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Page 1: Enantiomeric Separation of 13 New Amphetamine-Like Designer Drugs by Capillary Electrophoresis, Using Modified--Cyclodextrins

CHIRALITY 25:617–621 (2013)

Enantiomeric Separation of 13 New Amphetamine-Like DesignerDrugs by Capillary Electrophoresis, Using Modified-Β-CyclodextrinsLUCIA BURRAI, MARIA NIEDDU, MARIA ANTONIETTA PIRISI, ANTONIO CARTA, IRENE BRIGUGLIO, AND GIANPIERO BOATTO*

Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Sassari, Italy

© 2013 Wiley Perio

ABSTRACT An easy-to-prepare chiral CE method for the enantiomeric separation of 13 newamphetamine-like designer drugs, using CDs as chiral selectors, was developed. Sulfated-b-CDwas found to be the best chiral selector among the three used (sulfated-b-CD,caroboxymethyl-b-CD, dimethyl-b-CD). The separation of the analytes was achieved in a fused-silica gel capillary at 20 �C using an applied voltage of +25 kV. The optimized background electro-lyte consisted of 63.5mM H3PO4 and 46.9mM NaOH in water. Several electrophoretic parame-ters such as CD type, CD concentration (1 � 40mg/mL), buffer pH (2.6, 3.6, 5.0, 6.0), length ofthe capillary (70 � 40 cm total length), amount of the organic solvent (methanol and acetonitrile)were investigated and optimized. Chirality 25:617–621, 2013. © 2013 Wiley Periodicals, Inc.

KEY WORDS: trimethoxy-amphetamines; dimethoxy-amphetamines; paramethoxy-amphetamines;S-b-cyclodextrin; CM-b-cyclodextrin; DM-b-cyclodextrin; chiral separation

*Correspondence to: Gianpiero Boatto, Dipartimento di Chimica e Farmacia,Università degli Studi di Sassari, via Muroni 23/a, 07100, Sassari, Italy. E-mail:[email protected] for publication 21 February 2013; Accepted 2 April 2013DOI: 10.1002/chir.22185Published online 22 July 2013 in Wiley Online Library(wileyonlinelibrary.com).

INTRODUCTIONAmphetamine and its derivatives are a class of substances

that have gained more and more popularity as recreationaldrugs all over the world. Before the knowledge of organicchemistry and synthesis became refined, plants of differentkind (e.g. Papaverum somniferum and Erythroxylum coca)were used as drugs of abuse.In recent years the use of so-called designer drugs has

spread dramatically worldwide. According to the UnitedNations Office on Drugs and Crime, in 2011 amphetaminepsychostimulants were the second major class of illicit drugsconsumed for recreational purposes in the world (UNODC,2011).1

One of the reasons for the illegal market’s interest in de-signer drugs is that the production of these substances isnot dependent on geographical location (as is the case fordrugs of abuse such as cocaine or cannabis) because produc-tion occurs in clandestine laboratories, which can be orga-nized anywhere.2 Another cause, perhaps the mostimportant, for the fast growth of the black market of amphet-amines is that these new drugs cannot be considered illicituntil their names are officially recognized. Furthermore, am-phetamines are also attractive for the consumer because ofthe great number of positive effects, which can easily inducea psychological dependence: increased vigilance and concen-tration, increased physical and mental strength, reduction offatigue, sleep, and hunger (the amphetamine-like compoundsare often used as anorectic drugs).Amphetamine derivatives include phenylisopropylamines

(for example, Amphetamine), and phenylethylamines, gener-ally less potent than phenylisopropylamines (for example,Mescaline). The first group is characterized by a chiralcenter, and so two isoforms (S and R) exist. Few phenylethyl-amines have a substituent in the ethyl chain, so phenylethyl-amines can also have a chiral center.It is well known that a chiral active pharmaceutical molecule

may have different activity, different pharmaceutical effects,different potency, or an effect limited to only one optical isomer.3

It has been demonstrated that this is true also for amphetaminederivates. Dexamphetamine (dextroamphetamine, 2-S-(+)-

dicals, Inc.

amphetamine, (S)-1-phenyl-2-propionamine), the dextrorotatory(S)-enantiomer of amphetamine, is a central stimulant used intherapy for narcolepsy4 and in attention-deficit hyperactivitydisorder in children.5 It is not possible to attribute the same effectto the other isomer. Differences may be therefore recognizedfrom a legal point of view: in Japan, for instance, enantiomers of2-amino-1-phenylpropane-1-ol are regulated by different laws.6

It is therefore very important to develop an analytical proce-dure possessing high efficiency and high resolution capabil-ity for the enantiomeric resolution of racemic mixtures at alow cost and short analysis time. Knowledge of the enantio-meric composition of amphetamines could be very useful alsofor investigative purposes, since the enantiomeric excess cangive important information about the synthesis pathway andabout the laboratory of origin.7

Analytical methods so far used for the analysis of chiralcompounds include HPLC,8,9 GC,10 TLC,11 and CE.12,13 CEhas been shown to be an excellent choice to develop a chiralseparation with high resolution and efficiency. The chiralselector should interact in different ways with the two enan-tiomers by, for example, hydrophobic interaction, hydrogenbonding, and inclusion-complexation.14 In the literature,different methods for the chiral separation of amphetamineshave been described, including HPLC,15,16 GC,17,18 andCE.19–21 Excellent separations in CE have been performedjust by adding a chiral selector into the BGE.In this work we used 3 b-CD derivatives as chiral selectors

for the separation of 13 amphetamine-derivates designer drugs,synthesized in our previous works: 3,4,5-trimethoxyamphetamine(TMA), 2,4,5-trimethoxyamphetamine (TMA-2), 2,3,4-trime-thoxyamphetamine (TMA-3), 2,4,6-trimethoxyamphetamine(TMA-6), 2, 5-dimethoxy-4-bromoamphetamine(DOB),2,5-dimethoxy-4-chloroamphetamine (DOC), 2,5-dimethoxy-4-ethylamphetamine

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BURRAI ET AL.618

(DOET),2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-methylamphetamine (DOM), 2,5-dimethoxy-4-nitroamphetamine(DON), 2,5-dimethoxy-4-propylamphetamine (DOPR), p-methoxyamphetamine (PMA), and p-methoxymethamphetamine(PMMA) (Fig. 1). Four of these amphetamines have alreadybeen separated (DOM, DOPR, DOET and DOB), although notin the same conditions. To our knowledge, this is the first timethat the other analytes (DON, DOC, DOI, PMA, PMMA, TMA,TMA-2, TMA-3, TMA-6) have been separated.Several electrophoretic parameters such as the chiral selec-

tor (sulfate-b-CD, carboxymethyl-b-CD, dimethyl-b-CD), theCD concentration (1 � 40mg/mL), the buffer pH (2.6, 3.6,

Fig. 1. Structure of amphetamines used as analytes.

Fig. 2. Enantiomeric separation of DOB at pH 2.6, using 5mg/mLS-b-CD.

Chirality DOI 10.1002/chir

5.0, 6.0), the voltage (+15 � +30 kV), the length of the capil-lary (70 � 40 cm total length), and the amount of the organicsolvent (methanol and acetonitrile) were investigated andoptimized.

MATERIALS AND METHODSChemicals

Sulfated-b-CD (degree of substitution according to specification7-11 mol/mol), carboxymethyl-b-CD, and dimethyl-b-CD were pur-chased from Sigma Aldrich Chemicals (St. Louis, MO). To controlfor possible batch-to-batch differences due to the random sulfationof the sulfated-b-CD, all experiments were performed with the samebatch. Phosphoric acid, sodium hydroxide, methanol, and acetoni-trile were from Sigma Aldrich Chemicals. Ultrapure water was pro-vided by a MilliQ system (Millipore, Billerica, MA). All chemicalswere of analytical grade.TMA, TMA-2, TMA-3, TMA-6, DOB, DOC, DOET, DOI, DOM, DON,

DOPR, PMA, and PMMA were synthesized in our lab at their maximumlevels of purity according to the method of Shulgin and Shulgin,22 asreported in our previous works.

CE ConditionsAll CE separations were performed on a 3DCE (Hewlett-Packard, Palo

Alto, CA) equipped with a DAD 1040A. Measurements were optimized in50mM ID-fused silica capillaries with a total length of 40 cm and an effec-tive length of 31.5 cm, thermostated at 20 �C. Voltage was set at +25 kVand the UV detection at 210 nm. The UV spectra were collected beforethe analysis for each compound, in order to identify the optimum detec-tion wavelength between 200 and 400 nm. A sample solution was injectedby pressure.The buffer solution was 63.5mM H3PO4 and 46.9mM NaOH in water

(pH2.6); this buffer has a ionic strength of 50mM and a high capacitybuffer (31.8mM/pH), as indicated by Phoebus software.23 The samebuffer was adjusted to the appropriate pH (3.5, 5.0, 6.0) with concen-trated NaOH. The running buffer, containing single CD, was preparedat various concentrations by weighting an appropriate amount of chiralselector, which was dissolved in the phosphate buffer at appropriatepH. Each amphetamine was analyzed at several concentrations of chiralselector (1 � 40mg/mL). BGE was made with 5% or 10% in methanol oracetonitrile for the organic modifiers studies.The standard stock solution of each analyte was prepared in MilliQ

water (50mg/mL). Solutions were degassed for 5min by ultrasonificationand filtered through a 0.45mM pore size reg. cellulose filter before use.The capillary was rinsed with 0.1N NaOH (5min), water (5min), and

BGE (5min) every day before the start of the analysis. Before each injec-tion the capillary was rinsed with water (2min), 1N NaOH (3min), water(3min), BGE (5min), and running buffer (5min). Each experiment wasrun in triplicate.

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CHIRAL SEPARATION OF 13 NEW DESIGNER DRUGS 619

RESULTS AND DISCUSSIONCE separations of amphetamine enantiomers have been

reported in several studies using both native and modifiedCDs. The ability of different CD derivatives to separate 13new designer drugs was investigated in the present work.It is well known that CDs are able to separate a broad range

of compounds with different chemical characteristics. Unfor-tunately, it is not possible to predict which CD can separatewhich analyte or class of analytes, because of the aspecific in-teraction between enantiomers and chiral selector. The ana-lyte interacts with the polar surface or with the hydrophobiccavity of CDs unpredictably. Therefore, modifications on theexterior surface change the possibility of formation of inclu-sion complex and its stability, improving or worsening the en-antiomeric separation. Generally, the best chiral selector ischosen empirically, by screening several types of CD underdifferent conditions.Therefore, three CD derivatives, namely, sulfated-b-CD,

carboxymethyl-b-CD, and dimethyl-b-CD, were used to evalu-ate the effect on enantiomeric separation of the new 13amphetamine-like designer drugs considered.It was found that the sulfated-b-CD is able to separate all

amphetamines analyzed, with good or excellent resolution(Rs ranging from 1.1 to 9.3) and useful analysis time (rangingfrom 5.6–24.3min) as reported in Table 1, in the same buffer(63.5mM H3PO4, and 46.9mM NaOH), and at the same pH(2.6), but with a different concentration of chiral selector(ranging from 1–10mg/mL). In Figure 2 the enantiomericseparation of DOB in the best conditions has been reported.Under these conditions the enantiomer that interacts weaklywith the chiral selector passes the detector first. On the onehand, the increase of CD concentration leads to a higher reso-lution; on the other hand, however, it leads to an extension ofthe analysis time. At too high concentration, enantioseparationno longer occurs and some analytes were not detected within120min. This notwithstanding, the capability of separationusing this CD derivative is superior to using the others. SomeCE parameters were optimized (voltage, capillary length, CDconcentration, BGE pH, amount of organic solvent).

TABLE 1. Separation parameters of PMA, PMMA, DOB, DOC,DOET, DOI, DOM, DON, DOPR, TMA, TMA-2, TMA-3, and

TMA-6

Compound a Rs t2 (min)

TMAa

1.031 1.1 24.3TMA-2

a1.020 1.3 11.5

TMA-3a

1.023 1.4 15.1TMA-6

a1.054 2.5 9.7

DOBb

1.331 9.3 15.9DOC

b1.296 5.5 13.00

DOETa

1.050 2.6 14.45DOI

c1.032 1.9 5.6

DOMa

1.111 6.0 10.5DON

b1.028 1.1 9.1

DOPRa

1.059 2.8 15.6PMA

c2.145 1.5 11.5

PMMAc

2.136 2.2 12.9

Conditions: buffer 63.5 mM H3PO4 and 46.9 mM NaOH (pH 2.6) containingsulfated-b-CD, applied voltage +25 kV.a10 mg/mL S-b-CD,b5 mg/mL S-b-CD,c1 mg/mL S-b-CDt2 (min): migration time of the last peak.

Concerning the voltage, the best compromise between resolu-tion and analysis time was found at +25 kV. At lower voltagethe analysis time increased too much; at higher voltage therewas an excessive loss in resolution. The capillary length wasset at 40 cm (31.5 to the detector); greater length gave very longanalysis time (over 100min) with no relevant gain in resolution.The best S-b-CD concentration is variable depending on whichamphetamine is being tested.Variations in pH value were tested (2.6, 3.6, 5.0, 6.0) with

the optimized CD concentration for each analyte: the reduc-tion in migration times (data not shown), due to the increas-ing pH value, might be explained by intensified EOF. Withregard to the chiral resolution of the two enantiomers, it ispossible to find a correlation between increasing pH valueand decreasing resolution; separation is still good for someanalytes until pH 5.0 (none gave separation at pH 6.0 in theoptimized condition). The best pH value was found at 2.6. AtpH 5.0 for DOB and DOI the separation was optimized athigher concentrations of CD, with excellent resolution andvery short analysis time (about 3min). For the other analytesthere was no enantioseparation even at 20, 30, 40mg/mL CD.TMAs showed significant worsening with any variation in pH.DOC and PMMAmaintain a comparable resolution at 2.6, 3.6,5.0 pH values (Table 2).Further investigations were made adding various amounts of

organic solvent into the BGE at pH2.6 (Table 3). Often solventslike methanol or acetonitrile are used as organic modifiers forthe purpose of modifying the results of chiral separationperformed in CE.11,24,25 These substances are able to changeseveral parameters such as the stability constants of the inclu-sion complex, the EOF, and the analysis time. Dependingon the type of analyte studied, the enantiomers resolutioncan either improve or worsen. The addition of 5% or 10% ofmethanol or acetonitrile in the BGE with the appropriateamount of S-b-CD for each analyte greatly decreasesmigration times and causes significant loss of resolution forall amphetamines. However, while some amphetamines

TABLE 2. Effect of different pH (ranging from 2.6 to 6.0) onthe enantiomeric separation of TMA, TMA-2, TMA-3, TMA-6,DOB, DOC, DOET, DOI, DOM, DON, DOPR, PMA, and

PMMA

pH 2.6 pH 3.6 pH 5.0 pH 6.0

a1 Rs a1 Rs a1 Rs a1 Rs

TMAa

1.031 1.1 n.s. n.s. n.s. n.s. n.s. n.s.TMA-2

a1.020 1.3 n.s. n.s. n.s. n.s. n.s. n.s.

TMA-3a

1.023 1.4 n.s. n.s. n.s. n.s. n.s. n.s.TMA-6

a1.054 2.5 n.s. n.s. n.s. n.s. n.s. n.s.

DOBb

1.331 9.3 1.041 5.1 1.086 3.3 n.s. n.s.*

DOCb

1.296 5.5 1.039 4.8 1.050 4.6 n.s. n.s.*

DOETa

1.050 2.6 1.016 0.4 n.s. n.s. n.s. n.s.DOI

c1.032 1.9 1.051 0.6 n.s. n.s.* n.s. n.s.

DOMa

1.111 6.0 1.024 1.6 1.032 1.3 n.s. n.s.DON

b1.028 1.1 n.s. n.s. n.s. n.s. n.s. n.s.

DOPRa

1.059 2.8 1.056 0.8 n.s. n.s. n.s. n.s.PMA

c2.145 1.5 1.040 0.5 n.s. n.s. n.s. n.s.

PMMAc

2.136 2.2 1.126 1.8 1.151 2.1 n.s. n.s.*

a10 mg/mL S-b-CD,b5 mg/mL S-b-CD,c1 mg/mL S-b-CD;n.s.: not separated;*Good separation achieved with higher S-b- CD concentration (data not shown).

Chirality DOI 10.1002/chir

Page 4: Enantiomeric Separation of 13 New Amphetamine-Like Designer Drugs by Capillary Electrophoresis, Using Modified--Cyclodextrins

TABLE 3. Effect of the adding of organic solvents to the BGE for some analytes taken as a model

100% aq 5% MeOH 10% MeOH 5% ACN 10% ACN

a1 Rs a1 Rs a1 Rs a1 Rs a1 Rs

TMA-6a

1.054 2.5 1.015 1.2 1.023 1.2 1.020 1.2 1.011 0.9DOB

b1.331 9.3 1.069 3.7 1.043 2.9 1.076 3.9 1.033 2.2

DOCb

1.296 5.5 1.073 4.9 1.051 3.6 1.082 5.1 1.042 2.8DOI

c1.032 1.9 1.018 0.6 n.s. n.s. 1.010 0.5 n.s. n.s.

DOMa

1.111 6.0 1.027 1.6 1.030 1.9 1.036 2.1 1.027 1.3DON

b1.028 1.1 1.006 n.s. n.s. n.s. 1.015 0.4 n.s. n.s.

PMMAc

2.136 2.2 1.268 2.2 1.216 2.3 1.129 2.1 1.159 2.1

a10 mg/mL S-b-CD,b5 mg/mL S-b-CD,c1 mg/mL S-b-CD.n.s.: not separated.

BURRAI ET AL.620

maintain a good resolution (DOB, DOC, DOM, PMMA), twoanalytes are no longer resolved (DOI, DON). The general wors-ening in resolution might be attributed to a decrease of theanalyte-selector binding constant with increasing organic sol-vent percentage.26 The increased hydrophobicity of BGE ham-pers the formation of inclusion complexes. It is widely knownthat nonaromatic organic modifiers are able to form inclusioncomplexes withCD: in this way the analyte is displaced for com-petition with the organic solvent and the enantiomeric separa-tion is made worse. In general, the adding of organic solventsresults in a slightly worse peak shape.Under optimized conditions (voltage, temperature, analyte

concentration, CD concentration, BGE composition, pH, andsolvent) the 13 designer drugs were analyzed with other CDderivatives, such as CM-b-CD and DM-b-CD. Among them,from a theoretical standpoint the CD that should give goodseparation is CM-b-CD, because it is negatively charged.But the results were not satisfactory: only three amphet-amines were separated (DOPR, DOC, DOB) without goodresolution (data not shown).With neutral CD there were no enantioselective interactions

between chiral selector and analytes; indeed, it is well knownthat in the case of oppositely charged CD and analytes, resolu-tion is superior compared to neutral CD derivatives.27,28 Thiseffect is due to the increase of the mobility differences of thetwo enantiomers. The enantiomer that has no interaction withthe chiral selector has a net positive charge; in contrast, theenantiomer that interacts strongly with the chiral selectorhas no net positive charge, as the CD is negatively charged.

CONCLUSIONThis article describe an easy, fast, and reliable method for

the enantioseparation of a set of 13 amphetamine-like de-signer drugs under optimized conditions that gave good orexcellent resolution values ranging from 1.1–9.3, and usefulanalysis times ranging from 5.6–24.3min: aqueous BGE(63.5mM H3PO4 and 46.9mM NaOH), sulfated-b-CD at ap-propriate concentrations for each analyte, 20 �C operatingtemperature, +25 kV applied voltage, and 40 cm total capillarylength. Several pH values were tested; the best condition forall analytes was found at 2.6. The adding of methanol or ace-tonitrile at various percentages (5%, 10%) in the BGE atpH 2.6 showed a worsening of the separation for all analytes,and a great reduction in analysis times. DOB, DOC, DOM,and PMMA still showed good resolution. In general, theadding of organic modifiers in the BGE did not have positiveeffects on the separation of the studied amphetamines.

Chirality DOI 10.1002/chir

ACKNOWLEDGMENTS

The authors thank Mrs. Giuseppina Dessì for technicalsupport.

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CHIRAL SEPARATION OF 13 NEW DESIGNER DRUGS 621

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Chirality DOI 10.1002/chir


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