ + ref*
( G)
Energy
138
[M(An R)(ref*) 2
H]+
[M(An S)(ref*) 2
H]+
Reaction Coordinate
Fig. 3. Potential energy diagram showing two competitive dissociations for chiral
analysis by the kinetic method.
L. Wu, F.G. Vogt / Journal of Pharmaceutical and Biomedical Analysis 69 (2012) 133147
Fixed unit
CID
ligandligand interactions, and hence to maximize chiral recognition. Another advantage of the xed-ligand kinetic method is that
it simplies the dissociation kinetics.
When only one enantiomeric form with known optical purity
is available to develop a chiral method, the quotient-ratio kinetic
method is applicable for chiral analysis provided two independent
measurements for every unknown sample are made [44]. In addition, chiral analysis can be extended to enantiomeric quantitation
of a ternary mixture of a chiral compound [45] and a binary mixture
of different chiral compounds [46].
Dissociaon unit
AnR or S
Lxed
139
ref*
[M(An)(ref )2 H] [M(ref )2 H] + An
(3.1.8)
(G)R
RTeff
(3.1.9)
ln RS =
(G)S
RTeff
(3.1.10)
[(G)R + (G)S ]
1 + ee
1 ee
+ (G)S
=
2
2
2
[(G)R (G)S ]
ee
2
(3.1.11)
ee
(3.1.12)
This procedure starts with the formation of diastereomers; however, it is not the properties of the diastereomeric ions that are
examined. Instead, their formation is monitored simply by recording their relative abundances in a mass spectrometer. This method
uses simple single-stage MS to follow chiral-inclusion complex formation through hostguest (HG) interactions [5367]. Like any
single stage MS method it requires that the enantiomeric guest
(analyte) be isotopically labeled such that the HG diastereomeric
adduct can be mass-resolved and the ion abundance ratio can
be utilized for quantitative chiral analysis. This method is readily implemented using various ionization techniques such as fast
atom bombardment (FAB) [5463] and ESI [53,64,66]. However,
the method is best exploited when the examined samples are pure
because MS/MS is not performed. This method is either referred to
as the enantiomer labeled (EL)-host (Scheme 1a) or the enantiomer
labeled-guest method (Scheme 1b), given that either the host or
guest can be isotopically labeled. In practice, the EL-host method
rather than the EL-guest method is more conveniently employed.
Therefore, this review only covers the EL-host method.
3.2.1. Enantiomer labeled-host method
An equimolar mixture of HR and HS-dn (the chiral R and S forms)
is used as the host-pair reagent for ee determination of a chiral
guest (analyte). The host-pair reagent (HR /HS-dn = 1/1) is mixed
with the guest compound and is ionized via FAB-MS or ESI-MS.
Two diastereomeric HG complex ions simultaneously appear in
the single-stage MS spectrum. The ratio of the peak intensities,
called the IRIS value as termed in the original literature [54], reects
the degree of chiral discrimination as shown by Eq. (3.2.1).
I[(HR + G)+ ]
I[(HS-dn + G)+ ]
IR
= IRIS
IS-dn
(3.2.1)
140
L. Wu, F.G. Vogt / Journal of Pharmaceutical and Biomedical Analysis 69 (2012) 133147
Scheme 1. Guesthost diastereomeric ion formation for chiral recognition: (a) the host-labeled (EL-host) method; (b) the guest-labeled (EL-guest) method.
Host
Run No.
kR
kS
(3.3.1)
This method requires that the host and the guest should form
reasonably stable complexes. It is the cooperative interactions of
several weak forces (including dipoledipole, hydrophobic, and
electrostatic interactions as well as van der Waals and hydrogen
bonding) that lead to chiral differentiation. While the three-point
interaction can be either attractive or repulsive depending on the
functional groups [28], the attractive interaction between a host
and a guest has to be reconciled with the increasing steric repulsion.
Guest
Pattern of MS spectrum
H-G complexes
I R / IS-dn
HR
HS - dn
(R)-100% ee
2.0
HR
HS - dn
(S)-100% ee
0.5
HR
HS - dn
1/1 racemic
1.0
dn
HR
HS - dn
unknown
various
various
L. Wu, F.G. Vogt / Journal of Pharmaceutical and Biomedical Analysis 69 (2012) 133147
141
The DMS technique is another form of ion mobility spectrometry that separates ions at ambient pressure [133,134]. In contrast
to FAIMS, the DMS cell consists of two parallel at plates (instead
of two concentric cylindrical electrodes in FAIMS) that are applied
with asymmetric radiofrequency (RF) voltages. Ions are separated
in trajectory based on differences in their mobility between the
142
L. Wu, F.G. Vogt / Journal of Pharmaceutical and Biomedical Analysis 69 (2012) 133147
Gas
Ion 2
Ion
source
Mass
Analyzer
Ion 3
Electrode
Voltage (kV)
Fig. 6. Illustration of the FAIMS for separation of ions in the gas phase.
L. Wu, F.G. Vogt / Journal of Pharmaceutical and Biomedical Analysis 69 (2012) 133147
143
RF (+)
Ion exit
Ion entry
Ring
electrode
RF ()
Ions
Time
100
80
60
40
20
0
100
80
60
40
20
0
100
80
60
40
20
0
[CoII(N-Acetyl-L-Pro)2(FMAU) - H]+
632
475 (N-Acetyl-L-Pro)
632
475 (N-Acetyl-L-Pro)
632
250
300
350
400
450
(N-Acetyl-L-Pro)
500
550
600
650
700
m/z
Fig. 8. MS/MS product ion spectra of [CoII (N-Acetyl-L-Pro)2 (FMAU) H]+ (m/z 632) for the mixtures of D- and L-FMAU in different proportions. Note that the gure was
re-drawn from ref. [40].
144
L. Wu, F.G. Vogt / Journal of Pharmaceutical and Biomedical Analysis 69 (2012) 133147
600
80
60
60
40
20
600
403
0
300
419
400
(D-DOPA)
40
(L-Tyr)
20
600
0
300
700
HO
(L-DOPA)
419
500
L-DOPA
(L-Tyr)
NH2 OH
O
HO
403
400
500
600
700
Chirality
Switch
600
100
60
80
0
300
HO
400
(D-Tyr)
500
600
20
0
300
700
NH2 OH
(L-DOPA)
40
419
403
D-DOPA
60
(D-DOPA)
40
20
600
HO
403 419
400
(D-Tyr)
500
600
700
m/z
Fig. 9. Product ion (MS/MS) spectra of [(CuII + Ala-Ala H)(Tyr)(DOPA)]+ (m/z 600). Two product ions are [(Cu2+ + Ala-Ala H)(DOPA)]+ (m/z 419) and [(Cu2+ + AlaAla H)(Tyr)]+ (m/z 403). (a) Lxed = D-Ala-L-Ala, ref* = L-Tyr, An = D-DOPA; (b) Lxed = D-Ala-L-Ala, ref* = L-Tyr, An = L-DOPA; (c) Lxed = L-Ala-D-Ala, ref* = D-Tyr, An = D-DOPA;
(d) Lxed = L-Ala-D-Ala, ref* = D-Tyr, An = L-DOPA.
Note that the gure was re-drawn from Ref. [44].
L. Wu, F.G. Vogt / Journal of Pharmaceutical and Biomedical Analysis 69 (2012) 133147
145
[12] S. Miller, Scientic and regulatory aspects of quality control for chiral drugs,
in: The Eighteenth International Symposium on Chirality (ISCD-18), Busan,
Korea, June, 2006.
[13] International Conference on Harmonization of technical requirements for
registration of pharmaceuticals for human use, ICH harmonized tripartite
guideline, Pharm. Dev. Q8 (R2), August 2009.
[14] F.G. Vogt, A.S. Kord, Development of quality-by-design analytical methods, J.
Pharm. Sci. 100 (2011) 797812.
[15] International Conference on Harmonization of technical requirements for
registration of pharmaceuticals for human use, ICH harmonized tripartite
guideline, Specications: test procedures and acceptance criteria for new
drug substances and new drug products: chemical substances Q6A, October
1999.
[16] V.A. Davankov, The nature of chiral recognition: is it a three-point interaction,
Chirality 9 (1997) 99102.
[17] A.G. Ogston, Interpretation of experiments on metabolic processes, using isotopic tracer elements, Nature 162 (1948) 963.
[18] V.R. Meyers, M. Rais, A vivid model of chiral recognition, Chirality 1 (1989)
167169.
[19] L.A. Nguyen, H. He, C. Pham-Huy, Chiral drugs. An overview, Int. J. Biomed.
Sci. 2 (2006) 85100.
[20] W.H. Pirkle, M.H. Hyun, Effects of interstand distance upon chiral recognition
by a chiral stationary phase, J. Chromatogr. 328 (1985) 19.
[21] S. Topiol, M. Sabio, Computational chemical studies of chiral stationary phase models complexes of methyl N-(2-naphthyl)alaninate with
N-(3,5-dinitrobenzoyl)leucine n-propylamide, J. Chromatogr. 461 (1989)
129137.
[22] W.H. Pirkle, T.C. Pochapsky, Intermolecular 1H{1H} nuclear overhauser
effects in diastereomeric complexes: support for a chromatographically derived chiral recognition model, J. Am. Chem. Soc. 108 (1986)
56275628.
[23] V.A. Davankov, A.A. Kurganov, The role of achiral sorbent matrix in chiral
recognition of amino acid enantiomers in ligand exchange chromatography,
Chromatographia 17 (1983) 686690.
[24] V.A. Davankov, A.A. Kurganov, L.Y. Zhuchkova, T.M. Ponomareva, Chiral discrimination phenomena in mixed-ligand copper(II) complexes with amino
acids and 1,3-dicarbonyl compounds, Chirality 5 (1993) 303309.
[25] W.H. Pirkle, T.C. Pochapsky, Considerations of chiral recognition relevant to
the liquid chromatographic separation of enantiomers, Chem. Rev. 89 (1989)
347362.
[26] P. Abato, C.T. Seto, E.M.Dee, An enzymatic method for determining enantiomeric excess, J. Am. Chem. Soc. 123 (2001) 92069207.
[27] S.C. Sahoo, M. Ray, Three point chiral recognition and resolution of amino
alcohols through well-dened interaction inside a metallocavity, Chem. Eur.
J. 16 (2010) 50045007.
[28] S. Ahn, J. Ramirez, G. Grigorean, C.B. Lebrilla, Chiral recognition in gas-phase
cyclodextrin: amino acid complexesis the three point interaction still valid
in the gas phase? J. Am. Soc. Mass Spectrom. 12 (2001) 278287.
[29] W.A. Tao, R.G. Cooks, Chiral analysis by MS, Anal. Chem. 75 (2003) 25A31A.
[30] A. Filippi, A. Giardini, S. Piccirillo, M. Speranza, Gas-phase enantioselectivity,
Int. J. Mass Spectrom. 198 (2000) 137163.
[31] M.G. Finn, Emerging methods for the rapid determination of enantiomeric
excess, Chirality 14 (2002) 534540.
[32] W.Y. Shen, P.S.H. Wong, R.G. Cooks, Stereoisomeric distinction by the kinetic
method 2,3-butanediol, Rapid Commun. Mass Spectrom. 11 (1997) 7174.
[33] W.A. Tao, D. Zhang, W. Wang, P. Thomas, R.G. Cooks, Kinetic resolution of d,lamino acids based on gas-phase dissociation of copper(II) complexes, Anal.
Chem. 71 (1999) 44274429.
[34] W.A. Tao, D. Zhang, E.N. Nikolaev, R.G. Cooks, Copper(II)-assisted enantiomeric analysis of d,l-amino acids using the kinetic method: chiral
recognition and quantication in the gas phase, J. Am. Chem. Soc. 122 (2000)
1059810609.
[35] D. Zhang, W.A. Tao, R. Graham Cooks, Chiral resolution of d- and l-amino acids
by tandem mass spectrometry of Ni(II)-bound trimeric complexes, Int. J. Mass
Spectrom. 204 (2001) 159169.
[36] W.A. Tao, F.C. Gozzo, R.G. Cooks, Mass spectrometric quantitation of chiral
drugs by the kinetic method, Anal. Chem. 73 (2001) 16921698.
[37] W.A. Tao, R.G. Cooks, Parallel reactions for enantiomeric quantication
of peptides by mass spectrometry, Angew. Chem. Int. Ed. 40 (2001)
757760.
[38] W.A. Tao, R.L. Clark, R.G. Cooks, Quotient ratio method for quantitative
enantiomeric determination by mass spectrometry, Anal. Chem. 74 (2002)
37833789.
[39] L. Wu, W.A. Tao, R.G. Cooks, Ligand and metal ion effects in metal ion clusters
used for chiral analysis of alpha-hydroxy acids by the kinetic method, Anal.
Bioanal. Chem. 373 (2002) 618627.
[40] W.A. Tao, L. Wu, R.G. Cooks, Rapid enantiomeric quantitation of
an antiviral nucleoside agent (d,l-FMAU, 2-uoro-5-methyl-beta-d,larabinofuranosyluracil) by mass spectrometry, J. Med. Chem. 44 (2001)
35413544.
[41] W.A. Tao, L. Wu, R.G. Cooks, Rapid enantiomeric determination of alphahydroxy acids by electrospray ionization tandem mass spectrometry, Chem.
Commun. 20 (2000) 20232024.
[42] L. Wu, R.G. Cooks, Chiral analysis using the kinetic method with optimized
xed ligands: application to oxazolidinone antibiotics, Anal. Chem. 75 (2003)
678684.
146
L. Wu, F.G. Vogt / Journal of Pharmaceutical and Biomedical Analysis 69 (2012) 133147
[43] L. Wu, R.G. Cooks, Chiral, isomeric analysis by electrospray ionization and
sonic spray ionization using the xed-ligand kinetic method, Eur. J. Mass
Spectrom. 11 (2005) 231242.
[44] L. Wu, E.C. Meurer, R.G. Cooks, Chiral morphing and enantiomeric quantication in mixtures by mass spectrometry, Anal. Chem. 76 (2004) 663671.
[45] L. Wu, R.L. Clark, R.G. Cooks, Chiral quantication of d-, l-, and meso-tartaric
acid mixtures using a mass spectrometric kinetic method, Chem. Commun.
137 (2003) 136137.
[46] L. Wu, W.A. Tao, R.G. Cooks, Kinetic method for the simultaneous chiral analysis of different amino acids in mixtures, J. Mass Spectrom. 38 (2003) 386393.
[47] D.V. Augusti, F. Carazza, R. Augusti, W.A. Tao, R.G. Cooks, Quantitative chiral
analysis of sugars by electrospray ionization tandem mass spectrometry using
modied amino acids as chiral reference compounds, Anal. Chem. 74 (2002)
34583462.
[48] D.V. Augusti, R. Augusti, R.F. Carazza, R.G. Cooks, Quantitative determination
of enantiomeric composition of thalidomide solutions by electrospray ionization tandem mass spectrometry, Chem. Commun. 19 (2002) 22422243.
[49] B.L. Young, R.G. Cooks, M.C. Madden, M. Bair, J. Jia, A.-F. Aubry, S.A. Miller, Chiral purity assay for Flindokalner using tandem mass spectrometry: method
development, validation, and benchmarking, J. Pharm. Biomed. Anal. 43
(2007) 16021608.
ck, Chiral analysis by mass spec[50] K. Lemr, V. Ranc, P. Fryck, P. Bednr, J. Sev
trometry using the kinetic method in ow systems, J. Mass Spectrom. 41
(2006) 499506.
[51] R. Berkecz, A.R.M. Hyyrylinen, F. Flp, A. Pter, T. Janky, P. Vainiotalo, J.M.H.
Pakarinen, Chiral discrimination of -3-homo-amino acids using the kinetic
method, J. Mass Spectrom. 45 (2010) 13121319.
[52] H. Bagheri, H. Chen, R.G. Cooks, Chiral recognition by proton transfer reactions with optically active amines and alcohols, Chem. Commun. 23 (2004)
27402741.
[53] M. Sawada, Y. Takai, H. Yamada, M. Yoshikawa, R. Arakawa, H. Tabuchi,
M. Takada, J. Tanaka, M. Shizuma, H. Yamaoka, K. Hirose, K. Fukuda, Y.
Tobe, Depression of the apparent chiral recognition ability obtained in the
host-guest complexation systems by electrospray and nano-electrospray ionization mass spectrometry, Eur. J. Mass Spectrom. 1 (2004) 2737.
[54] M. Sawada, Chiral recognition detected by fast atom bombardment mass
spectrometry, Mass Spectrom. Rev. 16 (1997) 7390.
[55] M. Sawada, Y. Takai, H. Yamada, J. Nishida, T. Kaneda, R. Arakawa, M. Okamoto,
K. Hirose, T. Tanaka, K. Naemura, Chiral amino acid recognition detected by
electrospray ionization (ESI) and fast atom bombardment (FAB) mass spectrometry (MS) coupled with the enantiomer-labelled (EL) guest method, J.
Chem. Soc. Perkin Trans. 2 (1998) 701710.
[56] M. Sawada, Y. Takai, H. Yamada, S. Hirayama, T. Kaneda, T. Tanaka, K. Kamada,
T. Mizooku, S. Takeuchi, K. Ueno, K. Hirose, Y. Tobe, K. Naemura, Chiral recognition in host-guest complexation determined by the enantiomer-labeled
guest method using fast-atom bombardment mass spectrometry, J. Am.
Chem. Soc. 117 (1995) 77267736.
[57] M. Sawada, M. Shizuma, Y. Takai, H. Yamada, T. Kaneda, T. Hanafus, Enantioselectivity in FAB mass spectrometry, J. Am. Chem. Soc. 114 (1992) 44054406.
[58] M. Sawada, H. Yamaoka, Y. Takai, Y. Kawai, H. Yamada, T. Azuma, T. Fujioka,
T. Tanaka, Determination of enantiomeric excess for organic primary amine
compounds by chiral recognition fast-atom bombardment mass spectrometry, Int. J. Mass Spectrom. 193 (1999) 123130.
[59] M. Shizuma, H. Imamura, Y. Takai, H. Yamada, T. Takeda, S. Takahashi, M.
Sawada, Facile ee-determination from a single measurement by fast atom
bombardment mass spectrometry: a double labeling method, Int. J. Mass
Spectrom. 210211 (2001) 585590.
[60] M. Shizuma, H. Adachi, Y. Takai, M. Hayashi, J. Tanaka, T. Takeda, M. Sawada,
Combinatorial evaluation of the chiral discrimination of permethylated carbohydrates using fast-atom bombardment mass spectrometry, Carbohydr.
Res. 335 (2001) 275281.
[61] M. Shizuma, H. Adachi, A. Amemura, Y. Takai, T. Takeda, M. Sawada, Chiral
discrimination of permethylated gluco-oligosaccharide toward amino acid
ester salts, Tetrahedron 57 (2001) 45674578.
[62] M. Shizuma, M. Ohta, H. Yamada, Y. Takai, T. Nakaoki, T. Takeda, M. Sawada,
Enantioselective complexation of chiral linear hosts containing monosaccharide moieties with chiral organic amines, Tetrahedron 58 (2002) 43194330.
[63] M. Shizuma, Y. Kadoya, Y. Takai, H. Imamura, H. Yamada, T. Takeda, R.
Arakawa, S. Takahashi, M. Sawada, New articial host compounds containing galactose end groups for binding chiral organic amine guests:
chiral discrimination and their complex structures, J. Org. Chem. 67 (2002)
47954807.
[64] Y. Liang, J.S. Bradshaw, R.M. Izatt, R.M. Pope, D.V. Dearden, Analysis of enantiomeric excess using mass spectrometry: fast atom bombardment/sector and
electrospray ionization/Fourier transform mass spectrometric approaches,
Int. J. Mass Spectrom. 185/186/187 (1999) 977988.
[65] I.-H. Chu, D.V. Dearden, J.S. Bradshaw, P. Huszthy, R.M. Izattt, Chiral hostguest recognition in an ion-molecule reaction, J. Am. Chem. Soc. 115 (1993)
43184320.
[66] D.V. Dearden, C. Dejsupa, Y. Liang, J.S. Bradshaw, R.M. Izatt, Intrinsic contributions to chiral recognition: discrimination between enantiomeric amines
by dimethyldiketopyridino-18-crown-6 in the gas phase, J. Am. Chem. Soc.
119 (1997) 353359.
[67] D.V. Dearden, Y. Liang, J.B. Nicoll, K.A. Kellersberger, Study of gas-phase
molecular recognition using Fourier transform ion cyclotron resonance mass
spectrometry (FTICR/MS), J. Mass Spectrom. 36 (2001) 989997.
[68] G. Grigorean, J. Ramirez, S.H. Ahn, C.B. Lebrilla, A mass spectrometry method
for the determination of enantiomeric excess in mixtures of d,l-amino acids,
Anal. Chem. 72 (2000) 42754281.
[69] G. Grigorean, S. Gronert, C.B. Lebrilla, Enantioselective gas-phase ionmolecule reactions in a quadrupole ion trap, Int. J. Mass Spectrom. 219 (2002)
7987.
[70] G. Grigorean, C.B. Lebrilla, Enantiomeric analysis of pharmaceutical compounds by ion/molecule reactions, Anal. Chem. 73 (2001) 16921698.
[71] J. Ramirez, F. He, C.B. Lebrilla, Gas-phase chiral differentiation of amino-acid
guests in cyclodextrin hosts, J. Am. Chem. Soc. 120 (1998) 73877388.
[72] E. Camara, M.K. Green, S.G. Penn, C.B. Lebrilla, Chiral recognition is observed in
the deprotonation reaction of cytochrome c by (2R)- and (2S)-2-butylamine,
J. Am. Chem. Soc. 118 (1996) 87518752.
[73] J.F. Gal, M. Stone, C.B. Lebrilla, Chiral recognition of non-natural a-amino acids,
Int. J. Mass Spectrom. 222 (2003) 259267.
[74] G. Grigorean, X. Cong, C.B. Lebrilla, Chiral analyses of peptides by ion/molecule
reactions, Int. J. Mass Spectrom. 234 (2004) 7177.
[75] C.B. Lebrilla, The gas-phase chemistry of cyclodextrin inclusion complexes,
Acc. Chem. Res. 34 (2001) 653661.
[76] S.P. Gaucher, J.A. Leary, Inuence of metal ion and coordination geometry on
the gas phase dissociation and stereochemical differentiation of N-glycosides,
Int. J. Mass Spectrom. 197 (2000) 139148.
[77] T.T. Dang, S.F. Pedersen, J.A. Leary, Chiral recognition in the gas phase: mass
spectrometric studies of diastereomeric cobalt complexes, J. Am. Soc. Mass
Spectrom. 5 (1994) 452459.
[78] G. Smith, J.A. Leary, Mechanistic studies of diastereomeric Nickel(II) NGlycoside complexes using tandem mass spectrometry, J. Am. Chem. Soc. 120
(1998) 1304613056.
[79] A. Paladini, C. Calcagni, T. Di Palma, M. Speranza, A. Lagan, G. Fago,
A. Filippi, M. Satta, A.G. Guidoni, Enantiodiscrimination of chiral alphaaminophosphonic acids by mass spectrometry, Chirality 13 (2001) 707711.
[80] G. Fago, A. Filippi, A. Giardini, A. Lagan, A. Paladini, M. Speranza, Chiral recognition of O-phosphoserine, Angew. Chem. Int. Ed. 40 (2001) 40514054.
[81] A. Dob, M. Liptk, P. Huszthy, K. Vkey, Chiral recognition via hostguest
interactions detected by fast-atom bombardment mass spectrometry: principles and limitations, Rapid Commun. Mass Spectrom. 11 (1997) 889896.
[82] K. Vkey, G. Czira, Distinction of amino acid enantiomers based on the basicity
of their dimmers, Anal. Chem. 69 (1997) 17001705.
[83] V. Carlesso, F. Fournier, J.-C. Tabet, Stereochemical differentiation of four
mono-saccharides using transition metal complexes by electrospray ionization/ion trap mass spectrometry, Eur. Mass Spectrom. 6 (2000) 421428.
[84] Y. Cheng, D.M. Hercules, Measurement of chiral complexes of cyclodextrins
and amino acids by electrospray ionization time-of-ight mass spectrometry,
Rapid Commun. Mass Spectrom. 36 (2001) 834836.
[85] M.P. So, T.S.M. Wan, T.-W.D. Chan, Differentiation of enantiomers using
matrix-assisted laser desorption/ionization mass spectrometry, Rapid Commun. Mass Spectrom. 14 (2000) 692695.
[86] Z.-P. Yao, T.S.M. Wan, K.-P. Kwong, C.-T. Che, Chiral recognition of amino acids
by electrospray ionization mass spectrometry/mass spectrometry, Chem.
Commun. 20 (1999) 21192120.
[87] Z.-P. Yao, T.S.M. Wan, K.-P. Kwong, C.-T. Che, Chiral analysis by electrospray
ionization mass spectrometry/mass spectrometry. 1. Chiral recognition of 19
common amino acids, Anal. Chem. 72 (2000) 53835393.
[88] Z.-P. Yao, T.S.M. Wan, K.-P. Kwong, C.-T. Che, Chiral analysis by
electrospray ionization mass spectrometry/mass spectrometry. 2. Determination of enantiomeric excess of amino acids, Anal. Chem. 72 (2000)
53945401.
[89] J. Chen, C.-J. Zhu, Y.-F. Zhao, Enantiomeric quantication of the bioactive
peptide seryl-histidine methyl ester by electrospray ionization mass spectrometry and the kinetic method, Rapid Commun. Mass Spectrom. 16 (2002)
12511253.
[90] S.A. McLuckey, J.M. Wells, Mass analysis at the advent of the 21st century,
Chem. Rev. 101 (2001) 571606.
[91] W.Y. Feng, Mass spectrometry in drug discovery: a current review, Curr. Drug
Discov. Technol. 1 (2004) 295312.
[92] R. Ramanathan, M. Jemal, S. Ramagiri, Y.-Q. Xia, W.G. Humpreys, T. Olah, W.A.
Korfmacher, It is time for a paradigm shift in drug discovery bioanalysis: from
SRM to HRMS, J. Mass Spectrom. 46 (2011) 595601.
[93] J.B. Fenn, M. Mann, C.K. Meng, S.F. Wong, C.M. Whitehouse, Electrospray
ionization for mass-spectrometry of large biomolecules, Science 246 (1989)
6471.
[94] J.B. Fenn, M. Mann, C.K. Meng, S.F. Wong, Electrospray ionization-principles
and practice, Mass Spectrom. Rev. 9 (1990) 3770.
[95] E.C. Horning, M.G. Horning, D.I. Carroll, I. Dzidic, R.N. Stillwell, New picogram
detection system based on a mass spectrometer with an external ionization
source at atmospheric pressure, Anal. Chem. 45 (1973) 936943.
[96] J.A. Syage, M.D. Evans, K.A. Hanold, Photoionization mass spectrometry, Am.
Lab. 32 (2000) 2429.
[97] F. Hillenkamp, M. Karas, R.C. Beavis, B.T. Chait, Matrix-assisted laser desorption/ionization mass spectrometry of biopolymers, Anal. Chem. 63 (1991)
1193A1203A.
[98] A. Hirabayashi, M. Sakairi, H. Koizumi, Sonic spray ionization method for
atmospheric pressure ionization mass spectrometry, Anal. Chem. 66 (1994)
45574559.
[99] A. Hirabayashi, M. Sakairi, H. Koizumi, Sonic spray mass spectrometry, Anal.
Chem. 67 (1995) 28782882.
L. Wu, F.G. Vogt / Journal of Pharmaceutical and Biomedical Analysis 69 (2012) 133147
[100] Z. Takts, J.M. Wiseman, B. Gologan, R.G. Cooks, Mass spectrometry sampling
under ambient conditions with desorption electrospray ionization, Science
306 (2004) 471473.
[101] D.R. Ifa, C. Wu, Z. Ouyang, R.G. Cooks, Desorption electrospray ionization and
other ambient ionization methods: current progress and preview, Analyst
135 (2010) 669681.
[102] A. Venter, M. Neiu, R.G. Cooks, Ambient desorption ionization mass spectrometry, TrAC Trends Anal. Chem. 27 (2008) 284290.
[103] R.B. Cody, J.A. Laramee, H.D. Durst, Versatile new ion source for the analysis
of materials in open air under ambient conditions, Anal. Chem. 77 (2005)
22972302.
[104] T.R. Covey, B.A. Thomson, B.B. Schneider, Atmospheric pressure ion sources,
Mass Spectrom. Rev. 28 (2009) 870897.
[105] K.L. Busch, G.L. Glish, S.A. McLuckey, Mass Spectrometry/Mass Spectrometry:
Techniques and Applications of Tandem Mass Spectrometry, VCH Publishers,
New York, 1988.
[106] E.D. Hoffmann, Tandem mass spectrometry: a primer, J. Mass Spectrom. 31
(1996) 129137.
[107] A.K. Shukla, J.H. Futrell, Tandem mass spectrometry: dissociation of ions by
collisional activation, J. Mass Spectrom. 35 (2000) 10691090.
[108] R.A. Yost, C.G. Enke, Selected ion fragmentation with a tandem quadrupole
mass spectrometer, J. Am. Chem. Soc. 100 (1978) 22742275.
[109] R.A. Yost, D.D. Fetterolf, Tandem mass spectrometry (MS/MS) instrumentation, Mass Spectrom. Rev. 2 (1983) 145.
[110] I.V. Chernushevich, A.V. Loboda, B.A. Thomson, An introduction to
quadrupole-time-of-ight mass spectrometry, J. Mass Spectrom. 36 (2001)
849865.
[111] R.E. March, An introduction to quadrupole ion trap mass spectrometry, J. Mass
Spectrom. 32 (1997) 351369.
[112] J.C. Schwartz, M.W. Senko, J.E.P. Syka, A two-dimensional quadrupole ion trap
mass spectrometer, J. Am. Soc. Mass Spectrom. 13 (2002) 659669.
[113] A.G. Marshall, C.L. Hendrickson, G.S. Jackson, Fourier transform ion cyclotron
resonance mass spectrometry: a primer, Mass Spectrom. Rev. 17 (1998) 135.
[114] A. Makarov, Electrostatic axially harmonic orbital trapping: a highperformance technique of mass analysis, Anal. Chem. 72 (2000) 11561162.
[115] Q. Hu, R.J. Noll, H. Li, A. Makarov, M. Hardman, R.G. Cooks, The Orbitrap: a
new mass spectrometer, J. Mass Spectrom. 40 (2005) 430443.
[116] J. Guo, J. Wu, G. Siuzdak, M.G. Finn, Measurement of enantiomeric excess by
kinetic resolution and mass spectrometry, Angew. Chem. Int. Ed. 38 (1999)
17551758.
[117] M.A. Evans, J.P. Morken, Isotopically chiral probes for in situ high-throughput
asymmetric reaction analysis, J. Am. Chem. Soc. 124 (2002) 90209021.
[118] T.J. Ward, D.-M. Hamburg, Chiral separations, Anal. Chem. 76 (2004)
46354644.
[119] Y. Tang, J. Zukowski, D.W.I. Armstrong, Investigation on enantiomeric separations of uorenylmethoxycarbonyl amino acids and peptides by HPLC using
native cyclodextrins as chiral stationary phases, J. Chromatogr. A 743 (1996)
261271.
[120] K.D. Altria, M.A. Kelly, B.J. Clark, Current applications in the analysis of pharmaceutical by capillary electrophoresis, TrAC Trends Anal. Chem. 17 (1998)
214226.
[121] S.C. Chang, R. Charles, E. Gil-Av, Resolution of -methyl -amino acid derivatives by gas chromatography on optically active diamide stationary phases, J.
Chromatogr. 238 (1982) 2939.
[122] G. Sicoli, D. Kreidler, H. Czesla, H. Hopf, V. Schurig, Gas chromatographic
enantioseparation of unfunctionalized chiral alkanes: a challenge in separation science (overview, state of the art, and perspectives), Chirality 21 (2009)
183198.
[123] C. Bicchi, C. Brunelli, G. Cravotto, P. Rubiolo, M. Galli, Cyclodextrin
derivatives in GC separation of racemates of different volatility Part
XVIII: 2-methyl-3-acetyl- and 2-acetyl-3-methyl-6-O-t-hexyldimethylsilyl-cyclodextrin derivatives, J. Sep. Sci. 25 (2002) 125134.
[124] G.J. Teroth, Enantioseparations in super- and subcritical uid chromatography, J. Chromatogr. A 906 (2001) 301307.
[125] G.J. Teroth, Chiral chromatography by subcritical and SFC, in: J. Cazes (Ed.),
Encyclopedia of Chromatography, 3rd Edition, CRC Press, Boca Raton, Florida,
2010, pp. 416418.
[126] P.J. Stephens, F.J. Devlin, J.-J. Pan, The determination of the absolute congurations of chiral molecules using vibrational circular dichroism (VCD)
spectroscopy, Chirality 20 (2008) 643663.
[127] T.J. Wenzel, J.D. Wilcox, Chiral reagents for the determination of enantiomeric
excess and absolute conguration using NMR spectroscopy, Chirality 15
(2003) 256270.
147
[128] S.-S. Cai, K.A. Hanold, J.A. Syage, Comparison of atmospheric pressure
photoionization and atmospheric pressure chemical ionization for normalphase LC/MS chiral analysis of pharmaceuticals, Anal. Chem. 79 (2007)
24912498.
[129] D. Jin, A.P. Kumar, G.-C. Song, Y.-I. Lee, Determination of thyroxine
enantiomers in pharmaceutical formulation by high-performance liquid chromatographymass spectrometry with precolumn derivatization,
Microchem. J. 88 (2008) 6266.
[130] H.M. Fales, G.J. Wright, Detection of chirality with the chemical ionization
mass spectrometer. Meso ions in the gas phase, J. Am. Chem. Soc. 99 (1977)
23392340.
[131] P. Dwivedi, C. Wu, L.M. Matz, B.H. Clowers, W.F. Siems, H.H. Hill Jr., Gasphase chiral separations by ion mobility spectrometry, Anal. Chem. 78 (2006)
82008206.
[132] M. McCooeye, L. Ding, G.J. Gardner, C.A. Fraser, J. Lam, R.E. Sturgeon, Z. Mester,
Separation and quantitation of the stereoisomers of ephedra alkaloids in natural health products using ow injection-electrospray ionization-high eld
asymmetric waveform ion mobility spectrometry-mass spectrometry, Anal.
Chem. 75 (2003) 25382542.
[133] B.B. Schneider, T.R. Covey, S.L. Coy, E.V. Krylov, E.G. Nazarov, Chemical effects
in the separation process of a differential mobility/mass spectrometer system,
Anal. Chem. 82 (2010) 18671880.
[134] B.B. Schneider, T.R. Covey, S.L. Coy, E.V. Krylov, E.G. Nazarov, Planar differential mobility spectrometer as a pre-lter for atmospheric pressure ionization
mass spectrometry, Int. J. Mass Spectrom. 298 (2010) 4554.
[135] L. Dong, H. Shion, R.G. Davis, B. Terry-Penak, J. Castro-Perez, R.B. van Breemen,
Collision cross-section determination and tandem mass spectrometric analysis of isomeric carotenoids using electrospray ion mobility time-of-ight
mass spectrometry, Anal. Chem. 82 (2010) 90149021.
[136] K. Giles, J.L. Wildgoose, D.J. Langridge, I. Campuzano, A method for direct
measurement of ion mobilities using a travelling wave ion guide, Int. J. Mass
Spectrom. 298 (2010) 1016.
[137] R.G. Cooks, T.L. Kruger, Intrinsic basicity determination using metastable ions,
J. Am. Chem. Soc. 99 (1977) 12791281.
[138] R.G. Cooks, J.S. Patrick, T. Kotiaho, S.A. McLuckey, Thermochemical
determinations by the kinetic method, Mass Spectrom. Rev. 13 (1994)
287339.
[139] R.G. Cooks, P.S.H. Wong, Kinetic method of making thermochemical determinations, Acc. Chem. Res. 31 (1998) 379386.
[140] J. Yoon, D.J. Cram, Chiral recognition properties in complexation of two asymmetric hemicarcerands, J. Am. Chem. Soc. 119 (1997) 1179611806.
[141] D.J. Cram, Molecular container compounds, Nature 356 (1992) 2936.
[142] H. Uchida, E.N. Kodama, K. Yoshimura, Y. Maeda, P. Kosalaraksa, V. Maroun,
Y.-L. Qiu, J. Zemlicka, H. Mitsuya, In vitro anti-human immunodeciency virus
activities of Z- and E-methylenecyclopropane nucleoside analogues and their
phosphoro-l-alaninate diesters, Antimicrob. Agents Chemother. 43 (1999)
14871490.
[143] S.K. Ono, N. Kato, Y. Shiratori, J. Kato, T. Goto, R.F. Schinazi, F.J. Carrilho,
M. Omata, The polymerase L528 M mutation cooperates with nucleotide
binding-site mutations, increasing hepatitis B virus replication and drug resistance, J. Clin. Invest. 107 (2001) 449455.
[144] M.R. Blum, G.E. Chittick, L.H. Wang, L.J. Keilholz, L. Fang, G.M. Szczech, F.S.
Rousseau, Clevudine, (l-FMAU) a new agent under development for the treatment of hepatitis B virus (HBV): evaluation of the safety, pharmacokinetics
and effect of food following single-dose administration in healthy male volunteers, Hepatology 32 (2000) 17021706.
[145] G.Q. Yao, S. Liu, E. Chou, M. Kukhanova, C.K. Chu, Y. Cheng, Inhibition
of EBV replication by a novel l-nucleoside, 2-uoro-5-methyl--larabinofuranosyluracil, Biochem. Pharmacol. 51 (1996) 941947.
[146] L. Wu, R.G. Cooks, On-the-y chiral analysis by kinetic method using datadependent LC-MS/MS, in: Proceedings of 53th Annual Conference on Mass
Spectrometry and Allied Topics, June 59, San Antonio, TX, 2005.
[147] P. Chen, Electrospray ionization tandem mass spectrometry in highthroughput screening of homogeneous catalysts, Angew. Chem. 42 (2003)
28322847.
[148] J.C. Fromme, G.L. Verdine, Structural insights into lesion recognition and
repair by the bacterial 8-oxoguanine DNA glycosylase MutM, Nat. Struct. Biol.
9 (2002) 544552.
[149] Y.-W. Kwon, D.J. Triggle, Chiral aspects of drug action at ion channels: a commentary on the stereoselectivity of drug actions at volatge-gated ion channels
with particular reference to verapamil actions at the Ca2+ channel, Chirality
3 (1991) 393404.