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Potentiometric Sensing of Organics for HPLC and CE: Ready for Takeoff!

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Potentiometric Sensing of Organics for HPLC and CE: Ready for Takeoff! Potentiometric sensing of organics for HPLC and CE: Ready for takeoff! Luc Nagels Antwerp University Hergé, (Belgium) Potentiometric sensors for: HPLC detection, CE detection, dissolution testing conductive poly- and oligomers, ceramics, liquid membranes Potentiometry, the "sleeping lion" Hunting: metal ions, cationic drugs and amines, halogen ions, S2-, - - - - SCN , NO3 , NO2 and ClO4 , organic acids, … Not hunting: biomolecules, multiply charged biomolecules Why not? too hydrophilic, too expensive, too complex Pure and Applied Chemistry, to be published 2004 Potentiometry/HPLC or CE or microchip hyphenation Application in HPLC: 50 older references Application in CE and microchip: 20 recent references Electroanalysis, 15 (5-6): 533-538, 2003. Potentiometric sensors for LC and CE data station reference electrode coating on electronic conductor LC or CE outlet plastic wire Electronic conductor Ionically conducting membrane E Receptor molecules + Electronic conductor substrate electrode (or internal solution). surfaces! membrane E Analyte solution E depends on analyte concentration A potentiometric sensor has one or two important surfaces Substrate electrode Liquid membrane phase (polymer + plasticizer + ionophore) ++++ E ++++ + analyte anion counter cation is the analyte ion extracted or adsorbed? 2 1 Tartaric acid 2 Malonic acid 3 Malic acid 5 4 Lactic acid 3 5 Citric acid 6 Fumaric acid 7 Succinic acid 6 1 4 7 2 mV Column: RPC8, 4.6mm i.d. Eluent: 1 mM H3PO4, 1mL/min 010 Time, min pg detection limits for malonic N N NH NH NH NH NH NH O O O O O O NH NH NH NH NH NH C H C H C H 18 37 18 37 18 37 lipophilic tail ligand 1 ligand 2 polar head O O O ++++ C18H37 C H C H H N N N N 18 37 N N N N 18 37 2 H H H H N H H ligand 3 ligand 4 R R1 N N R R N N RN N R RN NR N N R N N R1 R R ligand 6 R = H, R1 = C H 10 21 + ligand 8 R = R1 = (CH2)3NHCONHC18H37 ligand 5 R = C8H17 ligand 9 R = R1 = CH2CONHC2H4N(C2H4NHCONHC18H37)2 “embedded” charge, MTDDACl R R N N (methyltridodecylammoniumchloride) CH R 3 NH HN N N N CH3 CH3 N NH HN N N N CH N CH3 3 R R ligand 7 R = C H 10 21 ligand 10 R = (CH2)4OCONHC18H37 0.2% MTDDACl (embedded type), and 1% ligand (head/tail type) Lichrosphere 100-5 RP8 column (Merck), 125x4mm, eluens 1mM H3PO4 at 0.5mLmin-1 flow-rate. 10 µL injection of a mixture of tartaric- (1, 10-5M ), malonic- (2, 2x10-7M), malic- (3, 4x10-6M), lactic- (4, 10-4M), citric-(5, 10- 5M), fumaric- (6, 2x10-5M), succinic acid (7, 2x10-5M). peak height, mV 10 5 25 50 injected micromolarconcentr concentrationation, ìM Calibration curves obtained with the HPLC potentiometric sensor. Upper curve: malonic acid, middle curve: tartaric acid, lower curve: citric acid. Substrate electrode Liquid membrane phase + “Embedded” charge type E ++ versus head/tail type + Eluent phase docking, molecular modeling, gasphase modeling interface behavior +++ -- malonic acid UMP AMP nucleotides UV X-terra C18 (3x50mm), ion-pair 4x10-5M inj in 10µL potentiometric 0.71mV UDP UTP ADP ATP 0 0 5 time, min 10 Oligonucleotides, FIA 25-mer CAGACAATAGTAAATGAGAATCAGG 4mV -5 10 M in 1mM H3PO4 0.3mL/min, 10 µL injection UV Potentiometry 0 60 time, s + Oligonucleotides d(T)12-18 5‘OH Na salt X-Terra RP18 3x50mm 10mM TEAE, 0.3mL min-1, 8 to 10% AcN Potentiometry 2mV UV 45 6 7 8 9 10 11 12 13 14 15 16 17 18-mer 0 9 volume, mL 18 unpublished results Substrate electrode Liquid membrane phase - + p-chloro tetraphenylborate E + + - Eluent phase sensing organic cationic substances Potentiometric det. of linear aliphatic amines 2 12 3 4 5 3 4 5 6 6 1 4 mV 21Time, min 26 1 Methylamine … 5 6 Hexylamine Alltech universal cation exchange 2 4 5×10-5 M 1 3 4.6 mm ID, 5mMHNO3 in 5% inj., 50µL acetonitrile, 1mL min-1, Analytica Chimica Acta 440 (2) 89-98, 2001. potentiometric detection of beta-adrenoceptors in RP 1 clenbuterol 2 practolol 3 oxprenolol 4 alprenolol 5 carazolol 6 bevantolol 7,8 unknowns 10-6 M injections, 20µL PVC/DOS/TCPB 32:66:2 wt% X-Terra RP18, 50mmx3mm, acetonitrile/20mM H3PO4, 25:75 Journal of Chromatography A, 973, 85-96, 2002 detection limits (molar conc., 20µL injected) analyte UV 230nm Borate OctylCD Calix mol/L mol/L mol/L Clenbuterol 2.6 x 10-7 6.7 x 10-7 1.1 x 10-7 1.7 x 10-6 Mabuterol 2.9 x 10-6 2.2 x 10-7 5.6 x 10-8 3.4 x 10-5 Cimaterol 3.0 x 10-7 2.5 x 10-5 4.8 x 10-6 3.6 x 10-5 Carbuterol 1.7 x 10-7 8.5 x 10-5 7.7 x 10-5 2.4 x 10-4 Bufuralol 3.5 x 10-7 2.8 x 10-7 2.2 x 10-8 1.5 x 10-6 Practolol 1.7 x 10-7 5.4 x 10-5 6.2 x 10-5 1.9 x 10-4 Alprenolol 2.2 x 10-6 6.7 x 10-7 3.6 x 10-7 3.0 x 10-7 Oxprenolol 1.0 x 10-6 1.7 x 10-6 7.7 x 10-7 5.8 x 10-7 p-Oxprenolol 0.7 x 10-6 1.6 x 10-6 7.5 x 10-7 3.5 x 10-7 Bisoprolol 3.5 x 10-7 1.3 x 10-5 3.7 x 10-6 2.7 x 10-6 Celiprolol 1.6 x 10-7 1.7 x 10-5 1.6 x 10-5 6.8 x 10-5 Bevantolol 1.3 x 10-6 2.2 x 10-6 1.0 x 10-6 1.6 x 10-6 Tolamolol 1.3 x 10-6 1.4 x 10-5 1.3 x 10-6 2.0 x 10-5 Propranolol 2.7 x 10-8 2.1 x 10-7 1.0 x 10-7 5.3 x 10-7 Nadolol 2.3 x 10-7 5.9 x 10-5 2.1 x 10-5 1.0 x 10-4 Tertatolol 1.2 x 10-6 3.5 x 10-7 1.2 x 10-7 1.8 x 10-6 Carazolol 4.4 x 10-7 6.0 x 10-4 2.0 x 10-5 2.1 x 10-4 lysosomotropic alkanolamines 1 Alltech universal cation exch. 35 mV 40 mM H3PO4/acetonitrile 85:15 Inj. conc.: 2x10-4M, 20 microL 2 3 1: aminoethanol 5 6 2: N-methyl- aminoethanol 4 3: N-ethyl- aminoethanol 4: N,N-dimethyl- aminoethanol 5: N,N -dimethylaminoisopropanol 6: N,N-diethyl- aminoethanol 0 time, min 2 Analytica Chimica Acta, 472, 11-26, 2002. liquid membrane phase + + + E Eluent phase + high extraction/adsorption tendency → low DL ∆Gtr = ∆Ghydr -(∆Gsolv + ∆Gion + ∆Gcomplex) logDL = a - blogP + cPvol Intermolecular interactions → “non-faradaic” potentiometry Nagels, L. J.; Bazylak, G.; Zielinska, D. Electroanalysis 2003, 15, 533-38. HPLC/Potentiometry of Mucolytic drugs -1 CN normal phase 250x4.6mm, 1mL min ACN/HClO4 CH 1.66mM/ethanol 60:38:4 v/v 3 Br N NH 2 Br bromhexin -5 OH bromhexin 10 M inj. Br 40mN V H det. lim: 2x10-10 M, 1pg! NH 2 40mV Br ambroxol clenbuterol 0 4 min Chromatographia 57 (11-12): 757-765, 2003 CH3 Br N NH 2 Br 10-9M bromhexin injected 1mV 0 min 4 Normal-phase, CN det. lim.bromhexin: 2x10-10M, 1pg! V Substrate electrode (electronic conductivity) Interface A Liquid membrane phase (ionic conductivity) E Interface A gives interfacial tensions depending on eluent composition. Little is known on substrate/membrane adhesion chemistry CE of linear chain aliphatic amines Potentiometric detection - polymeric electrode, 0.25mm C6 75 um, 60cm, 15kV, 50mM NaH2PO4 C5 C4 10mV C3 C2 C1 10-3 M inj 10-4 M inj C2 C3 C4 C5 C6 0 10 time, min 20 Cocaine 40 mV Amine Heroin 7 12 17 2227323742 Time [min] Electropherogram of aliphatic amines (1-6), heroin (7), and cocaine (8). Concentrations injected: 10-3M (amines), 10-4M (drugs). Cyclodextrin was added to the eluent. Clozapine Noscapine Cocaine 40mV Quinine 12 24 time, min Sample injection electrokinetically 10s at 12.5kV. Separation voltage 12.5kV. Capillary: 75 µm i.d., 30cm length, fused silica, uncoated. Electrolyte: 50mM NaH2PO4 +10% acetonitrile (pH 3.8). Cocaine 180 y = 73.29x + 380.8 160 140 R2 = 0.9993 mV 120 100 80 60 40 20 -3 -3.5 -4 -4.5 -5 -5.5 log [c] CO It did not always go that easy.. Electropherogram hexanoic- (6), pentanoic- (5), butyric- (4), propionic- (3), acetic- (2) and formic acids PPy electrode 5x10-4M in 5mM HEPES (pH 7.6). Electrokinetic inj. 10s 5kV 75µm i.d., 60 cm, fused silica, uncoated, +20kV Separation voltage: +20kV Electrolyte: 5mM HEPES pH 7.6 Anal. Chim. Acta 401, 21-27, 1999 Also terrible... Same acids in HEPES containing 0.5mM TTAB (tetradecyltrimethylammoniumbro mide) A: conducting trimer electrode, phenylene vinylene type, plus polycarbonate B: PPy electrode -20kV (negative polarity) Potentiometric detection for HPLC and CE can be made extremely sensitive for organic ionizable substances. New classes of compounds can be studied, especially bio- organics. More understanding of surface chemistry is needed Thanks to Grzegorz Bazylak, Danuta Zielinska, Jozef Everaert, Lily van Roy, Ying Bao, Hugo Bohets, Bert Vissers, David Dehous,Tom Wuyts, Justyna Sekula Thanks to the Belgian-Polish bilateral project.
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