Enantioselective Sensors and Biosensors in the Analysis of Chiral Drugs

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Enantioselective Sensors and Biosensors in the Analysisof Chiral DrugsHassan Y. Aboul-Enein a & Raluca-Ioana Stefan ba Bioanalytical and Drug Development Laboratory, Biological and Medical ResearchDepartment (MBC-03), King Faisal Specialist Hospital and Research Centre, P.O. Box 3354,Riyadh 11211, Saudi Arabiab Department of Analytical Chemistry, Faculty of Chemistry, University of Bucharest, Blvd.Republicii #13, 70346, Bucharest-3, RomaniaPublished online: 03 Jun 2010.

To cite this article: Hassan Y. Aboul-Enein & Raluca-Ioana Stefan (1998) Enantioselective Sensors and Biosensors in theAnalysis of Chiral Drugs, Critical Reviews in Analytical Chemistry, 28:3, 259-266, DOI: 10.1080/10408349891194199

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Critical Reviews in Analytical Chemistry,28(3):259–266 (1998)

I. INTRODUCTION

Enantioselective analysis of drugs re-quires reliable methods. The sampling pro-cess can introduce a lot of uncertainties, es-pecially when a separation method for theenantiomers, using nonadequate chiral se-lectors, is proposed.1 There are severalseparation methods, such as high-perfor-mance liquid chromatography (HPLC) orcapillary zone electrophoresis (CZE), appliedfor enantiomers discrimination. The mainproblem with the enantioselective analysisis the detection system. By assuring anenantioselective detection system, theseparation step can be canceled fromthe sampling process. One of the most reli-

able enantioselective detection systems areenantioselective membrane electrodes andelectrochemical biosensors. The enantiose-lective membrane electrodes contained inthe membrane as chiral selectors crown ethersand α, β, and γ cyclodextrins had been used.However, the best enantioselective electro-chemical biosensors are the ampero-metric ones due to the coupling betweenthe enantioselectivity of the enzyme andthe sensitivity of the amperometricdevices.

For the enantioselective analysis usingelectrochemical sensors and biosensors, thesampling process means only sample disso-lution in water or buffer. This fact renderedthe analytical information of high precision,

Enantioselective Sensors and Biosensors inthe Analysis of Chiral Drugs

Hassan Y. Aboul-Enein1* and Raluca-Ioana Stefan2

1Bioanalytical and Drug Development Laboratory, Biological and Medical Research Department(MBC-03), King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh11211, Saudi Arabia; 2Department of Analytical Chemistry, Faculty of Chemistry, Universityof Bucharest, Blvd. Republicii #13, 70346, Bucharest-3, Romania

* Author to whom correspondence should be addressed.

ABSTRACT: The opportunity to use electrochemical sensors in enantioselective analysis isdiscussed. Chiral selectors such as crown ethers, cyclodextrins, and enzymes had been used forboth chromatographic enantioseparation methods and enantioselective electrochemical sensorsand biosensors. New possibilities of membranes construction, like molecular imprinting-basedenantioselectivity sensors are also discussed. The advantages of use enantioselective sensors andbiosensors over separation methods (HPLC, MEKC, CZE) are presented. The reliability of chiraldrugs enantioselective assay is improved by using enantioselective sensors and biosensors.

KEY WORDS: enantioselective analysis, chiral drugs, electrochemical sensors, electrochemicalbiosensors.

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especially if the chiral selector formed a highstability complex with one of the enanti-omer.

II. ENANTIOMERS SEPARATIONMETHODS USED IN SAMPLINGPROCESS

One of the main problems of theenantioseparation technique is the selectionof the chiral selector. The first class of com-pounds used as chiral selectors is the crownethers. This class of organic selectors did notresolve the enantiomeric pairs adequatelyand the accuracy of the separation was poor.

Cyclodextrins assure the best reliabilityof the separation methods due to their betterinteractions with one of the enantiomers. Thebest chiral selectors in the cyclodextrin classof compounds is β-cyclodextrin and its de-rivatives. High-performance liquid chroma-tography (HPLC), capillary zone electro-phoresis (CZE), and micellular electrokineticchromatography (MEKC) are frequently usedseparation techniques for enantiomeric reso-lution.

A. HPLC

To predict the chiral chromatographicseparation, a multivariate regression analy-sis is proposed, combined with multilayerfeed-forward neural networks trained witherror back-propagation, to model theenantioselective chromatographic retentionbehavior of a series of aromatic acids andamides as a function of nonempirical solutedescriptors.2 Combinations of charge trans-fer, electrostatic, lipophilic, and dipole inter-actions, identified by multivariate regression,were found to describe retention andenantioselectivity, with highly predictivemodels being generated by the training ofback-propagation neural networks.

Macrocyclic glycopeptides antibiotics arethe newest class of chiral selectors for thechromatographic and electrophoretic sepa-ration of enantiomers. The two most suc-cessful macrocylic antibiotics used for sepa-rations are vancomycin and teicoplanin.3,4

Teicoplanin is a stable glycopeptide thatassures, as chiral selector, the integrity of thechiral stationary phase (CSP). Teicoplaninchiral stationary phase appears to have ex-cellent enantioselectivity for native aminoacids, peptides, α-hydroxycarboxylic acids,and a variety of neutral analytes includingcyclic amides and amines.5

The best chiral selectors for enantiomersseparation are cyclodextrins. Taking intoaccount that for chiral drugs, the reliabilitymust have the maximum value, and that theenantiomers separation is one of the mostdifficult problems in chemistry, and is ofgreat importance in fields such as chiral syn-thesis, kinetics, biochemistry, pharmacology,and medicine. The use of cyclodextrins aschiral selectors improve the quality and reli-ability of the separation when HPLC is usedas a separation technique. Cyclodextrins andmodified cyclodextrins can be used as eitherthe chiral stationary phases, as chiral mobilephase additives, or as chiral counterions.Also, cyclodextrins stationary phases arequite versatile when compared with otherchiral stationary phases as they have beenused in three different chromato-graphic modes (normal, reversed, and polarorganic). For this reason, they have beentermed a multimodal chiral stationaryphase.6

B. MEKC

By using micellular electrokinetic chro-matography (MEKC) with derivatizedcyclodextrins as chiral selectors, the qualityof the analytical information is improved.Resolution and migration time were found

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to be strongly dependent on the cyclodextrinsconcentration of the background electrolyteand to a lesser extent on the concentration ofthe analyte.7

C. CZE

For chiral drugs analysis, the CZE usingchiral selectors is the best analytical tech-nique due to the fact that it does not needhigh solvent quantities and is a more reliableseparation method.

By using cyclodextrins and their deriva-tives in CZE, high-quality analytical infor-mation is achieved.8-14 Sulfobutyl ether-β-cyclodextrin as a chiral selector has a largecountercurrent mobility, making it inherentlyadvantageous as selectors when comparedwith neutral cyclodextrins;15 it is an excel-lent chiral selector for a variety of structur-ally diverse drug compounds.

III. INSIGHTS INTO THEMECHANISMS OFENANTIOSELECTIVITY BYCYCLODEXTRINS

To understand the mechanisms ofenantioselectivity by cyclodextrins, 1H NMRand 13C NMR studies on chiral recognitionhave been examined.16-19 The resolution ofchromatographic methods is given by theapparent binding constants of enantiomersand by the chemical shift differences at satu-ration using 1H NMR and 13C NMR spec-troscopies.13

Chankvetadze et al.18 studied the effect ofthe nature and position of substituents of thechiral solute on the resolution using 13C NMR..

Sulfonated β-cyclo-dextrins such as sulfobutyland sulfoethyl ethers of β-cyclodextrins per-mit adequate enantio-separations at ratherlower concentrations as chiral selectors incomparison with carboxymethyl-β-cyclo-dextrin and native β-cyclodextrin.

Bodenhöfer proposed a model for thechiral discrimination process by superim-posing preferential and nonpreferential sorp-tion mechanisms.19 The model is applicableto any matrix containing preferential sorp-tion sites. The “molecular recognition” ef-fect can be observed by simply dissolvingthe supramolecular unit in an isotropic poly-mer.

IV. MOLECULAR IMPRINTING-BASED ENANTIOSELECTIVITYSENSORS

The molecular imprinting technologyleads to highly stable synthetic polymers thatpossess selective molecular recognition prop-erties because of recognition sites within thepolymer matrix that are complementary tothe analyte in the shape and positioning offunctional groups. Some of these polymershave high selectivities and affinity constantscomparable with naturally occurring recog-nition systems such as monoclonal antibod-ies or receptors, which make them especiallysuitable as constituents in chemical (bio-mimetric) sensors for analytical chemistry.

Chemical sensors provide an analyticallypowerful and inexpensive alternative to con-ventional technologies by enabling the iden-tification of a target molecule in the pres-ence of numerous interfering species.Methodologies have been developed formany different target species, including gas-eous substances such as anesthetics, respira-tory byproducts, compounds of biologicalimportance (glucose, urea), hormones, ste-roids, drugs of abuse, and also drugs enanti-omers discrimination.20,21 A chemical sensorselectively recognizes a target molecule in acomplex matrix and generates an output sig-nal using a transducer that correlates to theconcentration of the analyte.22,23

Rapid developments in electronics haveled to microprocessors that are suitable foruse in chemical sensors. Such microproces-

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sors offer advanced signal-processing capa-bility, and integrating the controller with thetransducer could minimize noise and resultin improved sensor performance. The prob-lem of long response time (15 to 60 min)could be minimized by optimizing the kinet-ics and selectivity of polymers.

V. PIEZOELECTRIC SENSORS

The enantioselective analysis of drugsthrough sensors having piezoelectric devicesas transducers assure high sensitivity.25,26

The piezoelectric sensor is usually coatedwith β-cyclodextrin or with a derivatives ofβ-cyclodextrin. The main advantage of thistype of enantiomer selector is the possibilityto be used for continuous on-line monitor-ing of the enantiomers.26 Furthermore,α-cyclodextrins and β-cyclodextrins werealso tested as coatings for piezoelectric sen-sors for chiral drug separations.26

VI. ENANTIOSELECTIVEMEMBRANE ELECTRODES

Enantioselective membrane electrodesare one of the best elecrochemical sensorsused for chiral drug assay. The constructionof these electrochemical sensors must takeinto account the stability constant of thecomplex formed between enantiomer andchiral selector. The main problem is thechoice of the best chiral selector; that willassure the enantioselectivity of the analysis.

Crown ethers proved to be effective chiralselectors for basic drugs containing a pri-mary amino group, including amino acidsand derivatives.27–30

Horváth et al.31 recently reported anenantioselective assay of ephedrinium ionsusing potentiometric sensors based on crownethers.

The chiral drug discrimination can alsobe also achieved by using cyclodextrins and

the derivatives of cyclodextrins in membraneconstruction.32 The enantioselectivity of thepotentiometric sensor is improved by usingthese chiral selectors which are used for PVC(polyvinylchloride) matrix membrane con-struction. Functionalized α, β, and γ-cyclodextrins recognize a wide spectrum ofonium ions of pharmaceutical importance.32

To assure the high reliability of mem-brane construction, liquid membranes im-pregnated with cyclodextrins must be used.A reliable construction of membrane elec-trodes for chiral drugs discrimination is thefirst step in the their accreditation. Now, thisproblem is solved by using biosensors basedon immobilization of enzymes in carbon pasteelectrodes.

VII. ENANTIOSELECTIVEAMPEROMETRIC BIOSENSORS

The enantioselective amperometricbiosensors assure the best enantioselectivityfor chiral drugs discrimination. The maindisadvantage is their short life time. To im-prove the life time, a novel design for anextended-life amperometric enzyme elec-trode is proposed.33 The enzyme electrode ismade by arranging the three components ofa biosensor (an electrode material, an en-zyme, and a stabilizer) on a shapableelectroconductive (SEC) film (a polyanion-doped polypyrrole film) surface by a layer-after-layer approach. First, a thin and com-pact platinum black layer is prepared ontothe SEC film by the heat-press method. Then,an ultrathin layer of enzyme (e.g., L-aminoacid oxidase) is casted on the platinized SECfilm, and after drying a thin gelatin layer isprepared on the enzyme-casted SEC film.Finally, the dried layer assembly is cross-linked by exposing it to a diluted substratesolution for a very short time. The sensorshows a shelf life of about 2 years when it isstored dry in a freezer at –18°C and about1 year when it is stored at room temperature.

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Of main importance for enantio-selec-tive analysis are amperometric biosensorsbased on enzymes immobilized on carbonpaste electrodes. The construction of thistype of biosensors is reliable. Amperometricbiosensors are shown for the first time towithstand prolonged high-temperature(>50°C) stress. Nearly full activity of someenzymes can be retained over periods of up4 months of thermal stress at 60 to 80°C.Dramatic improvements in the thermostabil-ity are observed for L-amino acid oxidase.Such resistance to heat-induced denaturationis attributed to the conformational rigidity tothese biocatalysts within the highly hydro-phobic (mineral oil or silicon grease) pastingliquid. Besides their implications for elec-trochemical biosensors, such observationsshould lead to a new generation of thermo-resistant enzyme reactors based on nonpolarsemisolid supports.34

Several chiral drugs used for the treat-ment of hypertention are derivatives of aminoacids. Biosensors based on L-amino acid oxi-dase (L-AAOD) and D-amino acid oxidase(D-AAOD) are proposed for L- and D-aminoacids assay.35,36

An amperometric biosensor based on L-AAOD in graphite paste as support is pro-posed for many chiral drug assay. By usingthis biosensor a high enantioselectivity levelwas assured — this fact made it reliable touse the amperometric biosensors for theenantio-purity analysis of active substanceas well as for its assay in the pharmaceuticalcompounds. The limit of detection is lowlevel µmol/L –pmol/L due to the high selec-tivity of the amperometric sensor (Ag/AgCl)used. This type of amperometric biosen-sor was tested for several angiotensin-converting enzyme (ACE) inhibitors: S-captopril,37 S-enalapril, S-ramipril,38 S-cilazapril, S-trandolapril, S-pentopril,39 andS-perindopril.40

For the enantiopurity assay of (+)-3,3′,5-triiodo-L-thyronine (L-T3) and L-thyroxine(L-T4) which are used in treatment of hy-

pothyroidism, the same construction for theamperometric biosensors is proposed 41.

VIII. ADVANTAGES ANDDISADVANTAGES OF USINGELECTROCHEMICAL SENSORSAND BIOSENSORS VERSUSENANTIOSEPARATION METHODSFOR THE ENANTIOSELECTIVEANALYSIS

The enantioseparation by HPLC, CZE,or MEKC is very laborious and generallyexpensive and there are a lot of problemsconcerning the selective retention of one ofthe enantiomers on the column. It is notenough to obtain a high selective chiral se-lector. The working conditions must be im-proved for every enantiomeric pair.

Cyclodextrins are one of the best chiralselectors especially for chiral drug discrimi-nation and were used for membrane elec-trode construction. The main advantages ofthe cyclodextrin-impregnated electrodes arethe high reproducibility, the rapidity, andsimplicity of the analysis. However, one ofthe greatest disadvantages of these con-structed membrane electrodes is the con-struction nonreproducibility. The proposedenantio-selective membrane electrodes arebased on PVC matrix membranes. The re-producibility of construction problem wassolved by using the amperometric biosensorsbased on a modified graphite paste. Theyassure at the same time a high reproducibil-ity of the assays, a high sensitivity and selec-tivity levels, and the best limits of detection.The main disadvantage of amperometricbiosensors is their short life time.

IX. CONCLUSIONS

The enantioselective analysis of chiraldrugs needs reliable methods. Separationmethods such as HPLC can be used for the

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separation of the enantiomers in order toobtain a high enantiopurity of chiral drug,but to assay its enantiopurity the use of anelectrochemical sensor or biosensor is sim-pler, more reliable, and cost effective thanHPLC. Through using electrochemical sen-sors and biosensors, the reliability of theenantiomers assay is improved. The highreproducibility for sensors construction wasachieved by ampero-metric biosensors basedon modified graphite paste. To improve thequality of plastic membranes, a lot of studiesconcerning the preparation and characteriza-tion of composite polymers were made thatcan serve for enantiomers discrimination inchiral drug analysis.42

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Documents

Enantioselective Sensors and Biosensors in the Analysis of Chiral Drugs