Effect of basic and acidic additives on the separation of some basic drug enantiomers on polysaccharide-based chiral columns with acetonitrile as mobile phase

Article abstract of DOI:10.1002/chir.22417

The separation of enantiomers of 16 basic drugs was studied using polysaccharide-based chiral selectors and acetonitrile as mobile phase with emphasis on the role of basic and acidic additives on the separation and elution order of enantiomers. Out of the studied chiral selectors, amylose phenylcarbamate-based ones more often showed a chiral recognition ability compared to cellulose phenylcarbamate derivatives. An interesting effect was observed with formic acid as additive on enantiomer resolution and enantiomer elution order for some basic drugs. Thus, for instance, the enantioseparation of several β-blockers (atenolol, sotalol, toliprolol) improved not only by the addition of a more conventional basic additive to the mobile phase, but also by the addition of an acidic additive. Moreover, an opposite elution order of enantiomers was observed depending on the nature of the additive (basic or acidic) in the mobile phase.

Full text of DOI:10.1002/chir.22417

CHIRALITY 27:228–234 (2015)
Effect of Basic and Acidic Additives on the Separation of Some Basic
Drug Enantiomers on Polysaccharide-Based Chiral Columns With
Acetonitrile as Mobile Phase
1
KHATUNA GOGALADZE,1 LALI CHANKVETADZE,1 MAIA TSINTSADZE,2 TIVADAR FARKAS,3 AND BEZHAN CHANKVETADZE
*
1Institute of Physical and Analytical Chemistry, School of Exact and Natural Sciences, Tbilisi State University, Tbilisi, Georgia
2Faculty of Chemistry, Georgian Technical University, Tbilisi, Georgia
3Phenomenex, Torrance, CA, USA
ABSTRACT
The separation of enantiomers of 16 basic drugs was studied using
polysaccharide-based chiral selectors and acetonitrile as mobile phase with emphasis on the role
of basic and acidic additives on the separation and elution order of enantiomers. Out of the stud-
ied chiral selectors, amylose phenylcarbamate-based ones more often showed a chiral recogni-
tion ability compared to cellulose phenylcarbamate derivatives. An interesting effect was
observed with formic acid as additive on enantiomer resolution and enantiomer elution order
for some basic drugs. Thus, for instance, the enantioseparation of several β-blockers (atenolol,
sotalol, toliprolol) improved not only by the addition of a more conventional basic additive to
the mobile phase, but also by the addition of an acidic additive. Moreover, an opposite elution
order of enantiomers was observed depending on the nature of the additive (basic or acidic) in
the mobile phase. Chirality 27:228–234, 2015. © 2015 Wiley Periodicals, Inc.
KEY WORDS: separation of enantiomers; polysaccharide-based chiral selectors; basic chiral
drugs; enantiomer elution order; effect of minor additives
INTRODUCTION
use of pure ethanol as mobile phase.18 A few articles have
been published on the application of polysaccharide
phenylcarbamates for HPLC separation of enantiomers in
combination with some alcohols in the 1980s and 1990s.19–21
However, these studies do not stress any potential advan-
tages of polar-organic mobile phases for HPLC separation of
enantiomers. More systematic studies in this area were
published since early 2000 and at present the polar-organic
mobile phase mode (PO) has been well established for analyt-
ical, as well as for preparative-scale enantioseparations.22–33
Major advantages of this separation mode include short anal-
ysis times, high plate numbers, favorable peak shape, and
commonly higher solubility of the analyte in the mobile
phase. The last advantage is important in preparative-scale
separations of enantiomers. The potential of pure acetoni-
trile,34 acetonitrile with minor basic or acidic additives,
Polysaccharide-based chiral selectors (columns) are
established as the most useful materials for analytical- and
preparative-scale separation of enantiomers in liquid chroma-
tography1,2 and several related techniques, such as super-/
subcritical fluid chromatography,3 nano-liquid chromatogra-
phy,4,5 and capillary electrochromatography.5–7 In spite of
the wide application of polysaccharide phenylcarbamates
and esters in liquid-phase separation of enantiomers, the chi-
ral recognition mechanism of these materials is still poorly
understood. Although many efforts involving various experi-
mental8–14 and computation techniques14–16 have been made
in the past, at present we are still far from being able to de-
velop a tailor-made chiral selector for the separation of the en-
antiomers of a given chiral analyte, or from predicting the
most effective separation mode or mobile phase (including
its additives), not to mention from predicting the enantiomer
elution order (EEO).
Polysaccharide phenylcarbamate-based chiral selectors
were initially proposed for the separation of enantiomers in
high-performance liquid chromatography (HPLC) in combi-
nation with hydrocarbon-alcohol mobile phases. In the very
first article on this topic published 30 years ago, Okamoto
and colleagues17 reported on separations conducted in a
water-ethanol mixture as a mobile phase but primarily empha-
sized the usefulness of hydrocarbon-alcohol-made mobile
phases, thus assuming that hydrogen bonding between the
chiral selector and chiral analytes to be the most important
contributor to chiral recognition. Initially, polysaccharide
phenylcarbamate-based chiral selectors were not recom-
mended to be used in combination with pure polar organic
solvents (such as alcohols or acetonitrile) as the mobile
phase, although an earlier article on the application of cellu-
lose triacetate as a useful chiral selector for liquid chromato-
graphic separation of enantiomers reported the successful
24–26,29,34
or acetonitrile in mixture with hydrocarbons
(e.g., n-hexane)27,28,30–33 as a mobile phase for HPLC sepa-
rations of enantiomers using polysaccharide-based chiral se-
lectors has been evaluated in several studies. Interesting
effects of basic and acidic additives in this separation mode
were reported for some basic drugs in our previous study.34
In the present study the separation of enantiomers of 16 ba-
sic drugs was investigated on six different polysaccharide-
type chiral columns and acetonitrile as the bulk mobile phase.
The emphasis was on the effect of minor basic and acidic
Contract grant sponsor: Rustaveli Georgian National Science Foundation
(RGNSF); Contract grant number: 31/90.
*Correspondence to: B. Chankvetadze, Institute of Physical and Analytical
Chemistry, School of Exact and Natural Sciences, Tbilisi State University,
Chavchavadze Ave 1, 0179 Tbilisi, Georgia. E-mail: jpba_bezhan@yahoo.com
Received for publication 27 June 2014; Accepted 16 October 2014
DOI: 10.1002/chir.22417
Published online 6 January 2015 in Wiley Online Library
(wileyonlinelibrary.com).
© 2015 Wiley Periodicals, Inc.

SEPARATION OF SOME BASIC DRUG ENANTIOMERS
229
additives present in the mobile phase on the resolution and
elution order of enantiomers.
EXPERIMENTAL
Pharmaceuticals, Chemicals, and Chiral Columns
Diethylamine, formic acid, and commercially available chiral basic
drugs, acebutolol, alprenolol, atenolol, betaxolol, bisoprolol, bupranolol
hydrochloride, bunitrolol hydrochloride, celiprolol, isoproterenol,
mabuterol, metoprolol, metipranolol, nifenalol, oxprenolol, sotalol, and
toliprolol were purchased from Sigma Aldrich (Taufkirchen, Germany).
The structures of these compounds are shown in Figure 1.
Enantiomerically pure fractions of each studied drug, if not commercially
available, were collected by using analytical columns and multiple se-
quential injections of the racemate and manual collection of effluents cor-
responding to each enantiomer. The eluent was evaporated at room
temperature and the enantiomerically pure residue used for spiking ex-
periments. Acetonitrile of HPLC quality was acquired from Carl Roth
(Karlsruhe, Germany). The amylose tris(3,5-dimethylphenylcarbamate)
(ADMPC)-based column was an experimental column provided by
Enantiosep (Münster, Germany), while the other chiral columns, Lux
Amylose-2, Lux Cellulose-1, Lux Cellulose-2, Lux Cellulose-3, and Lux
Cellulose-4, were kindly provided by Phenomenex (Torrance, CA). The
schematic structures of the chiral selectors of these chiral columns are
shown in Figure 2. All columns had the dimensions 250 x 4.6 mm and
were packed with 5-μm particles.
Fig. 2. The schematic structures of the chiral selectors part of the chiral
columns used in this study.
RESULTS AND DISCUSSION
General Overview of Separation of Basic Drug Enantiomers
An interesting tendency was observed when screening six
polysaccharide-based chiral columns for their separation abil-
ity towards the enantiomers of 16 chiral basic drugs (Table 1).
Thus, both amylose-based columns, Lux Amylose-2, and
ADMPC were more successful than cellulose-based columns
(Table 1, Fig. 3). Based on their suitability these columns
ranked in the order Lux Amylose-2>ADMPC>Lux
Cellulose-2=Lux Cellulose-4>Lux Cellulose-1. No separation
of enantiomers was observed on the cellulose ester type col-
umn, Lux Cellulose-3. The above-mentioned higher success
rate of amylose-based columns compared to cellulose-based
columns with ACN as the mobile phase is in agreement with
the results obtained on a larger set of chiral analytes ear-
lier.25,26,29 The two cellulose-based chiral columns with very
HPLC Separations
All HPLC experiments were performed with an Agilent 1200 HPLC in-
strument (Agilent Technologies, Waldbronn, Germany) equipped with a
G1367C HiP ALS-SL autosampler, a G1316B TCC-SL temperature control-
ler, a G1311A quaternary pump, and a G1314D VWD variable wavelength
detector. The Chemstation software (v. B.03.02-SR2) was used for instru-
ment control, data acquisition, and data handling. If not stated otherwise,
the samples were dissolved in the mobile phase used for the respective
separation at a concentration of 0.2 mg/mL. HPLC separations were per-
formed at 20°C with 1.00 ml/min mobile phase flow rate and detection at
220 nm. The elution order of enantiomers was determined in each case by
spiking racemic sample with enantiomerically pure isomers and/or by
correlation with previous studies. Diethylamine (DEA) additive to the mo-
bile phase was added in 0.1% amount (v/v) and formic acid (FA) in its
equivalent amount to 0.1% of DEA.
Fig. 1. Structure of studied basic drugs.
Chirality DOI 10.1002/chir

230
GOGALADZE ET AL.
Chirality DOI 10.1002/chir

SEPARATION OF SOME BASIC DRUG ENANTIOMERS
231
of the molecular mechanisms of EEO reversal may bring us
closer to an understanding of chiral recognition mechanisms.
It has been well established that EEO may be the opposite
with various polysaccharide-based chiral columns.1,33,34 How-
ever, molecular mechanisms bringing about reversals in
EEO are currently not well understood. Therefore, as many
as possible examples of this kind of EEO reversal must be ac-
cumulated and discussed systematically in order to get a clear
idea about the origin of this phenomenon, which definitely
may be different from case to case. As mentioned in the previ-
ous subsection, amylose-based columns exhibited a chiral rec-
ognition ability in more cases than cellulose-based ones for the
chiral basic drugs part of this study in combination with ACN
as mobile phase. In order to follow EEO, the R-(À) and S-(+)-
enantiomers of sotalol were available for our experiments.
The stereochemical configuration of each eluted fraction of
acebutolol was assigned based on correlations with the elu-
tion order of its enantiomers described in Ref. 35. Similarly,
the absolute stereochemical configuration of each eluted
fraction of atenolol was assigned based on the elution order
reported in the paper by Agustian et al.36 Such a correlation
was not possible for toliprolol enantiomers due to the
absence (at least to our knowledge) of any earlier HPLC
publication on the separation of toliprolol enantiomers with
a reliable description of experimental conditions and a clear
determination of EEO.
Fig. 3. Success rate of separation of basic drug enantiomers on various chi-
ral columns with ACN+0.1%DEA as the mobile phase.
similar chiral selector chemistry, namely Lux Cellulose-2 and
Lux Cellulose-4, exhibited similar overall success but were
quite complementary to each other. Thus, the enantiomers
of acebutolol and mabuterol were well resolved on Lux
Cellulose-2 but not resolved at all on Lux Cellulose-4. Contray
to this, the enantiomers of betaxolol, celiprolol, metipranolol,
and oxprenolol were not resolved on Lux Cellulose-2 column
but baseline or partially resolved on Lux Cellulose-4 column
(Table 1). Out of the various mobile phases used, ACN with
0.1% DEA was most successful with all columns studied
(Table 1). The success rate with ACN+FA and ACN+DEA
+FA was studied with Lux Amylose-2 and ADMPC and was
very similar with both chiral selectors (data not shown).
DEA was more successful as an additive compared to FA.
No complementarity was observed between these two addi-
tives, i.e., no new separation was observed with FA as addi-
tive. However, some difference was observed in terms of
EEO, which will be discussed in the next subsection.
An interesting example of reversal in EEO was observed
for the enantiomers of acebutolol between Amylose-2 and
ADMPC columns (Fig. 4). Thus, R-acebutolol eluted as the
first peak off the ADMPC column while second off the
Effect of Chiral Selector and Basic and Acidic Additive in the
Mobile Phase on the Enantiomer Elution Order of Chiral
Basic Analytes
EEO represents an important aspect of chiral separations
from both a practical and theoretical viewpoint. Understanding
Fig. 5. Separation of enantiomers of sotalol (1:2 ratio of R- and S-enantio-
mers, respectively) on Lux Amylose-2 column with the following mobile
phases: ACN (a), ACN+0.1% DEA (b), ACN+ eq. FA (c), and ACN+0.1%
DEA+ eq. FA (d).
Fig. 4. Separation of enantiomers of acebutolol (1:2 ratio of S- and R-enan-
tiomers, respectively) on ADMPC (a) and Lux Amylose-2 (b) columns. The
mobile phase was ACN+0.1%DEA.
Chirality DOI 10.1002/chir

232
GOGALADZE ET AL.
chiral analytes with the use of acidic additives, or of a com-
bination of acidic and basic additives, has been reported pre-
viously,33,37–39 reversals in EEO based on the alternative use
of basic or acidic additives was reported for the first time in
our recent study.34 Interestingly, the resolution of sotalol en-
antiomers with acidic additive or with a combination of
acidic and basic additives was superior to that with basic ad-
ditive only (Fig. 5d). The significantly different peak shape
of S-(+)-sotalol in the presence of an acidic additive or a
combination of acidic and basic additives in the mobile
phase also deserves attention and is the subject of further
studies.
Similar to the above-mentioned case of sotalol enantio-
mers, unsatisfactory separation was obtained for the enantio-
mers of atenolol on Amylose-2, again when ACN was used
as a mobile phase without any additive (Fig. 6a). While
the separation was improved, the EEO was not affected
when 0.1% DEA was added to ACN (Fig. 6b). Again, the sep-
aration was also improved and the EEO reverted when FA
was added instead of DEA to the ACN mobile phase
(Fig. 6c). This is an additional example of EEO adjustment
based on the alternative use of basic or acidic additives. In
both examples discussed, the presence of FA was the deter-
mining factor for EEO: it was the same with only FA or with
both FA and DEA present in the ACN mobile phase. The ex-
ception from this pattern was the case of toliprolol enantio-
mers. The EEO was opposite for this analyte on the
Amylose-2 column when the two additives, DEA and FA,
were used alternatively (Fig. 7a,c), but no separation of en-
antiomers was observed when both of these two additives
were used simultaneously (Fig. 7b). Significant widening
of the second peak was observed along with EEO reversal
whenever FA was used as additive for all three analytes
shown in Figures 5–7.
Fig. 6. Separation of enantiomers of atenolol (1:2 ratio of S- and R-enantio-
mers, respectively) on Lux Amylose-2 column with the following mobile
phases: ACN (a), ACN+0.1% DEA (b), ACN+ eq. FA (c), and ACN+0.1%
DEA+ eq. FA (d).
Amylose-2 column. Also, enantioresolution was significantly
better with the latter column. The EEO of sotalol enantiomers
was again different on Amylose-2 and ADMPC columns, with
S-(+)-sotalol eluting first off Lux Amylose-2 and second off
ADMPC with ACN + 0.1% FA mobile phase (data not shown).
Reversal in EEO based on the choice of chiral selector is a
useful approach but lacks expediency, first because it is not
predictable and, second because it requires at least two chiral
columns. From this viewpoint bringing about a reversal in
EEO by varying the mobile phase composition seems more
cost-effective. Although, this latter approach to reversing
EEO is also unpredictable because of our limited understand-
ing of chiral recognition mechanisms with polysaccharide-
based chiral selectors, at least it requires no more than a sin-
gle column. Several examples of EEO reversal based on the
nature of the mobile phase additive were observed in the cur-
rent study. For example, the separation of sotalol enantio-
mers was unsatisfactory on Lux Amylose-2 with ACN as the
mobile phase without any additive (Fig. 5a). This separation
improved significantly when 0.1% (v/v) of DEA was added
to the mobile phase, with S-(+)-sotalol eluting before R-(À)-
sotalol (Fig. 5b). Surprisingly, the separation of sotalol enan-
tiomers was also possible when the acidic additive FA was
present instead of DEA in mobile phase ACN (at the concen-
tration level equivalent to 0.1% DEA; Fig. 5c). Even more sur-
prisingly, the EEO inverted and R-(À)-sotalol eluted before
S-(+)-sotalol when FA was used. This is one of the very few
examples reported in the literature when the EEO can be ad-
justed based on the nature of the mobile phase additive. Al-
though the improvement in enantiomer separation of basic
Fig. 7. Separation of enantiomers of toliprolol (1:2 ratio of enantiomers) on
Lux Amylose-2 column with the following mobile phases: ACN+0.1% DEA (a),
ACN+0.1% DEA+ eq. FA (b), and ACN+ eq. FA (c).
Chirality DOI 10.1002/chir

SEPARATION OF SOME BASIC DRUG ENANTIOMERS
233
enantioselective interactions with benzoin enantiomers. J Phys Chem
2011;115:12785–12800.
CONCLUSION
Based on a study on the enantioseparation of 16 basic
drugs on 4 cellulose- and 2 amylose-based chiral HPLC col-
umns with acetonitrile as mobile phase, the enantiomer-
resolving ability of amylose-based columns was found to be
better than that of cellulose-based columns. In addition, some
interesting examples of reversal in enantiomer elution order
were observed as a function of the chemistry of the chiral se-
lector and the nature (basic or acidic) of the mobile phase ad-
ditive. Of special significance seems to be the possibility of
enantiomer elution order adjustment for atenolol, sotalol,
and toliprolol by alternative use of diethylamine or formic acid
as additives.
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ACKNOWLEDGMENTS
This study was financially supported in part by the
Rustaveli Georgian National Science Foundation (RGNSF)
grant No 31/90 for fundamental research.
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