Chiral separation of cathinone derivatives used as recreational drugs by HPLC-UV using a CHIRALPAK AS-H column as stationary phase

Article abstract of DOI:10.1002/chir.22048

Cathinone derivatives gained high popularity on the recreational drugs market during the past 10 years. All these compounds are chiral, and the pharmacological potency of the enantiomers of these stimulants is supposed to differ. The goal of this research was to develop a reliable and easy-to-perform high-performance liquid chromatography ultraviolet method for the chiral separation of a set of 24 cathinone derivatives. A commercially available CHIRALPAK AS-H column consisting of amylose tris [(S)-α- methylbenzylcarbamate] coated on 5-μm silica gel was found to be suitable to resolve a majority of the tested compounds. High-performance liquid chromatography measurements were performed in normal phase mode under isocratic conditions with a mobile phase consisting of hexane, isopropanol, and triethylamine at a flowrate of 1 ml/min. The ratio between hexane and isopropanol was optimized by means of three model substances. Under final conditions with a mobile phase of hexane, isopropanol, and triethylamine (97:3:0.1), 19 out of 24 compounds were successfully resolved into their enantiomers and detected at a wavelength of 254 nm. A correlation between the substituents of the nitrogen atom and the separation results are shown. Furthermore, enantiomer separation results of four cathinone derivatives were compared with the results of their amphetamine analogs. Copyright

Full text of DOI:10.1002/chir.22048

CHIRALITY (2012)
Chiral Separation of Cathinone Derivatives Used as Recreational
Drugs by HPLC-UV Using a CHIRALPAKW AS-H Column as
Stationary Phase
1
STEFAN MOHR,1,2 MAGDALENA TASCHWER,1 AND MARTIN G. SCHMID
*
1Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Karl-Franzens-University Graz, A-8010 Graz, Austria
2Research Center Pharmaceutical Engineering, Graz, Austria
ABSTRACT
Cathinone derivatives gained high popularity on the recreational drugs market
during the past 10 years. All these compounds are chiral, and the pharmacological potency of
the enantiomers of these stimulants is supposed to differ. The goal of this research was to de-
velop a reliable and easy-to-perform high-performance liquid chromatography ultraviolet method
for the chiral separation of a set of 24 cathinone derivatives. A commercially available CHIRAL-
PAKW AS-H column consisting of amylose tris [(S)-a-methylbenzylcarbamate] coated on 5-mm
silica gel was found to be suitable to resolve a majority of the tested compounds. High-performance
liquid chromatography measurements were performed in normal phase mode under isocratic
conditions with a mobile phase consisting of hexane, isopropanol, and triethylamine at a flowrate
of 1 ml/min. The ratio between hexane and isopropanol was optimized by means of three model
substances. Under final conditions with a mobile phase of hexane, isopropanol, and triethylamine
(97:3:0.1), 19 out of 24 compounds were successfully resolved into their enantiomers and detected
at a wavelength of 254 nm. A correlation between the substituents of the nitrogen atom and
the separation results are shown. Furthermore, enantiomer separation results of four cathi-
none derivatives were compared with the results of their amphetamine analogs. Chirality
00:000–000, 2012. © 2012 Wiley Periodicals, Inc.
KEY WORDS: mephedrone; legal highs; amphetamines; polysaccharide-based stationary phase
INTRODUCTION
thalidomide. All new designer drugs derived from cathi-
none have an asymmetric substituted carbon atom yielding
in two stereoisomers. Because of the novelty of these com-
pounds, limited pharmacological and toxicological data of
the racemic mixture and nearly no data about the single
enantiomers are available. It was found out that the S(À)
enantiomer of methcathinone and the S(+) enantiomer of
amphetamine are more potent stimulants than their R(+)
and R(À) antipodes, respectively.1–4 This potency differ-
ences and the possibility to collect information about the
lab of origin may be subject to the development of analyt-
ical methods for the determination of the enantiomer
purity of this substance class.
Some articles dealing with the chiral separation of compounds
related to amphetamine can be found in literature including
capillary electrophoresis,5–10 gas chromatography,4,11–13
and high-performance liquid chromatography (HPLC)
methods.14–18 Recently, our group succeeded in separating
19 cathinone derivatives by cyclodextrin-modified capillary
electrophoresis.10 Mathys’ group performed indirect chiral
separation of cathinone by derivatization with S(À)-phenylethyl
isocyanate on a 5-mm normal phase column.15 Direct chiral sep-
aration of cathinone and some analogs was performed by using
a (3,3-diphenyl-1,1-binaphtyl)-20-crown-6 dynamically coated
During the past 5 years, new chemical compounds
structurally related to the naturally occuring phenylpropane
alkaloid or beta-keto-amphetamine, cathinone gained high
popularity on the recreational drugs market. Among them,
mephedrone (4-methyl-methcathinone) is the most popular
substance still being merchandised via the Internet as plant
food, bath salt, or research chemical. Because it is easy and
nearly anonymous to procure these compounds, combined
with the low price and the high purity, mephedrone became
a very popular legal alternative to the well-known party drugs
amphetamine (Speed) or methylendioxymethamphetamine
(Ecstasy). In 2009, the mephedrone hype was on its top
in Europe, and authorities were forced to react. Since the
beginning of 2011, mephedrone is prohibited in nearly
entire Europe, leading to a swap of other cathinone
derivatives onto the drug market. The backbone of the
beta-keto-amphetamines can be modified by various substi-
tuents. Only a few countries, for example, Great Britain,
prohibited the entire class of cathinone substances to
avoid the shift of the market to analogs with nearly the
same spectrum of effects.
Because it is well known that the enantiomers of a
chiral active pharmaceutical ingredient may exhibit differ-
ent pharmacological effects, different potency, or an effect
limited to only one optical isomer of the molecule, the
development of chiral separation methods in analytical
and preparative scale is a big field of interest. During the
development process of a new racemic drug substance,
pharmacological and toxicological tests are performed
for each enantiomer to avoid scenarios known from
*Correspondence to: Martin Schmid, Department of Pharmaceutical Chemis-
try, Institute of Pharmaceutical Sciences, Karl-Franzens-University Graz, A-
8010 Graz, Austria. E-mail: martin.schmid@uni-graz.at
Received for publication 14 February 2011; Accepted 11 March 2012
DOI: 10.1002/chir.22048
Published online in Wiley Online Library
(wileyonlinelibrary.com).
© 2012 Wiley Periodicals, Inc.

MOHR ET AL.
on octadecylsilica gel18 and covalently bond to silica gel, respec-
MATERIALS AND METHODS
Chromatographic Conditions
tively.14,17 Further chiral stationary phases (CSPs) based on
cellobiohydrolase (CBH-I)20 and (+)-(18-crown-6)-2,3,11,12-
tetracarboxylic acid19 were reported to be successful. Because
the use of crown ether-based CSPs is limited to primary
amines, our goal was to find a CSP suitable to resolve most
of the new synthetic drug substances of abuse, which mainly
consist of secondary amines.
Analysis was performed on an Agilent (Waldbronn, Germany) HP
1090 series II HPLC System equipped with an autosampler and a diode
array detector. Ultraviolet (UV)-detection was performed at 254 nm.
The UV-spectra of all compounds were collected in a range from 200
to 400 nm. Measurements were performed at room temperature with
a mobile phase consisting of hexane, isopropanol, and triethylamine
(TEA) under isocratic conditions with a flow of 1 ml/min. A commer-
cially available CHIRALPAKW AS-H column, 150 Â 4.6 mm, coated on
5-mm silica gel was used as CSP. The injection volume was set to
5 ml. Prior to injection, the needle was flushed with 10 ml of the mobile
phase. Data analysis was performed with Chem Station for LC 3D Rev.
A. 10.01 (Agilent Technologies, CA, USA).
The goal of this work was to develop a chiral separation
method for cathinone derivatives available on the street
market. Four cathinone derivatives were compared
with their amphetamine analogs regarding the chiral reso-
lution. To our knowledge, it was the first time that such a
broad spectrum of cathinone derivatives was investigated
by HPLC.
For the reproducibility studies, a modular HPLC system consisting of
a D-7000 interface (Merck Hitachi, Darmstadt, Germany), a LaChrom
Fig. 1. Structures of the tested cathinone derivatives.
Chirality DOI 10.1002/chir

ENANTIOSEPARATION OF CATHINONE DERIVATIVES
L-7100 pump (Merck Hitachi), and a L-7400 single wavelength detector
RESULTS AND DISCUSSION
was used. Samples were injected manually with a loop size of 20 ml.
For data collection and analysis, a D-7000 HPLC system manager (Merck
Hitachi) was used.
Even though it was found out that polysaccharide-based
CSPs first introduced by Okamoto and co-workers
21
are
able to separate up to 95% of low and medium weight
chiral molecules from pharmaceutical interest, it is not
predictable which type of CSP is able to enantioseparate a
specific molecule or class of molecules. Mostly, the
optimal CSP has to be found out empirically by screening
different types of polysaccharide CSPs under different
conditions. In general, chiral resolution of enantiomers is
based on different interactions of each enantiomer with
the immobilized CSP. Therefore, the enantiomer with the
weaker interaction to the CSP passes the detector first.
Spatial effects of cavities built by the polysaccharide are
mainly responsible for the enantiomer–CSP interplay. Sec-
ondary interactions to be taken into account are hydrogen
bondings, p–p interactions, dipole–dipole interactions, and
steric effects.
On the basis of previous experiences with polysaccharide
CSPs in our group, a CHIRALPAKW AS-H column consisting
of amylose tris [(S)-a-methylbenzylcarbamate] coated on
5-mm silica gel was chosen as stationary phase. A mobile
phase consisting of hexane/isopropanol (90:10) with 0.1%
TEA as basic modifier was used as mobile phase for the opti-
mization procedure. With the use of mephedrone, butylone,
and MDPV as model compounds, the isopropanol content of
the mobile phase was reduced successively. The effect of
different ratios between hexane and isopropanol on the reten-
tion time and the resolution of the enantiomers is shown in
Table 1.
With the use of mobile phases with a specific content
of isopropanol ranging from 10% to 2%, mephedrone and
butylone were resolved successfully into their enantio-
mers. According to the instruction manual of the column,
retention times decreased with increasing alcohol content.
With decreasing retention times, lower resolution was
observed because the interaction with the CSP is weaker.
The resolution for mephedrone was ranging from 1.3 with
10% to 3.5 with 2% isopropanol and for butylone from 3.2 to
6.1. MDPV did not show any chiral discrimination with an
isopropanol consisting mobile phase. By using 100% hex-
ane with 0.1% TEA, butylone and MDPV were partially
separated, whereas enormous peak tailing was observed.
With mephedrone, no peak was detected within 1 h
Chemicals and Solutions
All chemicals were of analytical grade. Hexane, methylene
chloride, and isopropanol were purchased from Carl Roth (Karlsruhe,
Germany). TEA and ethcathinone were from Sigma-Aldrich Chemicals
(St Louis, MO, USA). Sodium sulfate and sodium hydroxide were
obtained from VWR (Darmstadt, Germany). Water was deionized
and double-distilled. Amphetamine HCl, methamphetamine HCl, 3,4-
methylendioxymethamphetamine HCl, 3,4-methylendioxyethylamphetamine
HCl, and methylbenzodioxolylbutanamine HCl were purchased from LGC
Standards (Wesel, Germany).
Because of their novelity, most analytes were not available from official
suppliers and therefore bought in relevant online stores.
4-Methylmethcathinone (mephedrone) and butylone were purchased from
http://naughtyplantfood.com. 3-Fluoromethcathinone (3-FMC) and 3,4-
dimethylmethcathinone (3,4-DMMC) were obtained from http://research-
chemicals24.hu. Methylone, 4-methylethcathinone (4-MEC), naphyrone,
and 4-fluoromethcathinone (4-FMC) were purchased from http://get-rc.to.
Methylendioxypyrovalerone (MDPV) was bought from http://RCshop.es.
Pentedrone, ethylone, and 4-methyl-alpha-pyrrolidinopropiophenon were
purchased from http://buybestrc.com. 4-Bromomethcathinone (4-BMC),
methedrone, buphedrone, alpha-pyrrolidinopropiophenone (a-PPP), and
N-ethylbuphedrone were obtained from http://labamin.pl. 4-Methyl-
buphedrone and 2-fluoromethcathinone were from http://sensearomatic.com.
Pentylone was purchased from http://jollyeffects.com and dimethylbutylone
from http://chem-guru.com. Prior to use, the compounds were characterized
by GC-EI-MS and NMR if necessary. Figures 1 and 2 show the structure of all
used analytes. The single enantiomers of cathinone and methcathinone were
synthesized by oxidation of (1R,2S)-(À) and (1S,2R)-(+)-norephedrine and
ephedrine with potassium permanganate.
The mobile phase was prepared by mixing hexane, isopropanol,
and TEA in required ratios. The solution was degassed for 2 min with
helium 5.0.
Sample Preparation
For sample preparation, 1.5 mg of the substance was dissolved in 1.5 ml
of water, 20 ml of a 1 M sodium hydroxide solution was added, and the free
base was extracted with 1.5 ml methylenchloride. The methylene
chloride layer was dried over anhydrous sodium sulfate, and methylene
chloride was evaporated under a soft nitrogen stream. The remaining
free base of the compounds was reconstituted in a mixture of hexane
and isopropanol (97:3).
Fig. 2. Structures of the tested amphetamine analogs.
Chirality DOI 10.1002/chir

MOHR ET AL.
TABLE 1. Effect of different isopropanol contents of the mobile phase on the resolution and the retention time
Mephedrone
t2 (min)
Butylone
t2 (min)
Methylendioxypyrovalerone
Isopropanol vol %
t1 (min)
a
Rs
t1 (min)
a
Rs
t1 (min)
t2 (min)
a
Rs
10
5
3
2
0
3.22
4.25
4.85
5.82
>60
4.50
6.41
7.94
10.62
–
1.875
1.908
2.047
2.228
–
1.3
2.0
2.6
3.5
–
4.31
6.01
7.05
8.45
9.66
6.58
9.68
12.07
16.13
9.87
1.897
1.883
1.972
2.170
1.027
3.2
3.2
5.1
6.1
0.0
2.82
3.25
3.55
3.88
10.87
–
–
–
–
–
–
–
–
–
–
–
–
11.73
1.100
0.4
Conditions: column: CHIRALPAKW AS-H, mobile phase: hexane/isopropanol + 0.1% triethylamine, ambient temperature, flow: 1.0 ml/min, UV: 254 nm,
injection: 5 ml.
because the mobile phase was not polar enough for the
elution from the column. Even if MDPV could not be
separated, with respect to retention time and resolution,
a mobile phase consisting of hexane/isopropanol/TEA
(97:3:0.1) was chosen for the screening of all 24 cathinone
derivatives. Under these conditions, 19 compounds were
baseline-separated within 25 min with resolution factors
ranging from 0.7 for 4-BMC to 4.2 for methylone. As it
was expectable from the experiments with the model
substances, MDPV, MPPP, a-PPP, and naphyrone could not
be separated into their enantiomers, as shown in Table 2.
It seems that under these conditions, the CHIRALPAKW
AS-H column is not suitable for enantioseparation of beta-keto
amphetamines with the nitrogen atom included in a ring
structure. This might be due to inability of the tertiary
amino group to form hydrogen bondings with the chiral
selector. The separation result of N,N-dimethylbutylone
confirms this hypothesis because the resolution result
was inferior to the, apart from the second methyl group
on the nitrogen, identical primary amine butylone. N,N-
dimethylbutylone was only partially separated, whereas
butylone was baseline-separated. The bulky pyrrolidinyl
moiety seems to represent a steric hindrance as well.
Figure 3 shows a comparison of the chromatograms of
butylone, N,N-dimethylbutylone, and MDPV.
The enantiomer elution order was checked by injecting
a methcathinone solution with an excess of the S(À) enan-
tiomer. As shown in Figure 4, the R(+) enantiomer elutes
first followed by the S(À) enantiomer. The same
enantiomer elution order was obtained with a cathinone
sample.
Furthermore, it was tried out to achieve simultaneous
enantioseparation for more racemic compounds per run;
therefore, samples consisting of different cathinone
derivatives were injected. A maximum of five cathinones
(3-FMC, 4-FMC, methedrone, buphedrone, and cathinone)
were separated simultaneously in one run (Fig. 5).
It can be emphasized here that, within this run, the
structural isomers 3-FMC and 4-FMC, which are only
different by the position of the fluoro atom on the phenyl
ring, were separated into its stereoisomers.
Another interesting sample consisted of methcathinone,
buphedrone, and pentedrone. The only difference between
this compounds is the length of the a carbon substituent
as seen in Figure 1. In Figure 6, the enantioseparation
of all three compounds in one run is shown, whereby
the elution order was pentedrone, buphedrone, and
methcathinone.
Additionally, the chromatographic separation behavior of
four cathinones was compared with their amphetamine
analogs. Because cathinones represent beta-keto amphe-
tamines, for each cathinone, an amphetamine analog
exists, for example, cathinone and amphetamine or methy-
lone and MDMA (Ecstasy), respectively. It was found
out that separation results of amphetamines are poor com-
pared with the cathinones (Table 3). Amphetamine could
not be detected within 1 h. The other four amphetamines
were only partially separated. Figure 7 shows the overlaid
chromatograms of MDMA and methylone. It seems that
the carbonyl oxygen with its two free electron pairs plays
a key role in promoting sufficient interaction between the
compounds and the CSP to obtain baseline separation of
the enantiomers.
TABLE 2. Chiral separation results of a set of 24 cathinone
derivatives
t1 (min)
t2 (min)
a
Rs
4-BMC
Buphedrone
Butylone
Cathinone
5.53
3.26
6.98
13.91
4.71
3.85
3.14
7.17
2.54
4.06
4.12
4.76
3.54
3.36
3.24
2.95
4.95
4.58
10.37
12.70
2.59
2.92
5.69
2.85
6.53
5.22
13.07
23.08
11.91
4.03
3.73
9.75
2.91
4.83
5.81
7.71
3.54
5.57
4.16
2.95
8.53
7.36
16.92
21.67
2.59
4.15
9.60
2.85
1.272
2.438
2.200
1.764
3.550
1.091
1.474
1.489
1.560
1.361
1.764
2.033
1.000
2.510
1.690
1.000
2.177
2.034
1.772
1.830
1.000
2.195
2.030
1.000
0.7
1.9
3.8
3.4
4.5
0.5
1.2
2.1
1.0
1.6
2.0
3.0
–
3,4-DMMC
N,N-Dimethylbutylone
Ethcathinone
Ethylone
Ethylbuphedrone
2-Fluoromethcathinone
3-Fluoromethcathinone
4-Fluoromethcathinone
MDPV
4-Methylbuphedrone
4-MEC
MPPP
Mephedrone
Methcathinone
Methedrone
2.3
1.0
–
2.9
2.5
3.3
4.2
–
Methylone
Naphyrone
Pentedrone
Pentylone
1.9
3.5
–
a-Pyrrolidinopropiophenone
Conditions: column: CHIRALPAKW AS-H, mobile phase: hexane/isopropanol/
triethylamine (97:3:0.1), ambient temperature, flow: 1.0 ml/min, UV: 254 nm,
injection: 5 ml.
The introduced method was validated with regard to re-
peatability and reproducibility concerning the retention time
Chirality DOI 10.1002/chir

ENANTIOSEPARATION OF CATHINONE DERIVATIVES
a)
b)
c)
Fig. 3. Comparison of the chromatograms of (a) butylone, (b) N,N-dimethylbutylone, and (c) MDPV. Conditions: column: CHIRALPAKW AS-H, mobile phase:
hexane/isopropanol/triethylamine (97:3:0.1), ambient temperature, flow: 1.0 ml/min, UV: 254 nm, injection: 5 ml.
with relative standard deviation (RSD) for the resolution
factor of 2.15% and for the retention times less than
0.15%. The day-to-day repeatability for the retention times
is below 1.6%, whereas the high RSD value for the resolu-
tion factor can be explained by an increase of the peak
efficiency from one day to the other. Reproducibility test
was performed using different HPLC equipment in another
laboratory, and measurements were conducted by another
person. Although retention times were very reproducible
with an RSD below 1.33%, a relatively high RSD of 18.3%
for the resolution was obtained because of the change in
peak shape.
CONCLUSION
Because cathinone derivatives reached high popularity
Fig. 4. Determination of the enantiomer migration order by means of
on the recreational drugs market as a legal alternative to
methcathinone. Conditions: column: CHIRALPAKW AS-H, mobile phase: hex-
the scheduled amphetamines, such as MDMA (Ecstasy)
ane/isopropanol/triethylamine (97:3:0.1), ambient temperature, flow: 1.0 ml/
and amphetamine (Speed), the development of achiral
and chiral analytical methods is of great interest. Cathi-
none derivatives are a relatively new substance class on
the drugs market, and therefore, data about the prolonged
abuse are not available for most of the compounds.
Chirality DOI 10.1002/chir
min, UV: 254 nm, injection: 5 ml.
of the two enantiomers and the resolution factor (Table 4).
For the validation, a mephedrone sample was used. The
intraday repeatability for all three parameters is quite good

MOHR ET AL.
Fig. 5. Simultaneous chiral separation of (1) buphedrone, (2) 3-FMC, (3) 4-FMC, (4) methedrone and (5) cathinone. Conditions: Column: CHIRALPAKW AS-H,
mobile phase: hexane/isopropanol/TEA (97:3:0.1), ambient temperature, flow: 1,0 ml/min, UV: 254 nm, injection: 5ml.
Fig. 6. Simultaneous chiral separation of (1) pentedrone, (2) buphedrone
and (3) methcathinone. Conditions: Column: CHIRALPAKW AS-H, mobile
phase: hexane/isopropanol/TEA (97:3:0.1), ambient temperature, flow:
1,0 ml/min, UV: 254 nm, injection: 5ml.
Fig. 7. Comparison of the chromatograms of MDMA and methylone. Con-
ditions: Column: CHIRALPAKW AS-H, mobile phase: hexane/isopropanol/
TEA (97:3:0.1), temperature: room temperature, flow: 1,0 ml/min, UV:
254 nm, injection: 5ml.
TABLE 3. Comparison of the separation results of cathinones
and their amphetamine analogs
compounds bear a tertiary amino group, whereas N,N-
dimethylbutylone was partially separated and the four com-
pounds with the nitrogen atom included into a pyrrolidine
heterocycle were not separated anyway. Nevertheless,
this leads to the assumption that the ability of primary
and secondary amines to build out hydrogen bondings is
compulsory for proper solute–CSP interaction. CHIRAL-
PAKW AS-H columns are well established in the field of
chiral separations; this research enables a broader spec-
trum of the areas of application. The method was vali-
dated with respect to intraday and interday repeatability
and reproducibility, respectively. Moreover, the simulta-
neous chiral resolution of a mix of five compounds in
one run was shown. Additionally, the chiral resolution of
four cathinone derivatives was compared with the resolution
of their amphetamine analogs. In all cases amphetamines
where worse separated. As a minor drawback, the sample
preparation step to obtain the free nitrogen base has to be
taken into account.
t1 (min)
t2 (min)
a
Rs
Cathinone
Amphetamine
Butylone
MBDB
Ethylone
MDEA
13.91
>60
6.98
4.44
7.17
3.75
12.70
5.79
23.08
>60
13.07
5.24
9.75
4.12
1.764
–
3.4
–
2.200
1.306
1.489
1.185
1.830
1.229
3.8
0.5
2.1
0.3
4.2
0.4
Methylone
MDMA
21.67
6.67
Conditions: column: CHIRALPAKW AS-H, mobile phase: hexane/isopropanol/
triethylamine (97:3:0.1), ambient temperature, flow: 1.0 ml/min, UV: 254 nm,
injection: 5 ml.
With the introduced isocratic normal phase HPLC method,
19 out of 24 cathinone derivatives were baseline-separated
into their enantiomers. All five not baseline-separated
Chirality DOI 10.1002/chir

ENANTIOSEPARATION OF CATHINONE DERIVATIVES
TABLE 4. Repeatability and reproducibility data including retention time and resolution by means of mephedrone
t1 (min)
t2 (min)
Rs
Repeatability
Intraday n = 5
Day-to-day n = 10
Reproducibility
Intraday n = 20
4.80 Æ 0.00, RSD = 0.08%
4.81 Æ 0.00, RSD = 0.06%
8.27Æ0.01 RSD = 0.11%
8.15 Æ0.12, RSD = 1.50%
2.63Æ0.06 RSD = 2.15%
2.88Æ0.27 RSD = 9.43%
4.76 Æ 0.05, RSD = 1.15%
8.19Æ0.11 RSD = 1.33%
3.45Æ0.63 RSD = 18.30%
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Chirality DOI 10.1002/chir