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Chiral Separations by Capillary Electrophoresis
Chromatographic Science 1st Edition Ann Van Eeckhaut
Digital Instant Download
Author(s): Ann Van Eeckhaut, Yvette Michotte
ISBN(s): 9781420069334, 1420069330
Edition: 1
File Details: PDF, 7.05 MB
Year: 2009
Language: english
Chiral Separations by
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Chiral Separations by
Capillary Electrophoresis

Ann Van Eeckhaut

Vrije Universiteit Brussel
Brussels, Belgium
Yvette Michotte
Vrije Universiteit Brussel
Brussels, Belgium

Boca Raton London New York

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Library of Congress Cataloging-in-Publication Data

Chiral separations by capillary electrophoresis / editors, Ann Van Eeckhaut, Yvette

Michotte.
p. cm. -- (Chromatographic science series ; 100)
Includes bibliographical references and index.
ISBN 978-1-4200-6933-4 (hardcover : alk. paper)
1. Chiral drugs. 2. Chirality. 3. Enantiomers. 4. Electrophoresis. I. Eeckhaut, Ann
Van. II. Michotte, Yvette. III. Title. IV. Series.

RS429.C484 2009
541’.372--dc22 2009031932

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Contents
Preface.......................................................................................................................xi
Editors .................................................................................................................... xiii
Contributors ............................................................................................................. xv

Chapter 1 Pharmacological Importance of Chiral Separations ............................1

Ann Van Eeckhaut and Yvette Michotte

Chapter 2 Principles of Chiral Separations by Free-Solution

Electrophoresis ................................................................................... 23
Radim Vespalec

Chapter 3 Cyclodextrin-Mediated Chiral Separations ....................................... 47

Gerald Gübitz and Martin G. Schmid

Chapter 4 Factors Influencing Cyclodextrin-Mediated

Chiral Separations .............................................................................. 87
Anne-Catherine Servais, Jacques Crommen,
and Marianne Fillet

Chapter 5 Macrocyclic Antibiotics as Chiral Selectors .................................... 109

Salvatore Fanali, Zeineb Aturki, Giovanni D’Orazio,
and Anna Rocco

Chapter 6 Chiral Separations Using Proteins and Peptides

as Chiral Selectors............................................................................ 139
Jun Haginaka

Chapter 7 Chiral Ligand Exchange Capillary Electrophoresis......................... 163

Vincenzo Cucinotta and Alessandro Giuffrida

Chapter 8 Chiral Separations by Micellar Electrokinetic

Chromatography ............................................................................... 195
Joykrishna Dey and Arjun Ghosh

ix
x Contents

Chapter 9 Chiral Microemulsion Electrokinetic Chromatography .................. 235

Kimberly A. Kahle and Joe P. Foley

Chapter 10 Chiral Separations in Nonaqueous Media ....................................... 271

Ylva Hedeland and Curt Pettersson

Chapter 11 Quantitative Analysis in Pharmaceutical Analysis .......................... 313

Ulrike Holzgrabe, Claudia Borst, Christine Büttner,
and Yaser Bitar

Chapter 12 Analysis of Chiral Drugs in Body Fluids......................................... 341

Pierina Sueli Bonato, Valquiria Aparecida Polisel Jabor,
and Anderson Rodrigo Moraes de Oliveira

Chapter 13 Chiral CE–MS.................................................................................. 363

Serge Rudaz, Jean-Luc Veuthey, and Julie Schappler

Chapter 14 Enantioseparations by Capillary Electrochromatography ............... 393

Michael Lämmerhofer

Chapter 15 Recent Applications in Capillary Electrochromatography .............. 459

Debby Mangelings and Yvan Vander Heyden

Chapter 16 Chiral Separations with Microchip Technology .............................. 501

Markéta Vlčková, Franka Kalman, and Maria A. Schwarz

Index ...................................................................................................................... 515

Preface
In 1848, Louis Pasteur, a French chemist renowned for his work on the vaccine for
rabies, discovered molecular chirality. He found that the sodium ammonium salt
of racemic tartaric acid crystallized as a mixture of nonsuperimposable mirror-
image crystals. Pasteur called these molecules dissymmetric. The terms “chiral”
and “chirality” were first introduced by Lord Kelvin in 1894: “I call any geomet-
rical figure or group of points chiral and say that it has chirality, if its image
in a plane mirror ideally realized, cannot be brought to coincide with itself.”
The enantiomeric terminology to refer to nonsuperimpossible mirror images was
already introduced in 1856 by Carl Friedrich Naumann, a German crystallographer.
However, this terminology was only accepted and widely used in the context of
stereochemistry in the 1890s.
Louis Pasteur was also the first to have observed enantioselectivity in a biochemical
process. In 1857, he discovered the enantioselective fermentation of tartaric acid
by microorganisms. At the end of the nineteenth century and the beginning of the
twentieth, other studies confirmed the pharmacological differences between
enantiomers. Despite these early insights, most of the studies have been performed
only since the 1980s when technology for chiral analysis advanced. These new tech-
nologies allowed, for example, the large-scale production of pure enantiomers and the
enantioselective analysis of biological samples.
Capillary electrophoresis has proven to be an effective tool for chiral separation.
The aim of this book is to provide a general overview of the principles of chiral
separation by capillary electrophoresis and of the different chiral selectors available.
In addition, pharmaceutical and biomedical applications and newer techniques, such as
capillary electrophoresis coupled to mass spectrometry and microchip technology, are
also included. In two chapters, the possibilities of capillary electrochromatography are
explained, including the different chiral columns available and some recent pharma-
ceutical and biomedical applications.
We gratefully acknowledge the contributors without whom this book would not
have existed and the staff at CRC Press for all their help.

Yvette Michotte
Ann Van Eeckhaut

xi
Editors
Yvette Michotte is the head of the Department of Pharmaceutical Chemistry and
Drug Analysis of the School of Pharmacy at the Vrije Universiteit Brussel, Belgium.
She is also heading the research group of experimental neuropharmacology.
Her main research topics are the development and validation of analytical methods
for the quantification of compounds for label claim control of drug substances and
drug products, and for the quantification of drugs, metabolites, and endogenous com-
pounds in biological matrices. One of her principal topics is the analysis of drugs,
neurotransmitters, and neuropeptides in microdialysates from in vivo neuropharma-
cological experiments. The analytical techniques used are micro- and nano-liquid
chromatography, coupled to amperometric and mass spectrometric detection
(LC–MS/MS), and capillary electrophoresis.

Ann Van Eeckhaut graduated in pharmaceutical chemistry at the Vrije Universiteit

Brussel, Belgium, in 1997. She received her PhD in pharmaceutical sciences in 2004
in the Department of Pharmaceutical Chemistry and Drug Analysis of the same uni-
versity under the supervision of Prof. Yvette Michotte. Her PhD thesis was entitled
“Chiral separations by cyclodextrin-mediated capillary electrophoresis.” Her current
interests as a postdoctoral researcher are oriented to the development and valida-
tion of methods for the quantification of small molecules and peptides in biological
samples, especially toward the analysis of neuropeptides in microdialysates using
miniaturized liquid chromatography coupled to tandem mass spectrometry.

xiii
Contributors
Zeineb Aturki Vincenzo Cucinotta
Institute of Chemical Methodologies Department of Chemical Sciences
Consiglio Nazionale delle Ricerche University of Catania
Monterotondo Scalo, Italy Catania, Italy

Yaser Bitar Joykrishna Dey

Faculty of Pharmacy and Food Department of Chemistry
Chemistry Indian Institute of Technology
Department of Pharmaceutical Kharagpur, India
Chemistry and Quality Control
University of Aleppo Giovanni D’Orazio
Aleppo, Syria Institute of Chemical Methodologies
Consiglio Nazionale delle Ricerche
Pierina Sueli Bonato Monterotondo Scalo, Italy
Faculty of Pharmaceutical Sciences
of Ribeirão Preto Anderson Rodrigo Moraes de Oliveira
University of São Paulo Faculty of Philosophy, Sciences
Ribeirão Preto, Brazil and Letters of Ribeirão Preto
University of São Paulo
Claudia Borst Ribeirão Preto, Brazil
Institute of Pharmacy and Food
Chemistry Salvatore Fanali
University of Würzburg Institute of Chemical Methodologies
Würzburg, Germany Consiglio Nazionale delle Ricerche
Monterotondo Scalo, Italy
Christine Büttner
Institute of Pharmacy and Food Marianne Fillet
Chemistry Department of Analytical
University of Würzburg Pharmaceutical Chemistry
Würzburg, Germany Institute of Pharmacy
University of Liège
Jacques Crommen Liège, Belgium
Department of Analytical
Pharmaceutical Chemistry Joe P. Foley
Institute of Pharmacy Department of Chemistry
University of Liège Drexel University
Liège, Belgium Philadelphia, Pennsylvania

xv
xvi Contributors

Arjun Ghosh Kimberly A. Kahle

Department of Chemistry Merck & Co. Inc.
Indian Institute of Technology West Point, Pennsylvania
Kharagpur, India
Franka Kalman
Alessandro Giuffrida Solvias AG
Department of Chemical Basel, Switzerland
Sciences
University of Catania Michael Lämmerhofer
Catania, Italy Department of Analytical Chemistry
and Food Chemistry
Gerald Gübitz University of Vienna
Department of Pharmaceutical Vienna, Austria
Chemistry
Institute of Pharmaceutical Sciences Debby Mangelings
Karl-Franzens-University Department of Analytical Chemistry
Graz, Austria and Pharmaceutical Technology
Vrije Universiteit Brussel
Brussels, Belgium
Jun Haginaka
School of Pharmacy and
Pharmaceutical Sciences Yvette Michotte
Mukogawa Women’s University Department of Pharmaceutical
Nishinomiya, Hyogo, Japan Chemistry, Drug Analysis and
Drug Information
Vrije Universiteit Brussel
Ylva Hedeland Brussels, Belgium
Department of Medicinal
Chemistry
Curt Pettersson
Division of Analytical Pharmaceutical
Department of Medicinal Chemistry
Chemistry
Division of Analytical Pharmaceutical
Biomedical Centre
Chemistry
Uppsala University
Biomedical Centre
Uppsala, Sweden
Uppsala University
Uppsala, Sweden
Ulrike Holzgrabe
Institute of Pharmacy and Food Anna Rocco
Chemistry Institute of Chemical Methodologies
University of Würzburg Consiglio Nazionale delle Ricerche
Würzburg, Germany Monterotondo Scalo, Italy

Valquiria Aparecida Polisel Jabor Serge Rudaz

Faculty of Pharmaceutical Sciences School of Pharmaceutical Sciences
of Ribeirão Preto University of Geneva
University of São Paulo University of Lausanne
Ribeirão Preto, Brazil Geneva, Switzerland
Contributors xvii

Julie Schappler Yvan Vander Heyden

School of Pharmaceutical Sciences Department of Analytical Chemistry
University of Geneva and Pharmaceutical Technology
University of Lausanne Vrije Universiteit Brussel
Geneva, Switzerland Brussels, Belgium

Martin G. Schmid Ann Van Eeckhaut

Department of Pharmaceutical Department of Pharmaceutical
Chemistry Chemistry, Drug Analysis and
Institute of Pharmaceutical Sciences Drug Information
Karl-Franzens-University Vrije Universiteit Brussel
Graz, Austria Brussels, Belgium

Maria A. Schwarz
Department of Chemistry Radim Vespalec
University of Basel Brno, Czech Republic
Basel, Switzerland
and Jean-Luc Veuthey
School of Pharmaceutical Sciences
Solvias AG University of Geneva
Basel, Switzerland University of Lausanne
Geneva, Switzerland
Anne-Catherine Servais
Department of Analytical
Pharmaceutical Chemistry Markéta Vlčková
Institute of Pharmacy Department of Chemistry
University of Liège University of Basel
Liège, Belgium Basel, Switzerland
 1 Pharmacological
Importance of Chiral
Separations

Ann Van Eeckhaut and Yvette Michotte

CONTENTS
1.1 General Terminology of Isomerism ................................................................2
1.2 Chirality ..........................................................................................................3
1.3 Stereoselectivity in Pharmacodynamics .........................................................5
1.4 Stereoselectivity in Pharmacokinetics ............................................................7
1.4.1 Absorption..........................................................................................8
1.4.2 Distribution ........................................................................................8
1.4.3 Metabolization ...................................................................................9
1.4.3.1 Substrate Stereoselectivity .................................................9
1.4.3.2 Product Stereoselectivity .................................................. 10
1.4.3.3 Substrate–Product Stereoselectivity ................................. 11
1.4.4 Renal Excretion ................................................................................ 12
1.5 Interspecies Differences ................................................................................ 12
1.6 Patient-Specific Factors ................................................................................. 12
1.6.1 Age ................................................................................................... 12
1.6.2 Gender .............................................................................................. 13
1.6.3 Genetic Factors ................................................................................ 13
1.6.4 Disease State .................................................................................... 14
1.7 Drug-Related Factors .................................................................................... 14
1.7.1 Input Rate ......................................................................................... 14
1.7.2 Interactions....................................................................................... 15
1.8 Single Enantiomer versus Racemate—“Chiral Switches”............................ 15
1.9 The Need for Analytical Tools ...................................................................... 17
1.10 Introduction to Capillary Electrophoresis ..................................................... 17
References ................................................................................................................ 18

1
2 Chiral Separations by Capillary Electrophoresis

1.1 GENERAL TERMINOLOGY OF ISOMERISM [1,2]

Isomers are compounds that have the same stoichiometric molecular formula.
However, they can differ in either connectivity or spatial orientation. There are two
major classes of isomers, namely, constitutional isomers and stereoisomers.
Constitutional isomers have a different binding pattern of the atoms in the
three-dimensional space. They often vary substantially in their physical and
chemical properties. For example, 1-propanol and 2-propanol bear the same
molecular formula C4H10 O, but their structural formula differs (Figure 1.1).
Another example is cortisone, prednisolone, and aldosterone, all of which have
C21H 28O5 as molecular formula [3].
Stereoisomers have identical constitution, but differ in the spatial arrangement of
certain atoms or groups. Stereoisomers can be subdivided into two distinct groups:
optical isomers or enantiomers and diastereoisomers. Enantiomers are nonsuper-
imposable mirror images of each other (Figure 1.1). A pair of enantiomers will
be identical in atomic constitution and bonding. However, they exhibit a different
configuration of nonequivalent groups around a stereogenic center (in most cases a

Isomers
Same stoichiometric molecular formula,
but different constitution or arrangement
of their atoms in space.

Binding pattern identical?

No Yes

Constitutional isomers Stereoisomers

Differ the way the atoms are connected Differ in arrangement of their atoms
CH3 in space

CH3-CH2-CH2-CH2OH CH -CH2OH
CH3
Mirror images?
1-propanol 2-propanol

No Yes

Diastereoisomers Enantiomers
Stereoisomers that are not related as Nonsuperimposable mirror images
mirror images of each other
Cl Cl H Cl CH3 Br
C C C C H C Br H C CH3
H H Cl H
C2H5 C2H5
cis-1,2- trans-1,2-
dichloroethylene dichloroethylene R-2-bromobutane S-2-bromobutane

FIGURE 1.1 Overview of isomerism.

Pharmacological Importance of Chiral Separations 3

O O H H
HO H H HO
N N
H2N H2N
H CH3 Diastereomers H3C H
HO HO
(R,S)-labetalol (R,R)-labetalol

Enantiomers Enantiomers

O Diastereomers O H H
H OH H HO
N N
H2N H2N
H3C H H CH3
HO HO
(S,R)-labetalol (S,S)-labetalol

FIGURE 1.2 The relationship between the diastereoisomers of labetalol.

carbon atom). They possess identical physicochemical properties in achiral media.

However, each enantiomer rotates the plane of polarized light in opposite direction,
the degree of rotation being identical (same number of degrees, but in opposite
direction). A second type of stereoisomers, referred to as diastereoisomers, are mole-
cules that are not mirror images of each other. Diastereoisomers, unlike enantiomers,
do exhibit different physicochemical properties. One example of diastereoisomerism
is the cis–trans isomers (Figure 1.1). Another example are molecules that contain at
least two chiral centers. In molecules with n (more than 1) chiral centers, the maxi-
mal possible number of stereoisomers is 2 n. Such a molecule possesses n pairs of
enantiomers and the remaining stereoisomers are diastereoisomers. An example is
given in Figure 1.2. The adrenoreceptor blocking agent labetalol has two chiral centers
and therefore, it possesses four stereoisomers of which two pairs of enantiomers.
Another well-known example is ephedrine and pseudoephedrine.

1.2 CHIRALITY
The term chirality originates from the Greek word “χειρ,” meaning hand, and it
describes drugs which have the property of molecular asymmetry and therefore exist
as a pair of nonsuperimposable mirror images. In 1848, Louis Pasteur initiated the
study of the physical and chemical properties of asymmetric molecules. He discov-
ered that tartaric acid exists as two crystalline salts, which rotate the plane of polar-
ized light in opposite directions [4].
The chiral center is usually, but not obligatory, a carbon atom. A chiral center is
then formed when four different groups are linked to the same carbon atom. Less
commonly, other atoms including phosphor, sulfur, and nitrogen may also form a
chiral center. A racemate is an equimolar mixture of a pair of enantiomers. It does
not show optical activity. Both enantiomers, on the other hand, have the ability to
rotate the plane of polarized light. Both with the same number of degrees, although in
4 Chiral Separations by Capillary Electrophoresis

opposite direction. The enantiomer that rotates the plane of polarized light clockwise
is called dextrorotatory and this is indicated by a d- or (+)-sign before the chemical
name. The enantiomer that rotates the plane counterclockwise is termed levorotatory
and is designated by the prefix l- or (−). This method of designation is based upon a
physical property of the molecule and it does not provide any information concern-
ing the absolute configuration or three-dimensional arrangement of atoms around
the chiral center [5,6]. Since both the direction and magnitude of rotation may vary
with experimental conditions, like for example the solvent, one should look carefully
at using the direction of rotation as a stereochemical descriptor [5].
Currently, the International Union of Pure and Applied Chemistry (IUPAC)
recommends the Cahn–Ingold–Prelog method of designation. This model uses the
absolute structural configuration of the enantiomers. It does not relate to the direc-
tion of rotation of polarized light. The enantiomers are classified R (rectus) or S
(sinister), according to the sequence-rule procedure [7,8]. In this sequence rule,
the atoms attached to a chiral center are assigned priorities according to some
rules. The most important are the atomic number and mass. In Figure 1.3, a car-
bon atom is depicted to which four different ligands (a, b, c, d where a > b >c >d)
are attached. If the left molecule is viewed remote from the group with the lowest
priority d, the path from a to b to c follows a clockwise direction. This molecule is
assigned as the R configuration. In the molecule, on the right-hand side, the path
from a to b to c traces a counterclockwise direction. This molecule is assigned as
the S-enantiomer.
A third way of designation, the d/l convention, is commonly used by biochemists
to describe the stereochemical configuration of sugars and amino acids. This des-
ignation should not be confused with the d/l nomenclature. Sugars are designated
as d or l corresponding to the configuration of the chiral carbon farthest from the
carbonyl group, using d- and l-glyceraldehyde as reference molecules. In the case
of α-amino acids, the molecule is viewed along the C–H axis between the hydrogen
and the asymmetric carbon atom. If the clockwise order of the other three groups is
–COOH, –R, –NH2, then the amino acid belongs to the d-series; otherwise it belongs
to the l-series.

a a

d b d c

c b

R S

FIGURE 1.3 The R/S convention. A carbon atom is depicted to which four different ligands
a, b, c, d are attached, where a > b > c > d. When the left molecule is viewed remote from the
group with the lowest priority d, the path from a to b to c follows a clockwise direction. This
molecule is assigned the R configuration. In the molecule on the right, the path from a over b
to c traces a counterclockwise direction. This molecule is assigned the S-enantiomer.
Pharmacological Importance of Chiral Separations 5

Enantiomers have the same physicochemical properties (e.g., melting point,

solubility, etc.) in achiral media. Any passive, nonstereoselective pharmacological
process will be identical for both enantiomers. Even so, they should be considered
as different chemical entities. Since the molecules they interact within biological
systems are chiral, differences in potency, pharmacological activity, and pharma-
cokinetic profile can occur between enantiomers. At the molecular level, biological
systems are homochiral. The essential amino acids are all l-enantiomers, whereas
carbohydrates have the d-configuration. Therefore, when a chiral, exogenous com-
pound is introduced into the body, physiological processes will show a high degree
of chiral distinction. Each enantiomer will interact differently with chiral targets
as receptors, enzymes, and ion channels. Consequently, this could lead to different
effects observed for the enantiomers. If the chiral center of the molecule is involved
in the interaction with these targets, large differences between the enantiomers can
be observed. As a result, both enantiomers of a chiral compound can differ in their
pharmacological and toxicological properties. The more active enantiomer is called
eutomer and the less active, the distomer. However, these terms can be misleading
as seen in the example of propoxyphene. Dextropropoxyphene is the eutomer for its
analgesic properties, but it is the distomer when the antitussive properties are con-
sidered [9]. The ratio of the activity of the eutomer and distomer, the eudismic ratio,
is a measure of the stereoselectivity [10].
Despite the early understanding that enantiomers often differ in potency, the
stereospecific aspects of chiral drugs were completely ignored till the 1980s [11–13].
A major reason was that the available synthesis methods yielded racemates and
that full-scale production of pure enantiomers was not judged to be feasible, as
well for technical as for economical reasons [11]. In most cases, the pharmaco-
logical and clinical evaluation was therefore carried out with racemates and using
achiral analysis methods. In 1984, Ariëns described this practice as “sophisticated
nonsense in pharmacokinetics and clinical pharmacology” [10]. Since then there
was an emerging growth in chemical technologies, allowing the production of pure
enantiomers. For their development of catalytic asymmetric synthesis Knowles,
Noyori, and Sharpless, were awarded the Nobel Prize in Chemistry in 2001. Also
large advances were made in the development of stereoselective analysis methods,
which opened opportunities to study the importance of stereospecificity in phar-
macology [11,12].
The goal of this chapter is to give an overview of all potential differences in
pharmacodynamic properties and pharmacokinetic effects between enantiomers of
a chiral drug. To illustrate this, several examples will be given. However, we do not
aim at given a complete overview of all the existing literature.

1.3 STEREOSELECTIVITY IN PHARMACODYNAMICS

Pharmacodynamics is the study of the biochemical and physiological effects of drugs
and their mechanisms of action. Four possible reasons can be given for differential
effects of enantiomers in vivo.
Firstly, most of the pharmacological activity can reside in one enantiomer. The
other enantiomer, which can be regarded as an impurity, can be inactive or even be
6 Chiral Separations by Capillary Electrophoresis

responsible for toxic effects. Thus, the racemate can contain up to 50% of impu-
rity or ballast. Examples are escitalopram and levodopa. Escitalopram is the active
S-enantiomer of citalopram, a selective serotonin reuptake inhibitor. It is approxi-
mately 100 times more potent as reuptake inhibitor than its R-enantiomer [14–17].
While the R-enantiomer is practically devoid of uptake inhibition potency, it does
appear to interact with histamine receptors. Therefore, the single enantiomer drug
escitalopram will be less sedating than the racemate [16]. In addition, it has been
shown that R-citalopram counteracts the binding of escitalopram to the allosteric
site of the serotonin transporter [18]. Serious side effects limited the use of racemic
dopa for the treatment of Parkinson’s disease. These adverse effects included nau-
sea, vomiting, anorexia, involuntary movements, and granulocytopenia. The use of
levodopa instead of the racemate was found to halve the required dose, to reduce
toxicity, and to improve the motor function. The occurrence of granulocytopenia was
related to the dextrorotary enantiomer [3].
Secondly, the two enantiomers can have almost identical qualitative and quan-
titative pharmacological activity. The enantiomers of promethazine, for example,
have nearly identical antihistaminic properties and toxicity [5,19,20]. Similarly, both
enantiomers of flecainide and propafenone have equivalent antiarrhythmic potency
[5,20,21].
Thirdly, the enantiomers can possess similar pharmacological properties;
however, they can differ in potency. Most chiral drugs belong to this category.
Examples of this class of chiral drugs are warfarin, verapamil, levocetirizine,
and (R,R)-methylphenidate. S-warfarin has a five times larger anticoagulant
potency than its antipode R-warfarin [15,22,23]. S-verapamil is approximately
20 times more potent than its R-enantiomer with regard to negative dromotropic
effects on atrioventricular node conduction [24]. Levocetirizine has an approxi-
mately 30-fold higher affi nity for human H1-receptor than dextrocetirizine [25].
(R,R)-methylphenidate, used for the treatment of attention-deficit hyperactivity
disorder, is approximately 10 times more potent than (S,S)-methylphenidate in
the inhibition of dopamine and noradrenaline from striatal and hypothalamic
synaptosomes respectively [26].
Fourthly, enantiomers can have qualitatively different pharmacological activities.
For example, dextropropoxyphene is used as an analgesic while levopropoxyphene
has antitussive properties. Another example is the mixed adrenoreceptor blocker
labetalol. The (S,R)-isomer has α-blocking effects, while the β-blocking activities
are due to the (R,R)-isomer [19,27].
According to these pharmacodynamic differences seen between enantiomers,
in several cases the use of a single enantiomer instead of the racemate could be
suggested. However, it is not always clear-cut as seen in the example of ibuprofen.
Although R-ibuprofen is not active, it is the precursor of the active S-enantiomer
via a unidirectional metabolic chiral inversion pathway (Figure 1.4). R-ibuprofen
is metabolized to an intermediary R-CoA thioester which is then epimerized to an
S-CoA thioester and in turn converted to S-ibuprofen. This results in a nonsignificant
difference in activity in vivo between the racemate and the individual enantiomers
[3,20,28–31]. Another example is the well-known thalidomide. Racemic thalidomide
was introduced as a relatively safe sedative drug in the late 1950s, but soon thereafter
Pharmacological Importance of Chiral Separations 7

H Acyl CoA H
H3C H3C
synthetase
CH-CH2 C CH3 CH-CH2 C CH3
H3C COOH Thioesterase H3C CO SCoA

R(–)-ibuprofen R(–)-ibuprofen-CoA

Epimerase

CH3 H3C CH3

H3C Thioesterase
CH-CH2 C H CH-CH2 C H
H3C COOH H3C SCoA
CO

S(+)-ibuprofen S(+)-ibuprofen-CoA

FIGURE 1.4 Stereospecific inversion of R- to S-ibuprofen. (Adapted from Ali, I. et al.,

Chirality, 19, 453, 2007. With permission; From Tan, SC. et al., Enantiomer, 4, 195, 1999.
With permission.)

it was withdrawn because it caused serious fetal malformations [11,32]. Studies have
shown that the sedative effect of thalidomide is related to the R-enantiomer and that
probably the S-enantiomer is responsible for the teratogenic effect [32]. These find-
ings have led to the wrong statement in literature that the thalidomide tragedy could
have been avoided if only the R-enantiomer would have been used. Since rapid race-
mization occurs in vivo, their difference in toxicity cannot be exploited [2]. Indeed,
the enantiomers of thalidomide undergo spontaneous hydrolysis and fast chiral
interconversion at physiological pH [20,32]. Since 1998, the use of thalidomide is
again approved by the Food and Drug Administration. However, now it is used for
the treatment of the debilitating and disfiguring lesions associated with erythema
nodosum leprosum (ENL), a complication of Hansen’s disease, commonly known
as leprosy. Recently, thalidomide was also approved for the treatment of multiple
myeloma. Known or possible pregnancy is of course an absolute contraindication to
the use of thalidomide [32].

1.4 STEREOSELECTIVITY IN PHARMACOKINETICS

Besides pharmacodynamic considerations, the pharmacokinetic properties must
also be taken into consideration. Pharmacokinetics refers to how the body affects the
drug and how the body handles absorption, distribution, metabolization, and excre-
tion of drugs in relation to their pharmacological, therapeutic, or toxic response [19].
The pharmacokinetic importance of drug chirality depends on the process under
consideration. Stereochemistry does not influence passive processes such as diffu-
sion across membranes. However, when an enzyme or transporter system is involved,
chiral discrimination can be observed [33,34]. Enantiospecificity in pharmacoki-
netics is generally quite low and the contribution to the eudismic ratio is usually
quite small. However, the clinical implications with respect to dosages and routes of
administration may be very important [6].
8 Chiral Separations by Capillary Electrophoresis

1.4.1 ABSORPTION
Absorption is the process of the movement of the drug from the place of adminis-
tration into the bloodstream. This process requires the transport of drug molecules
through cell membranes. Three possible mechanisms are described: passive dif-
fusion through the membrane, facilitated diffusion via channels or carriers, and
active transport via carriers and pump systems. The absorption of most drugs is
a passive process; however, drugs can also be absorbed via active processes like
receptor-mediated transport. Active absorption may favor one enantiomer or the
two enantiomers may differ in absorption characteristics. l-Dopa, for example, is
actively absorbed from the gastrointestinal tract. d-Dopa, on the other hand, enters
the bloodstream via passive diffusion [20].
The absorption rate is also an important parameter. An example is ibuprofen that
is already described earlier. The chiral inversion of inactive R-ibuprofen to the active
S-enantiomer in the gastrointestinal tract depends on the absorption rate: the longer
the drug stays in the gastrointestinal tract (i.e., low absorption rate), the greater will
be the extent of inversion [35].

1.4.2 DISTRIBUTION
Once the drug is available in the bloodstream, it will distribute throughout the
different compartments of the body. Two physicochemical properties are essentially
responsible for the distribution of drugs: plasma- and tissue protein binding and
the partition coefficient. Partitioning into various sites is a physical property and is
therefore not considered as enantioselective. However, binding to proteins, which
consists of chiral building blocks, can show stereoselectivity.
Stereoselective binding of chiral drugs to serum albumin and α1-acid glyco-
protein has already been shown. For example, the affinity for the binding of the
essential amino acid S-tryptophan to the benzodiazepine and indole site of human
serum albumin is about 100 times greater than that of R-tryptophan. An interesting
example is the antihypertensive drug propranolol. S-propranolol binds to α1-acid
glycoprotein to a slightly greater extent than R-propranolol [19,27,35]. However, the
stereoselective binding to human serum albumin is opposite of that observed for
α1-acid glycoprotein [20]. The overall stereoselectivity in the binding of propranolol
to human serum resembles that seen for α1-acid glycoprotein, meaning that the
free fraction of the R-enantiomer is higher than that of the pharmacological active
S-enantiomer [27].
Stereoselective distribution may also occur as a result of drug–lipid interactions.
Hanada et al. [36] have observed stereoselective binding of verapamil and disopyra-
mide to phosphatidylserine, a tissue-binding site for basic drugs, with R-verapamil
and R-disopyramide being preferentially bound [20,21,36].
Stereoselective interactions with tissue uptake transporter systems and storage
mechanisms have also been reported [20]. van Bree et al. [37] have studied the trans-
port of baclofen and its enantiomers across the blood–brain barrier in rats. They
showed that the blood–brain barrier clearance of R-baclofen was approximately four
times higher than that of the S-enantiomer. On the basis of their obtained results,
Pharmacological Importance of Chiral Separations 9

they hypothesized that S-baclofen is preferentially transported into the central

nervous system. Barraud de Lagerie et al. [38] demonstrated that in mice mefloquine
enantiomers undergo efflux in a stereoselective manner and that this stereoselectiv-
ity was due to the efflux proteins P-glycoprotein and/or breast cancer resistance
protein. Alves et al. [39] studied the stereoselective disposition of the antiepileptic
drug licarbazepine in mice. Although both enantiomers had comparable systemic
exposure, the extent of brain penetration for S-licarbazepine was found to be two
times higher than for the R-enantiomer. Further investigations into the exact mecha-
nism still have to be performed.

1.4.3 METABOLIZATION
Much of the stereoselectivity observed in pharmacokinetics is caused by stereose-
lective metabolic pathways. Both phases I and II metabolic reactions are capable of
discriminating between enantiomers. Three different groups can be distinguished
and are discussed in the following.

1.4.3.1 Substrate Stereoselectivity

Substrate stereoselectivity is the preferential enzymatic metabolization of one
enantiomer. The oxidation of warfarin in human, for example, is stereoselective for
the S-enantiomer of the drug yielding (S)-7-hydroxywarfarin [23,33].
Both enantiomers of omeprazole are prodrugs, which are converted within the
+ +
parietal cell to the active proton pump (H , K -ATPase) inhibitor, an achiral sulfen-
amide. Therefore, once within the parietal cell, R- and S-omeprazole are equipotent
inhibitors of H+, K+-ATPase. However, in vitro experiments have shown that there
is a significant stereoselectivity in the metabolism of the enantiomers of omepra-
zole. The three main metabolites are omeprazole sulfone, 5-hydroxy-omeprazole,
and 5-O-desmethyl omeprazole. The hydroxy and 5-O-desmethyl metabolites of
both enantiomers are mainly formed by CYP2C19, whereas sulfoxidation is cat-
alyzed by CYP3A4. S-omeprazole (also called esomeprazole) is metabolized to
a relatively greater extent via CYP3A4 compared to the R-enantiomer, which is
almost completely metabolized by CYP2C19. In addition, the intrinsic clearance of
esomeprazole is approximately three times lower than that of R-omeprazole, mainly
due to its lower intrinsic clearance through CYP2C19 to the 5-hydroxy metabolite
(Figure 1.5). Consequently, increased plasma concentrations of esomeprazole and
an increased inhibitory effect on acid secretion are observed. As a result, at equal
doses, esomeprazole achieves 70%–90% higher steady-state serum concentrations
than the racemic omeprazole [40–44].
Substrate stereoselectivity also includes enantiomer inversion and fi rst-pass
metabolism. Examples of enantiomer inversion have already been described in
Section 1.3. Enantiomer inversion has been extensively described for several
2-arylpropionic acid derivatives, the so-called profens. In Section 1.3, the chiral
inversion of R-ibuprofen to the active S-ibuprofen is, for example, shown. A well-
known example of stereoselectivity in fi rst-pass metabolization is verapamil.
This l-type calcium channel blocker is less potent after oral administration than
following single intravenous administration. It has been shown that after oral
10 Chiral Separations by Capillary Electrophoresis

CLint Metabolites CLint

4.0 40
2C19 6.7 Hydroxy 1.8 2C19
Esomeprazole R-isomer
3A4 5-O-Desmethyl 3A4
3.9 0.8
Sulphone
Total CL int = 14.6 Total CL int = 42.6

FIGURE 1.5 Metabolism scheme illustrating the intrinsic clearance values (CLint) for
the different metabolic pathways of esomeprazole and R-omeprazole from in vitro experi-
ments on human liver microsomes [40,43]. (Reproduced from Andersson, T. et al., Clin.
Pharmacokinet., 40, 411, 2001. With permission.)

administration of racemic verapamil, the proportion of the pharmacologically

more active S-enantiomer of the total plasma verapamil concentration is substan-
tially lower than that of the R-enantiomer [5,24,45]. This can be explained by
stereoselective differences in the first-pass metabolism of both enantiomers
following single oral administration of racemic verapamil [46].

1.4.3.2 Product Stereoselectivity

In this case, an achiral drug is transformed into chiral metabolites. In Figure 1.6, it
is shown how some reductive or oxidative metabolization reactions can form new
chiral centers.

R R H
*
C O C
R1 R1 OH
(a)

R H
R1 R
* R1
C C C C
H
H R2 R2
H
(b)
R R
*
S S O
R1 R1

(c)
R R OH
*
CH2 C

R1 R1 H
(d)

FIGURE 1.6 Introduction of new chiral centers via reductive and oxidative metaboliza-
tion pathways. (a) Reduction of carbonyl to alcohol, (b) hydrogenation of alkenes to alkanes,
(c) sulfoxidation, and (d) hydroxylation. Asterisks indicates chiral center.
Pharmacological Importance of Chiral Separations 11

OH

N N
*
O N O O N O

FIGURE 1.7 p-Hydroxylation of phenytoin. Asterisks indicates chiral center.

O HO

N N

O NH2 O NH2
(a) (b)

FIGURE 1.8 Structure of (a) oxcarbazepine and (b) licarbazepine. Asterisks indicate the
chiral center.

An example of product stereoselectivity is the aromatic p-hydroxylation of one of

the phenyl rings of phenytoin, creating a chiral center at C-5 of the hydantoin ring
(Figure 1.7) [31,34]. A second example is the antiepileptic drug oxcarbazepine. In
humans, this achiral prodrug is rapidly reduced in the liver to the pharmacologically
active and chiral metabolite 10-hydroxycarbazepine or licarbazepine (Figure 1.8).
This metabolic reduction is stereoselective, resulting in a 4:1 ratio between the active
S-enantiomer and R-licarbazepine [39,47].

1.4.3.3 Substrate–Product Stereoselectivity

Substrate–product stereoselectivity means the stereoselective metabolization of
one of the enantiomers whereby another chiral center is introduced and diastere-
oisomers are thereby formed. Warfarin is metabolized via two principal routes:
aromatic hydroxylation of the coumarin ring (see substrate stereoselectivity) and
ketone reduction in the side chain that produces a new chiral center (Figure 1.9).
The latter pathway shows marked substrate stereoselectivity for the R-enantiomer,
as well as product stereoselectivity, namely, the formation of alcohols of the
S-configuration [23,33,48].

CH3 CH3

OH O OH * OH

* *

O O O O

FIGURE 1.9 Structure of warfarin and warfarin alcohol. Asterisks indicate the chiral center.
12 Chiral Separations by Capillary Electrophoresis

1.4.4 RENAL EXCRETION

Renal excretion consists of glomerular filtration, with or without additional tubu-
lar secretion and/or tubular reabsorption. Since glomerular filtration is a passive
process, stereoselectivity may only be observed with tubular secretion that occurs
via active processes or with tubular reabsorption. Although tubular reabsorption is
usually passive, it may also be active. However, only few examples of active tubular
reabsorption exist [25]. In contrast, tubular secretion is an active process consist-
ing of uptake from blood across the basolateral membrane of renal epithelial cells
followed by efflux into urine across the apical membrane [25]. Apparent stereose-
lectivity in renal clearance may also be observed as a consequence of preferential
protein binding, since only the unbound fraction of the drug is available for glom-
erular filtration [20,25].
Cetirizine is mainly eliminated unchanged in urine through both glomerular
filtration and tubular secretion. The higher renal clearance of dextrocetirizine is
partly due to the higher unbound fraction available for glomerular filtration com-
pared to levocetirizine. However, the major difference in renal clearance between
both enantiomers is determined by stereoselectivity in tubular secretion. The exact
mechanism leading to a higher tubular secretion of the distomer is not known. It may
be due to the higher free fraction available for secretion and/or to a higher affinity
for renal drug transporters [25].

1.5 INTERSPECIES DIFFERENCES

An important aspect to remember is that some drugs can display significant interspe-
cies differences. An interesting example is the proton pump inhibitor omeprazole.
Initial in vivo experiments to assess the plasma concentrations following oral admin-
istration and the effects on stimulated acid secretion of both omeprazole enantiomers
were carried out in rats as well as in dogs. No differences between the enantiomers
could be detected in the dog. However, in the rat the R-enantiomer was significantly
more active than the S-enantiomer or the racemate. In contrast, the S-enantiomer
exhibited the highest bioavailability and oral potency in inhibiting gastric acid secre-
tion in humans [41].

1.6 PATIENT-SPECIFIC FACTORS

Various factors related to the drug and the patient may affect the stereospecificity seen
in the pharmacodynamics and kinetics. Factors related to the drug include the dosing
rate, interaction between both enantiomers, and interaction between the enantiomers
and other drugs. These factors will be discussed in the next section. Patient-related fac-
tors include age, gender, disease state, and the patient metabolic profile [27,49].

1.6.1 AGE
Some studies have found that different age groups may be associated with age-
specific levels of exposure to drug enantiomers [49]. One example is here given. Tan
et al. [50] have shown that in elderly volunteers the free fraction of S-ibuprofen, and
Pharmacological Importance of Chiral Separations 13

not of the R-enantiomer, was increased when compared to young volunteers. They
also observed a decrease in the clearance of S-ibuprofen, particularly via oxida-
tive pathways, in these elderly volunteers. This higher availability of the active
S-enantiomer may contribute to the incidence of adverse reactions observed in the
elderly population.

1.6.2 GENDER
Not so much information can be found concerning the gender differences on the
level of stereoselective dispositions [49]. Although the antihypertensive effect of
labetalol was the same for men and women, the total plasma concentrations were
80% higher in women. This discrepancy could be explained by stereoselective
differences in the pharmacokinetics of the labetolol isomers in both groups. Indeed,
while the concentration of the (S,R)-isomer which has α-blocking properties and the
two relatively inactive (S,S)- and (R,S)-isomers were between 60% and 80% higher
in women, the concentrations of the main β-blocking (R,R)-isomer were the same in
both groups. This explains why similar antihypertensive effects were observed in
men and women [27,51].

1.6.3 GENETIC FACTORS

Genetic factors are known to be significant in drug disposition, particularly for
those agents whose metabolism is associated with the debrisoquine oxidation
genetic polymorphism [5]. Approximately 10% of the Caucasian population is
deficient in the expression of the cytochrome P450 isozyme CYP2D6. They are
called poor metabolizers. CYP2D6 activity ranges from complete deficiency in
these poor metabolizers, over extensive metabolism (homozygous and heterozy-
gous) to ultrarapid metabolism [52]. The administration of a racemate, which
is substrate for CYP2D6, to one of these subtypes may lead to different drug
concentrations and enantiomeric compositions depending on the phenotype.
Therefore, the therapeutic response may be influenced by the genetic make-up
of the patient. Scordo et al. [52] have studied the influence of CYP2D6 genetic
polymorphism on the steady-state plasma concentrations of the enantiomers of
fluoxetine and norfluoxetine. They observed a significantly higher S-norfluoxetine/
S-fluoxetine ratio in homozygous compared to heterozygous CYP2D6 extensive
metabolizers. In addition, very low concentrations of S-norfluoxetine and very
low S-norfluoxetine/S-fluoxetine and S/R-norfluoxetine ratios were seen in the
CYP2D6 poor metabolizers included in their study. These fi ndings led to the sug-
gestion that CYP2D6 plays a role in the stereoselective conversion of S-fluoxetine
to S-norfluoxetine [52].
Genetic polymorphism also exists for CYP2C19 expression, with approximately
3%–5% of Caucasian, 4%–7% of the black Africans, and 15%–20% of Asian popula-
tions being poor metabolizers with no CYP2C19 function [12,51]. This isoenzyme
is also called mephenytoin hydroxylase. An example is the proton-pump inhibitor
omeprazole, which showed a significant intervariability in its pharmacokinetics and
also regarding its effect on gastric acid secretion. This difference in response was
14 Chiral Separations by Capillary Electrophoresis

especially pronounced between slow and rapid metabolizers, since omeprazole is

mainly metabolized by CYP2C19. After repeated administration of esomeprazole
or racemic omeprazole to extensive metabolizers, the area under the curve (AUC)
of esomeprazole was found to be twofold higher than that of omeprazole. In poor
metabolizers the plasma concentrations of esomeprazole were lower than those of
omeprazole. Thus, the use of the single enantiomer drug esomeprazole results in less
overall variability in the pharmacokinetics. This demonstrates the lower influence
of CYP2C19 on the metabolism of esomeprazole as compared with omeprazole (see
also Section 1.4.3.1) [12,40,42–44].

1.6.4 DISEASE STATE

Disease states may cause changes in enantiomer ratios of pharmacokinetic parame-
ters [49]. For example, Jamali et al. [53] have observed that surgery for wisdom tooth
removal resulted in substantial decrease in the serum concentration of both ibuprofen
enantiomers and in delayed absorption of the enantiomers. In addition, dental extrac-
tion resulted in a reversal of the serum ibuprofen enantiomer concentrations, result-
ing in lower concentrations of the active S-enantiomer. The authors suggested that
this may be as a result of a change in the metabolic chiral inversion of R-ibuprofen to
the pharmacological more important S-enantiomer. Thus, dental patients may expe-
rience a delay of onset of the pain relief and even treatment failure may occur in
patients taking a normal dose (200–600 mg) of ibuprofen after surgery.
Differences in both pharmacodynamic effects and pharmacokinetic profile of
drugs undergoing significant and enantioselective first-pass metabolism can be
observed in patients with liver cirrhosis [5]. Neugebauer et al. [54] have shown that
in patients with liver cirrhosis, the hepatic first-pass extraction of the antihyperten-
sive drug carvediol is markedly reduced, eliminating the difference in bioavailability
between the two enantiomers which is observed in healthy subjects.
Similarly, in renal disease patients, Imamura et al. [55] have demonstrated that
the stereoselective serum protein binding of the beta-adrenergic blocking agent
alprenolol, seen in healthy volunteers, was significantly altered. Alprenolol mainly
binds to α1-acid glycoprotein, whose levels are increased in case of renal disease.
Consequently, the binding percentage of alprenolol in serum was higher in renal
disease patients compared to healthy volunteers. Since the pharmacologically active
S-enantiomer has a higher binding constant for this protein than R-alprenolol,
the free concentration of S-alprenolol decreased more markedly than that of the
R-enantiomer.

1.7 DRUG-RELATED FACTORS

1.7.1 INPUT RATE
An alteration in the oral input rate may affect the plasma concentrations of both
enantiomers of a racemic drug. A significant effect on first-pass metabolism and sub-
sequently on the clinical response can be observed, especially for drugs with a high
hepatic extraction rate, like verapamil and metoprolol [27]. For example, significant
Pharmacological Importance of Chiral Separations 15

different R/S ratios of verapamil in plasma were observed when racemic verapamil
was administered either in an immediate release or sustained release formulation
[56,57]. Mistry et al. [58] have studied the influence of the input rate on the ste-
reoselective pharmacokinetics of metoprolol. They have shown that the S/R ratio
for plasma metoprolol concentrations show significant differences in the absorption
phase (1–4 h) versus the terminal elimination phase (8–16 h) when fast input of the
drug is obtained. However, slow input displayed no significant difference in S/R ratio
between the absorption and elimination phase.

1.7.2 INTERACTIONS
The two enantiomers of a racemic drug may interact with each other at different
pharmacokinetic or pharmacodynamic levels. The R-enantiomer of propafenone,
a class Ic antiarrhythmic drug, for example, reduces the metabolism of the
S-enantiomer, leading to a significantly reduced oral clearance of S-propafenone
in the presence of the R-enantiomer [21]. When the enantiomers of disopyramide,
a class Ia antiarrhythmic drug, were administered separately to humans, no dif-
ferences in clearance, renal clearance, or volume of distribution were observed.
However, when racemic disopyramide was given, an important pharmacokinetic
interaction was observed, resulting in lower plasma and renal clearance, a longer
half-life, and a smaller volume of distribution for the S-enantiomer [6,45].
In addition to enantiomer–enantiomer interactions, a racemic drug may interact
stereoselectively with other drugs. For instance, the anticoagulant warfarin exhib-
its enantiomer–enantiomer interactions and in addition its elimination is altered in
a stereospecific manner by cimetidine [19,21]. R-warfarin inhibits the hydroxyla-
tion of S-warfarin, the pharmacologically more active enantiomer [59]. In addi-
tion, cimetidine decreases the rate of metabolism of R-warfarin and not that of the
S-enantiomer [60,61]. This results in an accumulation of R-warfarin which in turn
further suppresses the metabolism of S-warfarin. As a result, the active S-enantiomer
is accumulated and an increased anticoagulant activity is observed [19].

1.8 SINGLE ENANTIOMER VERSUS

RACEMATE—“CHIRAL SWITCHES”
Besides de novo synthesis of an enantiomerically pure drug, like the cholesterol
lowering drug rosuvastatine and the antiepilepticum tiagabine, there is also the pos-
sibility of switching from the existing racemic drug to the single enantiomer of
that drug. Chiral switches are defined as drugs that have already been claimed,
approved and/or marketed as racemates or a mixtures of diastereoisomers, but have
since been redeveloped as single enantiomers [2,62,63].
Since the early 1980s, the importance of stereochemistry and the use of sin-
gle enantiomers instead of the racemate have been debated [4,64]. The European
Medicines Evaluation Agency (EMEA) states in its guideline on investigation of
chiral active substances that if a new racemate appears promising, both enantiomers
should also be studied as early as possible to assess the relevance of stereoisomerism
for effects and fate in vivo [65].
16 Chiral Separations by Capillary Electrophoresis

Four reasons for considering the enantiomers instead of the racemate are
proposed [64]. Firstly, the use of a single enantiomer may allow the reduction of
the dose while either maintaining or improving outcome. Secondly, the assessment
of the dose–response relationship of a single enantiomer may be simpler than for
a racemate. Thirdly, pharmacodynamic and pharmacokinetic variability between
patients may be reduced and fourthly, any toxicity from the inactive enantiomer
may be minimized [4,45,63,66]. Another reason, commercially, is that when patents
on racemic drugs expire, pharmaceutical companies may have the opportunity to
extend patent coverage through development of the chiral switch enantiomers with
desired bioactivity.
Although the aforementioned reasons appear to present compelling arguments
in favor of single enantiomers, there have been commercial failures as well as
successes [66]. In the case of bupivacaine, for example, improved tolerability was
gained using levobupivacaine. In 1979, seven cases of sudden cardiovascular col-
lapse with difficult resuscitation or death were reported after intravenous injection
of racemic bupivacaine. Levobupivacaine is significantly less cardiotoxic than the
racemate and has the same anesthetic profile. Therefore, the racemate was replaced
by the single enantiomer [66–68]. On the other hand, not all chiral switches were
as promising as levobupivacaine. The anorectic agent fenfluramine was one of the
first to undergo the chiral switch process with the marketing of the dextrorotary
S-enantiomer, dexfenfluramine. The levorotatory R-enantiomer was responsible for
most of the side effects seen with the racemate. Both fenfluramine and dexfenflu-
ramine were, however, withdrawn from the market because of a perceived risk of
pulmonary hypertension [2,14,66,68].
Besides switching from a racemate to an active enantiomer, the drug can also be
replaced by the active, chiral metabolite and, if possible, by the active enantiomer
of this metabolite. An example is the switch of hydroxyzine to its racemic active
metabolite cetirizine. Cetirizine is formed from oxidation of the primary alcohol of
hydroxyzine (Figure 1.10) [69,70]. Levocetirizine, the active enantiomer of cetiriz-
ine, is also on the market. A second example is eslicarbazepine, the S-enantiomer
of licarbazepine. Eslicarbazepine is a new drug currently undergoing clinical devel-
opment for the treatment of epilepsy [39]. Licarbazepine is the active metabolite
of oxcarbazepine (Figure 1.8). More information concerning these compounds is
already given in Section 1.4.3.2.

Cl

* CH N N CH2-CH2-O-CH2-R

FIGURE 1.10 Structures of hydroxyzine (R=CH2OH) and cetirizine (R=COOH). Asterisks

indicate the chiral center.
Pharmacological Importance of Chiral Separations 17

1.9 THE NEED FOR ANALYTICAL TOOLS

The knowledge of chirality of drugs exists already for a long time. However, until the
development of analytical tools that were able to discriminate between enantiomers,
not much research could be done. Enantioselective analysis methods were required
not only for pharmacodynamic and pharmacokinetic studies, but also for toxicologi-
cal studies, in development and during quality control of drug substances and drug
products. Thus, there was a real need for stereospecific detection, identification, and
quantification of individual enantiomers of drugs and their metabolites in various
biological media [19]. Even if a drug is given as a pure enantiomer, methods that can
discriminate between enantiomers will be required because, for example, racemiza-
tion can occur [19].
On analytical scale, a large variety of chromatographic methods, such as liquid
chromatography (LC), gas chromatography (GC), and thin layer chromatography
(TLC) were first developed [71,72]. At present, LC still dominates chromato-
graphic enantiomeric analysis in industry [73]. However, over the lasts two to three
decades capillary electrophoresis (CE) has proven to be a powerful alternative to
chromatography. CE offers a tremendous flexibility for enantiomeric separations,
because a wide variety of chiral additives are available. Compared to other analyti-
cal techniques like LC, CE offers several advantages including simplicity, short
analysis times, high efficiencies, different separation mechanisms, small volumes,
and low running costs. Nowadays capillary electrochromatography (CEC) offers
some alternative mechanisms for solving individual separation problems. CEC
combines features of both CE and LC: the efficiency of CE with the selectivity of
stationary phase. Therefore, it represents a very useful extension to CE [71,74–76].
In Chapters 14 and 15, this technique is further explained.

1.10 INTRODUCTION TO CAPILLARY ELECTROPHORESIS

Electrophoresis as a separation technique was first described by Tiselius in 1937,
for which he was awarded a Nobel Prize in 1948. Tiselius’ basic concept of using a
tube for electrophoretic separation received little notice until Hjerten described the
first CE apparatus in 1967 [77,78]. Even then, CE stayed relatively unknown until
Jorgenson and Lukacs advanced the technique by using 75 μm internal diameter cap-
illaries [78–81].
The European Pharmacopoeia defines CE as a physical method of analysis based
on migration, inside a capillary tube, of charged analytes dissolved in an electro-
lyte solution, under the influence of a direct-current electric field. The separation
of compounds is based upon their charge to mass ratio. The migration of ionic
species through a capillary depends on two forces: the electrophoretic mobility or
the mobility of the ion and the electroosmotic flow or the mobility of the solvent.
The advantages of CE, compared to LC, GC, and TLC, are its simplicity and its
applicability for the separation of a wide range of compounds using the same instru-
ment and, in most cases, the same capillary while changing only the composition of
the background electrolyte. In addition, CE possesses high resolving power due to its
plug flow and minimal diffusion [82]. Although, CE has also a few disadvantages.
18 Chiral Separations by Capillary Electrophoresis

Because of the low injection volume, the concentration sensitivity is low and stacking
procedures are therefore sometimes needed. Compared to LC and GC, precision is
worse due to the different injection mechanism. However, instrument manufacturers
and scientists have worked on improving the system performance. In recent years,
many fully validated CE methods have been described and CE is becoming a well-
established technique not only in academia but also in industry [83].

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electrophoresis to the analysis of small molecules. J Chromatogr A 1023: 1–14.
Exploring the Variety of Random
Documents with Different Content
with frequency pictures of native life that are vivid and finely
written.”

+ N Y Times p10 O 10 ’20 600w

MARTYN, WYNDHAM. Secret of the silver car.

*$1.75 Moffat
20–5579

Another book of the adventures of Anthony Trent, master

criminal. In an indiscreet moment while they were shut in a caved-in
dugout in Flanders, expecting death at any moment, Trent had told
the story of his life to his unknown and unseen companion. Both
escape and with the war over, he sets himself to find this unknown
“William Smith” who knows too much about him for his own safety.
He meets “William Smith’s” sister, falls in love with her and for her
sake resolves to give up his brilliant criminal career. In her service he
goes out to the Balkans, becomes involved in international intrigue,
has many hairbreadth escapes, but secures the papers that mean so
much to Lady Daphne’s father and is rewarded with her hand.

Boston Transcript p6 Jl 3 ’20 300w

“Nor is this book mere swashbuckling. It is written always adroitly,

sometimes humorously, and with the zest of the author’s own
enjoyment.”

+ N Y Evening Post p20 Ap 24 ’20 200w

 Reviewed by M. K. Reely

Pub W 97:996 Mr 20 ’20 320w

+ Springf’d Republican p11a My 16 ’20
200w

MARVIN, FRANCIS SYDNEY, ed. Recent

developments in European thought. *$6.25 Oxford
901
20–17403

“This volume, which is a sequel to ‘The unity of western

civilization’ (1915) and ‘Progress’ (1916), is, like them, the fruit of a
course of lectures given at a summer school at Woodbrooke,
Birmingham. The addresses composing it were given in August, 1919,
and it traces the idea of progress in European history since 1870.
Among the contributors, besides the editor, are Mr A. E. Taylor, who
writes on ‘Philosophy,’ Dr F. B. Jevons, who writes on ‘Religion,’ Mr
A. D. Lindsay, of Balliol, whose subject is ‘Political theory,’ and Mr A.
Clutton Brock, who discusses ‘Art.’ Each article is followed by a
bibliographical note as a guide to further reading.”—The Times
[London] Lit Sup N 11 ’20

Ath p509 Ap 16 ’20 1400w

“In spite of the difficulties of handling the vast intricate masses of

still fluid material, the contributors have given readable and yet
valuable summaries of the progress of thought. For the beginner,
there could be no better introduction to the essential contributions of
man’s recent achievement.” M. J.

+ Int J Ethics 31:114 O ’20 460w

“Naturally, the essays by different authors vary in value. The least

satisfactory is the first, on philosophy.... The most brilliant essays are
those dealing with the fields of thought most intensively cultivated by
the last generation.... Compared with the treatment accorded history,
the studies here offered of political theory and of economic progress
are slightly disappointing.... Taken as a whole, the cumulative
impression of these various lectures is greater than that of any one
taken separately.” Preserved Smith

+ − Nation 111:379 O 6 ’20 1000w

“The personality of each of the twelve writers is given full

expression. It makes the diversity more interesting than the unity.”
H. W. C.

+ − Nature 105:607 Jl 15 ’20 500w

“The aim of the writers is to trace the progress and acquisitions of

thought and give a general picture of the results obtained by modern
knowledge; and they have succeeded in producing essays that are of
a high quality and also thoroughly readable.”

+ The Times [London] Lit Sup p247 Ap

22 ’20 2450w
 The Times [London] Lit Sup p742 N 11
’20 110w

MARX, MAGDELEINE. Woman; tr. by Adele

Szold Seltzer. *$1.90 (6c) Seltzer
20–11894

A translation of a novel that is said to have created a sensation in

France. It is a record of emotional moments. The characters have no
names, no appearances. They are only personalities. The “woman” of
the story loves and marries and bears a child. While still loving her
husband she takes a lover and then loses both husband and lover in
the war. Out of these experiences she emerges invincible, with an
undimmed capacity for life and an indomitable will to live. Henri
Barbusse says in his introduction, “In no other book perhaps so
markedly as in this has the integrity of an individual been more
respected, and never has an imaginary character so consistently
warded off whatever is not of itself. You don’t even seem to feel that
this ‘woman’ talks or tells a story. You simply know what she knows.”

Reviewed by Theodore Maynard

− + Bookm 52:75 S ’20 700w

Dial 69:433 O ’20 70w

“To those in search of a well-written book, not to mention a

contribution to real literature, Magdeleine Marx has nothing
whatever to offer. The style is wordy, pretentious and empty, a
disjointed collection of hollow phrases embodying all the platitudes
of the so-called revolt of woman.” E. A. Boyd

− Freeman 2:43 S 22 ’20 960w

Ind 104:64 O 9 ’20 500w

“The story is frank and sincere and full of isolated perceptions that
are both searching and beautiful. But it is also thin and scrappy and
disjointed, and the complete shadowiness of all the characters robs
its theories of the inner energy of a human content. In a word,
Madame Marx has felt very deeply and reflected intensely, and those
who agreed with her passionately have taken it for granted that she
has written a great book. But that is taking for granted far too much.”
Ludwig Lewisohn

− + Nation 111:134 Jl 31 ’20 900w

“A very great deal of it gives the reader the impression of a mind

out-stretching itself, to the point of dislocating all its joints, in order
to perceive and express something that nobody else has ever
perceived or expressed.”

− N Y Times 25:25 Jl 4 ’20 850w

“The book is written in a resignedly magnanimous strain, and

passages occur, which, taken by themselves, might affect us as noble.
Yet as a whole its absence of elevation in the midst of calls to
elevation is confounding.”

− + Review 3:347 O 20 ’20 750w

 “‘Woman,’ if nothing else, is an interesting psychological study of
the type of mind that dwells upon sex and psychoanalysis with a
neurasthenic intensity, when the world is full to overflowing with
real woman problems.” M. E. Sangster

+ − Social Hygiene 6:590 O ’20 260w

“It does seem to me that the book might more appropriately have
been called ‘A woman.’ For the rest, the book is perfervid in a way
that we do not quite like in America, perhaps because we are not
wholly acclimated to it. It has pages of unusual beauty, and a high
degree of unity and directness.”

+ − World Tomorrow 3:350 N ’20 350w

MASEFIELD, JOHN. Enslaved. *$2.50

Macmillan 821
20–13322

The long narrative poem of the title depicts courage born of love
and begetting the brotherhood of man even in the untamed. A fair
damsel is carried off by a pirate galley into the captivity of a khalif’s
harem. Her lover follows into slavery to rescue her. He does so with
the aid of a brother slave who must kill a traitor to accomplish their
purpose. Recaptured and brought before the khalif they are set free
because their tale causes human stirrings in the hawk breast of the
latter. The other poems are: The hounds of hell; Cap on head;
Sonnets; The passing strange; Animula; The Lemmings; Forget; On
growing old; Lyric.
 + Ath p718 My 28 ’20 60w

“It seems to us that Mr Masefield’s first business is to regain

control of his words; and that he can only do this by deliberately
attempting a subject that bristles with psychological nuances, and
insisting that his language shall accommodate itself to them.
Otherwise we fear he will never succeed in expressing that elusive
beauty which he sees, but which at present comes to us only in
assertion or in fitful gleams through the interstices of an opaque
style.” J. M. M.

+ − Ath p823 Je 25 ’20 2300w

+ Booklist 17:22 O ’20

“Mr Masefield is the single poet writing in English today who both
in popular esteem and by the most exacting critical estimate
legitimately belongs to the august line of poets who are among the
chief glories of our race: to his greatness no journalistic cavil can add
or take away.” R. M. Weaver

+ Bookm 52:65 S ’20 240w

“In this poem, [On growing old], as in so many aspects of the other
poems in this volume, one feels the shadows of the world, deepened
by the tumult of war, settling upon the radiance of a brave visionary
spirit. The thrill, the excitement, the adventures of living are all now
subdued to this key of sadness, in which the passion and beauty that
was once a flame becomes an effable glow.” W. S. B.

+ − Boston Transcript p6 Ag 18 ’20 2400w

 “The whole thing seems bookish, remote, unreal. The characters
do not become sufficiently interesting: seem, in fact, insufficiently
equipped with a back-ground of flesh and blood experience.” J: G.
Fletcher

− + Freeman 2:163 O 27 ’20 1050w

“One of the signs that the times are good in English poetry is the
fact that Mr Masefield keeps on writing poems which tell stories.”
Mark Van Doren

+ − Nation 111:sup670 D 8 ’20 310w

“In his latest volume there are some serious offenses against
rhyming, euphony, and scansion, but in the larger aspects, in the
essential substance and indescribable quality of authentic poesy, he
is more richly endowed than any other living writer.” Lawrence
Mason

+ New Repub 23:340 Ag 18 ’20 1250w

“‘Enslaved,’ his latest book of poems, offers a peculiarly fine view

of Masefield in all his variety. There is no poet in England, unless we
except Hardy, who possesses keener insight into the hearts of men. It
is this attitude toward life, this same fatalism that recognizes the
worst, yet sees the best behind, that makes John Masefield one of the
finest living figures in the whole field of English poetry.”

+ N Y Times 25:1 Jl 11 ’20 2450w

 “A volume which reveals anew the amazing power and versatility
of that English poet.”

+ Outlook 127:68 Ja 12 ’21 450w

“‘Enslaved’ is a dramatic adventure tale. But ‘Enslaved’ is likewise

a dreamy, semi-lyrical, murmurous, and caressing tale. It is
Masefieldian in its power to be both these things at once.” O. W.
Firkins

+ Review 3:317 O 13 ’20 600w

“The book is extraordinarily rich, for it contains beside others,

‘Forget’ and ‘On growing old,’ two of the most beautiful poems that
Mr Masefield ever wrote, and in this age of singers Mr Masefield
remains our poet of greatest achievements.”

+ Spec 124:765 Je 5 ’20 500w

[2]
MASEFIELD, JOHN. Right Royal. *$1.75
Macmillan 821
20–18954

“In ‘Right Royal’ Mr Masefield celebrates in a narrative poem the

story of a horse-race. The story of Mr Masefield’s poem is that of a
horse with great points and virtues, for speed and endurance, but
very undependable, having lost a number of races by going panicky
from fear. He was bought by Charles Cothill, who believed that all his
potential qualities as a winner could be developed. Cothill backed his
own horse to the extent of all his possessions, which created a crisis
in his love for the woman he hoped to marry. If he lost, his love was
lost. In fact, it was win all or lose all.”—Boston Transcript

“It will be acknowledged that the preliminaries of the race, the

discussions in the stables, the professional tips and omens, the
catalogue of the entries, are sandy soil for the growth of poetry. The
best of the poem has no relation to the worst; the worst might have
been sacrificed. Even in the best are imperfections, but we have
learnt to swallow Mr Masefield’s longer poems without straining at
the gnats.” E. B.

+ − Ath p692 N 19 ’20 600w

+ Booklist 17:146 Ja ’21

“It is growing very trite to say that Mr Masefield does this thing or
that thing better than any contemporary poet. He does the things
that nobody else does and is thus in competition with himself. ‘Right
Royal’ may not be as fine a poem as ‘Enslaved,’ but no one can
dispute that it is the best narrative of a horse-race that has been
written by any modern poet.” W: S. Braithwaite

+ Boston Transcript p5 N 20 ’20 1500w

“‘Right Royal’ is a bad poem, both intrinsically and because it fails

to satisfy certain necessary expectations. It promised to be as good as
‘Reynard the fox,’ but it is woefully, incredibly worse.” Mark Van
Doren

− + Nation 111:sup670 D 8 ’20 240w

Reviewed by W. B. D. Henderson
 + N Y Evening Post p2 N 20 ’20 1650w

Reviewed by R: Le Gallienne

+ N Y Times p17 D 26 ’20 1700w

“The feeling that ‘Right Royal’ deserves to be placed below the

earlier volume [‘Reynard the fox’] may be purely a matter of
individual temperament on the part of the reviewer. In any case, it is
a volume which occupies an enviable place in the field of modern
poetry.”

+ Outlook 127:68 Ja 12 ’21 120w

Reviewed by G: D. Procter

+ Pub W 98:1893 D 18 ’20 320w

“The weather—cloud, sun, wind, and shower—is given more

prominence and is better conceived in ‘Right Royal’; but to balance
this, the unsuccessful passages are decidedly worse than those in
‘Reynard the fox.’ Another fault it seems to the present writer to
possess, which the incomparable ‘Reynard the fox’ does not: it is a
little monotonous. As a ‘galloping poem,’ however, it is certainly one
of the best in English.”

+ − Spec 125:675 N 20 ’20 1200w

“He piles simile on simile and each simile is beautiful in itself, each
is a patch of ornament stuck on, not woven into the fabric. Mr
Masefield has told a brave tale bravely. If his courage had been like
Right Royal’s, he would have dared to leave undecorated the beauty
inherent in the tale.”

+ − The Times [London] Lit Sup p734 N 11

’20 1050w

MASON, ALFRED EDWARD WOODLEY.

Summons. *$2 (2c) Doran
20–18656

Harry Luttrell had a strong sense of military honor and of the

necessity for self-discipline. The first drove him to join the army, the
second to tear himself away from the woman he loved and accept a
post in Egypt. His friend and classmate, Martin Hillyard, had had a
chequered career: as a sailor; in a three years’ struggle for existence
in the port-towns of Spain; as an Oxford student and successful
playwright; and during the war his knowledge of Spain serves him in
good stead as a secret service agent. Stella Croyle, Luttrell’s one-time
love, in his absence eats her heart out in neurotic, undisciplined
longing and occasionally has recourse to the comfort of drugs. While
on a leave of absence during the war, Luttrell meets Stella again
without experiencing the old-time thrill and at the same time he
meets and falls in love with Joan Whitworth. Poor Stella commits
suicide under circumstances that throw suspicion on Joan. Through
his experiences in the secret service, Hillyard is enabled to clear Joan
and smooth the way for her and Luttrell.

“An interesting variant of the modern detective story.”

+ Booklist 17:159 Ja ’21

 “It is a splendid story which Mr Mason has written, based upon his
experiences in the war, full of dramatic vigor—a real novel in every
sense of the word—and permeated with the atmosphere of England,
Spain, and Egypt.”

+ Bookm 52:368 D ’20 90w

“This novel is an excellent substitute for a modern detective story.

Instead of possessing a single, unified plot it is composed of a rosary
of minor plots which endows it with somewhat of the character of
real life.”

+ N Y Evening Post p21 O 23 ’20 250w

“One cannot help wishing that the important character of Joan

Whitworth were less exaggerated and more likable, for she does
more than a little to harm the book, but it is easy to forgive this
shortcoming when one remembers Martin Hillyard and the
picturesque José Medina, the very amusing Sir Chichester Splay,
Millie, and several others among the varied figures depicted on Mr
Mason’s richly colored canvas.”

+ − N Y Times p24 O 10 ’20 660w

“Mr Mason, here as always, has an exciting and unusual story to

unfold. This novel is hardly the equal of the ‘Four feathers’ or ‘The
broken road,’ for the author attempts to ming a not very successful
humorous vein with his natural plot-and-action type of fiction
writing.”

+ − Outlook 126:470 N 10 ’20 60w

 “The touch of melodrama in the last section of the book is well
conceived and exciting. The best piece of writing in the book is the
description of the night passed by Martin Hillyard on the shore of a
river in the Sudan. This vivid picture of the life of the game-hunter in
wild countries affords a striking contrast to the sophisticated
chapters at the beginning of the book.”

+ − Spec 125:539 O 23 ’20 470w

“Mr Mason has shown better form than this.”

− The Times [London] Lit Sup p683 O 21

20 650w

MASON, ARTHUR. Flying bo’sun. *$1.75 (4c)

Holt
20–19236

The narrative, the author claims, is of his own experience. It tells

of the voyage of a sailing schooner from San Francisco to the Fiji
Islands, of the superstitious sailors’ taking alarm at the alighting on
the ship of the “flying bo’sun,” the bird of bad omen, the subsequent
death of the captain, his haunting of the cabin and spiritualistic
rappings. On the return voyage the Hindoo stowaway has a
mysterious illness and is left in a state of coma on the captain’s bed
while a terrific hurricane is raging. During a critical moment, when
all seems lost, the frail little Hindoo is suddenly seen in charge of the
wheel giving commands in the captain’s voice with the captain’s
ghost standing beside him. With the ship safe and calm restored the
Hindoo is found just coming to life on the captain’s bed. He
disclaims all knowledge of commanding a ship but is still shaken by
the memory of the hideous dream he has had.

“The feeling persists that, with the exception of the spiritual

phenomenon, the whole dramatic voyage actually occurred.” S. M. R.

+ Bookm 52:371 D ’20 90w

“As a story of the sea it ranks with the best of Jack London or
Morgan Robertson, and as a story of the uncanny it is comparable
with ‘Dracula’ and ‘The master of Ballantrae.’”

+ N Y Evening Post p22 O 23 ’20 200w

“In spite of the undoubted accuracy of Mr Mason’s idiom,

however, the discriminating layman is likely to find less of the
authentic or communicable essence of the sea in ‘The flying b’sun’
than in the spiritual reaction of Masefield, Conrad, Tomlinson and
McFee.”

+ − N Y Times p25 Ja 16 ’21 340w

MASON, AUGUSTUS LYNCH. Guiding

principles for American voters. *$2 Bobbs 320
20–18679

“Mr Mason aims this ‘handbook of Americanism’ chiefly at the

newly enfranchised women and at the young men about to cast their
first vote. He analyzes the make-up of the government and argues for
what he aptly calls a ‘re-dedication to those principles which have
made America great’—i.e., a conservative application of the
underlying ideas of the Constitution. He objects to radical methods
of taxation, to too much government ownership, governmental price
fixing, etc., and he sees ‘Socialism’ as a menace.”—N Y Evening Post

“His arguments are cogently presented and supported by carefully

examined data: an excellent brief for the preservation of a
conservative republic rather than a radical democracy.”

+ N Y Evening Post p11 O 30 ’20 100w

“Its purpose is to popularize an argument, and it has no other

value.”

− Springf’d Republican p8 N 9 ’20 50w

MASON, WILLIAM LESLEY. How to become

an office stenographer. (Just how ser.) il $1.50
Pitman 652
20–26543

“A handy book intended for the untrained shorthand student who

is ambitious to secure a good position without previous experience.”
(Title page) The book is adapted for use as a text in business schools
and in high school commercial departments. There are thirteen
chapters, entitled: Your attention, please! “Safety first”; What
business men expect of a stenographer; Preparedness; Your “busy”
day; Taking the business letter; Transcribing the business letter;
Typing the business letter; Typing business forms; The use and care
of the typewriter; Words: their use and abuse; Filing letters; Time-
saving office appliances. There are two appendixes giving postal
regulations and information regarding the civil service.

Booklist 16:303 Je ’20

MASSENET, JULES ÈMILE FRÉDÉRIC. My

recollections. il *$3 Small
19–15403

“An autobiography telling the story of this modern French musical

leader’s career, and especially of his many works. [It is] translated,
by express desire of the author, by his friend H. Villiers Barnett.
Illustrated.”—Brooklyn

“Will be enjoyed by the average reader as well as the opera-goer

and student of music.”

+ Booklist 16:79 D ’19

Reviewed by H: T. Finck

Bookm 51:171 Ap ’20 180w

“A charming autobiography.”
 + Brooklyn 12:68 Ja ’20 40w

“His narrative, like his music, reveals facility, grace, and charm,
and is alternately gay and sentimental to the point of pathos. One is
not very much wiser after reading the book, but one closes it with a
certain regret at parting from such amiable company.” Henrietta
Straus

+ − Nation 111:76 Jl 17 ’20 190w

Reviewed by Lawrence Gilman

Yale R n s 9:872 Jl ’20 1100w

MASSEY, MRS BEATRICE (LARNED). It

might have been worse. *$1.75 (6½c) Wagner, Harr
917.3
20–4452

An account of a motor trip from coast to coast taken in the

summer of 1919, with notes on roads, hotels, and other matters of
interest to travelers. Contents: The start; New York to Pittsburgh;
Ohio and detours; On to Chicago; Through the dairy country;
Clothes, luggage, and the car; The Twin cities and ten thousand
lakes; Millions of grasshoppers; The Bad lands; The dust of
Montana; A wonderland; Westward ho! Nevada and the desert; The
end of the road.
 MASSINGHAM, HAROLD JOHN. Letters to
X. *$2.50 Dutton 824
20–26887

“In ‘Letters to X,’ H. J. Massingham discourses on a great many

phases of modern life and literature. There is hardly a modern
English author of any consequence who does not come under the
appraisement of his pen.”—Springf’d Republican

“The book contains many excellences of detail, and reaches at

times and maintains for a while a level notably above its average.
Perspective is perhaps Mr Massingham’s outstanding quality.” F. W.
S.

+ − Ath p110 Ja 23 ’20 950w

“Familiar, rambling essays of a book lover that will please the

‘gentle reader’ with like leanings, particularly if he be fond of the
Elizabethans and Carolines. Their exclusive bookishness will make
them seem cold and remote to others.”

+ − Booklist 17:62 N ’20

Reviewed by S. P. Sherman

Bookm 52:108 O ’20 1950w

“These are essays of rare quality in which the essayist is writing

continuously of the alliance between literature and life.” E. F. E.
 + Boston Transcript p7 Jl 17 ’20 1100w

“Mr Massingham’s essays are delivered ex-cathedra and in a style

both heavy and dense. He is a lover of dust covered books, but he
seems widely read rather than discriminating, and though he ranges
all the way from Richard de Bury’s ‘Philobiblon’ to John Gould
Fletcher, he hardly does much to illuminate the names which he
mentions. He declares many enthusiasms but lacks the gift of
differentiation.”

− + Nation 111:162 Ag 7 ’20 180w

“It is a pity that Mr Massingham has chosen to hide this wise,

witty, companionably learned and most comforting book under the
bushel of a title which not only gives no hint of its quality, but is
actually dry and forbidding. Of the value of good literature, of the
qualities which constitute it and of the laws of its making, he says
some of the wisest, most pertinent, things written in a long day.” R:
Le Gallienne

+ N Y Times p7 Ag 8 ’20 2650w

“The word which fits his style exactly is one of the best adjectives
in our language which the language is guilty of criminal negligence in
permitting itself gradually to lose—the word ‘lusty.’ If it were dead
instead of merely decaying, it might be recalled to life by the easy,
careless, rushing vigor of Mr Massingham’s undaunted prose.”

+ − Review 3:172 Ag 25 ’20 360w

 “Mr Massingham’s attacks on his own age, sharp, dipped in
bitterness, aimed with truth though they are, do not really touch the
monster. Bad though the age may be, he is too impatient and
petulant with it; and he is divided in his desires.”

+ − Sat R 129:232 Mr 6 ’20 1050w

Springf’d Republican p8 Jl 10 ’20 40w

“Treating his work as art, susceptible to form, even in the rather

strained sense of that word which he adopts, we find it deficient in
that very quality, and especially in that element of form, tranquillity,
upon which he so insists.”

+ − The Times [London] Lit Sup p30 Ja 15

’20 1300w

MASSINGHAM, HAROLD JOHN, ed.

Treasury of seventeenth century English verse, from
the death of Shakespeare to the Restoration (1616–
1660). (Golden treasury ser.) il *$1.50 Macmillan
821.08
(Eng ed 20–10754)

“Mr Massingham has marked out as his claim the most

characteristic part of the century in time, and has not excluded any
kind except the dramatic. Most of his selections are naturally lyrical,
but by no means all; and he has thus been able to find room for at
least specimen fruits from the half-wilderness gardens of
‘Pharonnida’ and ‘Cupid and Psyche.’ He has also cast his gathering
net unusually wide, and his readers will make acquaintance with
authors who will pretty certainly be new to them, such as Thomas
Fettiplace and Robert Gomersal. In giving uniform modern spelling
throughout Mr Massingham may invite censure from some purists,
but certainly not in this place. Whatever may be the case earlier, the
printers’ spelling of the mid-seventeenth century is, as he justly says,
‘only externally archaic.’ Half its differences from present use are not
uniform and are evidently haphazard. One may not perhaps approve
quite so heartily his practice of excluding some beautiful things as
‘too well known.’ The authors are alphabetically arranged.”—Ath

Reviewed by G: Saintsbury

+ Ath p40 Ja 9 ’20 1400w

“A fresh, provocative, beautiful little book. Palgrave’s volume was

not a bit better gauged for Palgrave’s time than Mr Massingham’s is
for ours. The purest twentieth-century principles are in operation
here. Mr Massingham’s notes are lively to the end, though often they
are cleverly irrelevant and gloriously slap-dash. It is as if Mr
Saintsbury were twenty again.”

+ Nation 110:151 Ja 31 ’20 370w

“The completeness of the book makes it an excellent compendium

for any one studying that era, although it is to be feared that many a
general reader will be frightfully bored by the stiff artificiality that
marks many of the poems, especially after they get past the
Elizabethan era.” H. S. Gorman

+ − N Y Times 25:21 Jl 25 ’20 170w

 “The poems, as a whole, are excellently chosen, and the
enthusiasm of the introduction makes pleasant reading. The notes,
with their short biographical summaries, are especially valuable. But
it needs a certain type of mind to appreciate seventeenth century
literature, and if all readers are not stirred to the same joy in it as Mr
Massingham, it is not his fault, but that of the period.”

+ Sat R 129:39 Ja 10 ’20 480w

“Mr Massingham’s introduction is a delightful essay written in a

style that has caught something of the curious felicity of the poets in
whose work he has steeped himself.”

+ Spec 124:212 F 14 ’20 1000w

“He claims, and with justice, that the ordinary reader will find here
a whole body of poetry with which he has never before had the
chance of making acquaintance. This is a service for which the
student of English poetry will be heartily grateful to Mr Massingham.
But if he be a lover as well as student he will probably find it hard to
keep down some irritation at an anthologist who sets out with the
resolve to give him as few as possible of the poems which he is
known to like.”

+ − The Times [London] Lit Sup p129 F 26

’20 3400w

MASTERS, EDGAR LEE. Domesday book.

*$4.50 Macmillan 811
20–19678
 In this volume Mr Masters has told a long story in verse. The body
of Elenor Murray is found by the river near Starved Rock in Illinois
and the coroner, William Merival, sets out to assemble the evidence,
the material evidence from the man who finds the body, the doctor
who performs the autopsy and the spiritual evidence from those who
had known the girl from her birth or her parents before her. The
effect of these testimonies brought together is to throw light on the
many-sided character of one human being when all secrets are laid
bare and to show how one life, however humble or pitiful, affects
countless other lives, its influence radiating like ripples in a pool
when a stone is dropped.

“If Masters can rid himself of his oracular airs and the bad
Browning-Shakespeare patois with which he wearies his staunchest
admirers, there are few limits to his possible achievements.
‘Domesday book’ is too diffuse and prosy to be a masterpiece of
poetic fiction, but it contains the seeds and strength—and the hope—
of one.” L: Untermeyer

+ − Bookm 52:363 Ja ’21 550w

“The great American poem of the war has come in the ‘Domesday
book’ and come from the hand of the poet who laid the foundation in
the synoptic Americanism of the ‘Spoon river anthology.’ The latter
was a great work; ‘Domesday book’ is greater.... ‘Domesday book’ is a
great national topic of America’s soul symbolized in the character of
Elenor Murray.” W: S. Braithwaite

+ Boston Transcript p7 D 4 ’20 1900w

“The trouble with ‘Domesday book’ is chiefly that it thins this raw
material out until it becomes hopelessly prosaic. The realism of
‘Spoon river’ had the virtue of selection and of epigram. In his latest
work, Mr Masters has become extensive without any corresponding
enlargement of the imagination and the power behind his broader
canvas.” O. M. Sayler

− + Freeman 2:357 D 22 ’20 600w

“The total effect is often crude and heavy, now pretentious, now
hopelessly flat; and yet beneath these uncompleted surfaces are the
sinews of enormous power, a greedy gusto for life, a wide imaginative
experience, an abundance of the veritable stuff of existence—all this,
and yet not an authentic masterpiece. ‘Spoon river anthology’ still
has no rival from the hand of its creator.” C. V. D.

+ − Nation 111:566 N 17 ’20 470w

“For all its largeness of intention, all its vitality and forcefulness,
‘Domesday book’ is not, to my mind, finally articulated. It seems to
me unfinished. I do not mean that the poem is not brought to a
conclusion. It is concluded, and, I believe, appropriately concluded.
But it has parts that should have been cut away or have been more
wrought over.” Padraic Colum

+ − New Repub 25:148 D 29 ’20 1700w

“It could have been produced nowhere but in America and

nowhere so justly as in the Middle West. The epigrammatic
compactness of ‘Spoon river anthology’ is lacking in it, but it takes on
a huge strength that the former book lacked.” H. S. Gorman

+ N Y Times p18 Ja 16 ’21 840w

 “If there be any one who does not clearly realize that life is
infinitely complex, that it is in the last analysis practically impossible
to assign responsibility for evil, that much good may be where
convention sees only evil ... if there be any one who is not convinced
of these things already or cannot learn them from his own
observations and the daily papers, he may derive great benefit from
reading Mr Masters’ book. But those to whom these things are
commonplaces will perhaps not care to wade through the poem.”

− + No Am 213:286 F ’21 900w

“The Edgar Lee Masters, whose ‘Spoon river anthology’ blazed a

new trail thru American literature, returns with ‘Domesday book.’
Perhaps he is less sardonic now, but the vision of ‘Domesday book’ is
broader and it is, happily, gently suffused with a very human
tolerance and forgiveness.” G: D. Proctor

+ Pub W 98:1894 D 18 ’20 430w

“The first part is very interesting, and the whole book is readable.
Its essence is prosaic, though a back door is left open through which
poetry can let herself in in a neighborly fashion, if she chooses. Her
visits are infrequent.” O. W. Firkins

+ − Review 4:15 Ja 5 ’21 1350w

MASTERS, EDGAR LEE. Mitch Miller. il *$3.50

Macmillan
20–17009
 Mitch Miller’s story is told by his friend Skeeters Kirby. It is a story
of boys and a boy’s town written for adults. Mitch has read “Tom
Sawyer” and Tom is to him a living personality. The two boys hunt
for buried treasure and try to repeat all of Tom’s exploits. They dig
for treasure in Old Salem where Lincoln lived, and an old man who
knew Lincoln talks to them of a different kind of treasure. They run
away intending to visit Tom Sawyer but are brought back home.
Later their fathers take them on a journey to Hannibal, Missouri,
where they meet life’s first disillusionment. Mitch is something of a
dreamer and a poet. He is killed stealing rides on the cars, and in the
epilogue, written thirty years after, the author can say that he is now
glad that his chum did not live to face the shattered idealism of the
present day.

+ Booklist 17:72 N ’20

“The best boy’s story in our generation of American authors has

been written by Mr Masters in ‘Mitch Miller.’” W: S. Braithwaite

+ Boston Transcript p5 O 9 ’20 1500w

“Those who have neatly ticketed Mr Edgar Lee Masters as a cynic

will be obliged after reading ‘Mitch Miller,’ to change their label—if
they must have labels. There is, to be sure, a sub-acid quality in the
epilogue. But the mood of the book is one of dedication rather than
of challenge. Its tone is sunny and fresh and sweet; its beauty quiet
and unobtrusive. ‘Mitch Miller’ comes close to being a masterpiece
with its breadth of interpretation, and the fineness and singleness of
its mood. It is complete, even to the tragedy at the end.” C. M. R.
 + Freeman 2:214 N 10 ’20 250w

“The narrative is tangled in a snarl of moods. Its movement is

often thick, its wings gummed and heavy. Only in flashes does the
powerful imagination of Mr Masters shake itself free and burn with
the high, hot light which so often glows in the ‘Anthology.’ There are
touches of admirable comedy and strong strokes of character and
some racy prose; but as a whole ‘Mitch Miller’ falls regrettably
between the clear energy which might have made it popular and the
profound significance which might have made it great.” C. V. D.

+ − Nation 111:566 N 17 ’20 480w

“If fidelity to nature were the whole of art, Mitch Miller would be a
perfect book, or almost perfect.... The defect in the author’s method
comes out in the end of the book.... Is there nothing in American life
significant and interesting enough to make it worth while for a boy
like Mitch to grow up? Perhaps there is not; but if that is true, it is an
artistic problem to be faced, not evaded through a petulant
dismantling of a stage well set.” Alvin Johnson

+ − New Repub 24:276 N 10 ’20 1250w

“Mr Masters’s novel is put down with mingled feelings. It has

many faults, but it has quite as many virtues. There is so much to the
book that it leaps into the mind to advise the author to write novels
henceforth and forevermore and let poetry rest.”

+ − N Y Times p20 N 7 ’20 980w

“The book is unusual and captivating.”

 + Outlook 126:600 D 1 ’20 80w

“We are in the habit of looking to Mr Masters for clear-cut

character drawing and for sympathetic, if sometimes ironic,
understanding of the motives of men but we have often felt
regretfully, that he seemed to be too much interested in the morbid
side of human nature. ‘Mitch Miller’ comes as a grateful answer to
that doubt.” Marguerite Fellows

+ Pub W 98:1192 O 16 ’20 300w

Reviewed by E. L. Pearson

Review 3:447 N 10 ’20 630w

+ Wis Lib Bul 16:238 D ’20 70w

MASTERS, EDGAR LEE. Starved Rock. *$1.75

Macmillan 811
19–17050

For descriptive note see Annual for 1919.

“Perhaps the poet’s first worthy successor of ‘Spoon River’; but

while displaying something of its sardonic spirit the present
collection is of far wider range.”

+ Booklist 16:162 F ’20

 “He is at his ripest and surest in such mordant and merciless
analyses as Lord Byron to Doctor Polidori, The barber of Sepo.
They’d never know me now, Oh you Sabbatarians! and that profound
disquisition on Poe, Washington hospital. And the man who wrote
Sagamore Hill, that incomparable portrait of Theodore Roosevelt;
who wrote Chicago and I shall go down into this land, manifests an
intimate understanding of the American heart at its noblest.” H: A.
Lappin

+ Bookm 51:216 Ap ’20 250w

+ Cleveland p86 O ’20 20w

“In ‘Starved Rock’ there is little music but much food for thought.”

+ Ind 104:165 O 9 ’20 40w

“It is beginning to be apparent that Mr Masters neither can nor

needs to depart from his original tone and method. He cannot do so
profitably and there is no need, since the vein which served them
seems inexhaustible. There are not lacking here the old familiar
notes of sour, practical tragedy, of hoarse, heroic scepticism, of good,
round, pagan, Chicago fleshliness. But [the reader] is sorry for a
certain strenuous complacency which has been growing in Mr
Masters over a considerable period and which is particularly
objectionable in the present volume.”

+ − Nation 110:557 Ap 24 ’20 550w

“Unfortunately, Mr Masters frequently fails to sing because he fails

to simplify. He is a thinker, first of all, and the thinker is naturally
more discursive than the singer. And now a word for the best of the
book. It is a poem about Roosevelt, called At Sagamore Hill. Here is a
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