Table 1.
Pre-2006 polarographic and voltammetric methods for the determination of benzodiazepines at mercury-based electrodes.
| Benzodiazepine | Electrode Material | Linear Range (M) | Detection Limit (M) | Electrolyte | Waveform and Technique | Sample (s) | Reference |
|---|---|---|---|---|---|---|---|
| 7-acetamido-nitrazepam, dimethyl-diazepam, chlordiazepoxide lactam, 7-amino-diazepam | Dropping mercury electrode | - | - | Britton-Robinson buffer, 0.04 M, plus 0.1 M NaOH to obtain desired pH | DPP | Mechanistic study | [43] |
| Bromazepam, clonazepam, diazepam, flurazepam, midazolam, and medazepam | Hanging mercury drop electrode | Clonazepam 1 × 10−7 to 1 × 10−5, bromazepam 1 × 10−7 to 1 × 10−5, midazolam 1 × 10−7 to 1 × 10−5, diazepam 1 × 10−7 to 1 × 10−5, SWCSV clonazepam 1 × 10−8 to 8 × 10−8¸ bromazepam 1 × 10−8 to 8 × 10−8, midazolam 1 × 10−8 to 8 × 10−8, diazepam 1 × 10−8 to 8 × 10–8, medazepam 1 × 10−8 to 8 × 10−8 | SWV, clonazepam 1.3 × 10−8, bromazepam 1.2 × 10−8, midazolam 1.6 × 10−8, diazepam 1.0 × 10−8, SWCSV clonazepam 2.9 × 10−9, bromazepam 2.6 × 10−9, midazolam 2.0 × 10−9, diazepam 2.0 × 10−9, medazepam 1.3 × 10−9, flurazepam 2.5 × 10−9 | 0.10 M KNO3, and Britton–Robinson pH 6.0 buffer | SWV and SWCSV | Tablets | [44] |
| Diazepam, oxazepam nitrazepam, and flurazepam | Dropping mercury electrode | 2 × 10−7 to 10 × 10−7 | 2 × 10−7 | 0.2 M acetate pH 4.8 buffer | DPP, DC polarography | Rabbit urine | [45] |
| Midazolam | Static mercury drop electrode | 3.6–36 µM | 100 pM | Acetate pH ca. 4.8 buffer | SWAdSV, NPV | - | [46] |
| Midazolam | Static mercury drop electrode | - | - | 0.1 M acetate pH 4.8 buffer | NPV | Mechanistic study | [47] |
| Midazolam | Hanging mercury drop electrode | 1.9 × 10−6 to 10−9 | Britton-Robinson pH 5.00 buffer | AdSV | Pharmaceutical formulations | [48] | |
| Midazolam and metabolites (α-hydroxy-midazolam, 3-hydroxy-midazolam and α,3-hydroxy-midazolam) | Static mercury drop electrode | 10−4 to 10−7 | 6 × 10−8 | Sulphuric acid 1.0 M | DPP | - | [49] |
| Camazepam and bromazepam | Hanging Hg drop electrode | Camazepam 1 × 10−9 to 9 × 10−9, bromazepam 1 × 10−8 × 10−8, 270 s at −0.60 V | Camazepam 20 ng/mL and bromazepam 200 ng/mL | DPAdSV | Human serum after isolation with Sep-Pak CI8 cartridges | [50] | |
| Flurazepam and metabolites | Dropping mercury electrode | Three orders of magnitude | 5 × 10−8 | Formate pH 4 buffer | DPP | 15 mg and 30 mg capsules | [51] |
| Loprazolam mesilate | Static mercury drop electrode | 2.5 × 10−10 to 8.0 × 10−9 | 2.5 × 10−10 | 0.04 M ammonium chloride pH 4.0 | SWAdCSV | - | [52] |
| Loprazolam mesilate | Dropping mercury electrode and a static mercury electrode | - | - | DC, AC, normal and inverse pulse polarography, CV, and controlled potential coulometry | Mechanistic study | [53] | |
| Oxazepam and lorazepam | Dropping and hanging mercury electrodes | 1.0 × 10−5 to 1.5 × 10−7 for oxazepam and 2.5 × 10−7 to 2.0 × 10−7 for lorazepam | 1.25 × 10−7 for oxazepam, 1.85 × 10−7 for lorazepam |
Britton-Robinson buffer | DC and AC polarography, CV, DPP, rotating disk voltammetry | Oxazepam in serepax, serenal tablets, and serenid forete capsule; lorazepam in Larpose, activan, trapex tablets | [54] |
| Oxazepam, lorazepam, and quinazolinecarboxaldehyde | Dropping and hanging mercury electrodes | 10−5 to 10−3 in 10% DMSO/water, 10−5 to 10−4 in water | - | 0.1 M tetraethyl ammonium perchlorate in 90% DMSO/10% water | polarography | Serenid-D and Ativan tablets | [55] |
| Oxazepam | Forced drop mercury electrode | 1 × 10−5 to 1 × 10−2 | - | 0.1 M aqueous tetraethyl ammonium iodide | polarography | 10 mg tablets | [56] |
| Halazepam | Dropping and hanging mercury electrodes | 1 × 10−8 to 1.6 × 10−7 | 25 ng/mL | 0.04 M acetate pH 4.8 buffer | DPAdSV −0.5 V | Human serum and urine | [57] |
| Bromazepam and N-1-Desalkylflurazepam | Dropping mercury electrode | 5–500 ng/mL | 10–20 ng/mL | 1 M phosphate pH 4.0 and pH 7.0 buffers containing 0.005% methoxypolyethylene glycol 550 | DPP | Human blood | [58] |
| Flunitrazepam | Hanging mercury drop electrode | 0.6 × 10−8 to 3.1 × 10−7 | 9.0 × 10−10 | 0.02 M Britton-Robinson pH 10 buffer | Staircase voltammetry and DPAdSV | Urine, following extraction with diethyl ether | [59] |
| Flunitrazepam | Dropping Hg electrode | 1.5 × 10−5 to 2.5 × 10−7 | - | 0.2 M boric acid, 0.05 M citric acid, and 0.1 M trisodium orthophosphate pH 4 buffer, containing 0.2% Triton X-100 | DPP | Rohypnol tablets | [60] |
| Clonazepam | Hanging mercury drop electrode | Up to 550 ng/mL | 10 ng/mL | 0.025 M carbonate pH 10.0 buffer | DPAdSV | Urine, after extraction | [61] |
| Nitrazepam | Nafion-coated Hg film glassy carbon electrode | Up to 7 × 10−6 | - | Acetate pH 4.6 buffer | DPAdSV | - | [62] |
| Nitrazepam | Dropping mercury electrode | - | 0.27 µg/mL | McIlvaine pH 3.1 buffer | Polarography | Tablets: Nitravet, Nirven, Sedamon, Hypnotex, Restorem, and Capsule: Hypnotex | [63] |
| Nitrazepam | Hanging mercury drop | 0.5–80 µg/mL in serum by polarography | 0.5 µg/mL | Phosphate pH 6.9 buffer | Polarography, CV, chronopotentiometry, controlled coulometry | Serum (without dilution or pre-treatment) | [64] |
| Nitrazepam, flunitrazepam, and clonazepam as their 2-amino-5-nitrobenzophenones acid hydrolysis products | Glassy carbon electrode | - | - | Polarography, 0.11 M pyridine, and 0.12 M formic acid pH 4.5, CV formate buffer | CV, polarography | - | [65] |
| Camazepam, oxazepam, and temazepam | Hanging mercury electrode | Oxazepam 2.8 × 10−8 to 4.0 × 10−7 | Oxazepam 3.6 × 10–10 | 0.008 M Britton–Robinson pH 2.0 buffer | DPAdSV | Human serum albumin | [66] |
| Temazepam | Hanging mercury electrode | 10–100 µg/mL | Acetate pH 4.7 buffer solution containing 10% dimethylfonnamide | Polarography and DPP | Soft gelatine capsule formulations after enzyme dissolution | [67] | |
| Pivazepam | Hanging mercury electrode | 10−7 to 10−5 | Urine 15 ng/mL, following diethyl ether extraction | DPAdSV 0.1 M McIlvaine pH 4.0 buffer, 10% methanol, DPP 0.04 M Britton-Robinson pH 5 buffer | DPP, DPAdSV | Pharmaceutical tablet formulations and urine | [68] |
| Chlordiazepoxide, nitrazepam, clonazepam, flunitrazepam, oxazepam, lorazepam, diazepam, bromazepam, prazepam, flurazepam, -otassium chlorazepate, and medazepam | Dropping mercury electrode | - | - | Britton–Robinson pH 4.0 and pH 12.0 buffers | Polarography | Mechanistic studies, hydrolysis products investigated | [69] |
| chlorazepate | Dropping Hg electrode | 10−7 to 3 × 10−5 | ca. 10−7 | Britton-Robinson pH 4 buffer | Cathode ray polarography | Urine after adjustment to pH 9 and liquid-liquid extraction with ethyl acetate | [70] |
| Oxazepam | Dropping Hg electrode | - | - | 0.1 M HCl/20% methanol | Polarography | Unsuccessful for the direct determination of pharmaceutical formulation | [71] |
| Diazepam | Dropping mercury electrode | 2 × 10−6 to 10−3 | - | Britton-Robinson pH 1.81 buffer—0% methanol | DCP, CV, coulometry | Mechanism study | [72] |
| Diazepam | Dropping mercury electrode | Alternating current polarography 17.4–167 µM; DPP 4.8–96 µM | - | 2 M acetate pH 4.6 solution | DCP, DPP, and alternating current polarography | 10 mg tablets | [73] |
| Diazepam | Hanging mercury drop electrode | - | 1 µg/mL | 0.1 M KCl solution in 50% ethanol | DPP | Forensic investigations of Toddy (fermented sap or exudate of date, Palmyra, coconut, sago, etc.) | [29] |
| Diazepam | Hanging mercury drop electrode | 5.6 × 10−8 to 8.8 × 10−6 and 8.8 × 10−6 to 2.0 × 10−4 | 9.6 × 10−9 | 0.20 M pH 4.7 acetate buffer, −2.0 × 10−2 M K2S2O8 | Polarographic parallel catalytic wave of persulfate | Tablets | [74] |
| Mexazolam | Hanging mercury drop electrode | Up to 13 µg/mL | 80 ng/mL | DPP | [75] | ||
| Bentazepam | Hanging mercury drop electrode | 1.9–9.4 ng/mL by DPAdSV | 2.7 ng/mL in urine by DPAdSV; 3.1 × 10−9 M by DPP | DPP in 0.04 M Britton-Robinson pH 9 buffer; DPAdSV in 0.08 M phosphate pH 8.0 buffer | DPP, DPAdSV | Tiadipona tablets by DPP and in urine by DPAdSV | [76] |
| Chlordiazepoxide | Hanging mercury drop electrode | 5 × 10−9 to 2 × 10−7 in human serum by SWAdCSV | 4.4 × 10−10 and 6.6 × 10−10 for pharmaceutical and human serum, respectively, by SWAdCSV | Britton-Robinson pH 8 buffer | Polarography, CV, controlled potential coulometry and SWAdCSV | Bulk form, Librax tablets and human serum (after protein precipitation with ethanol and centrifugation) | [77] |
| Chlordiazepoxide | Static mercury drop electrode | - | - | 0.1 M acetate buffer | SWAdCSV | Synthetic solutions measured in the presence of chloramphenicol, metronidazole, oxytetracycline, cephalothin, and trimethoprim | [78] |
| Chlordiazepoxide | Hanging mercury drop electrode | Quasilinear over the ranges: 3.20 × 10−8 to 1.60 × 10−7; 1.60 × 10−7 to 1.44 × 10−6; 1.44 × 10−6 to 1.44 × 10−5 | 9 × 10−9 | 0.12 M NH3/NH4Cl pH 10.2/0.016 M K2S2O6 | Polarography | - | [79] |
| Chlordiazepoxide | Hanging mercury drop electrode | 0.8 to 11 × 10−8 | 0.9 × 10−9 | Britton-Robinson pH 6.8 buffer | DPAdCSV | Human serum, after solid phase extraction with Sep-Pak C18 cartridge | [80] |
| Chlordiazepoxide | Dropping Hg electrode | 2.5 × 10−6 to 10−3 | 2.5 × 10−6 | 0.1 M sulphuric acid | Polarography, CV, coulometry | Alpoxide and Prodixamon tablets, serum | [81] |
| Chlordiazepoxide and metabolites: N-desmethylchlordiazepoxide, and demoxepam | Dropping Hg electrode | 0.05–1.0 µg/mL | Chlordiazepoxide and its desmethyl metabolite approximately 0.05 µg/mL for plasma; demoxepam, 0.10 µg/mL | 0.1 N sulphuric acid | DPP | Plasma after 30 mg dose extracted with diethyl ether at pH 9 and analytes isolation by thin layer chromatography | [82] |
| Chlordiazepoxide and diazepam | Dropping Hg electrode | - | - | 0.1 M sulphuric acid | Automated polarography | Alpoxide and Vival tablets | [83] |
| Lorazepam | Hanging mercury drop electrode | 0.05–1.15 µg/mL | 0.019 µg/mL | Britton-Robinson pH 2 buffer | CAdSV | Urine, plasma, Chemidarou and Zahrav tablets | [84] |
| Lorazepam | Hanging mercury drop electrode | 15 ng/mL in urine | Britton-Robinson pH 2 buffer | DPAdSV | Human urine | [85] | |
| Nimetazepam | Dropping Hg electrode | 30–150 µg/mL | 30 µg/mL | Britton–Robinson pH 3.8 buffer, 50% methanol | Polarography, 0.0 to −0.7 V | Serum and whole blood after extraction with ethyl acetate/toluene 1:1 | [86] |
| Pinazepam and BrTDO | Hanging mercury drop electrode | Pinazepam 2.8 × 10−10, BrTDO 2.2 × 10−10 | 0.04 M Britton-Robinson buffers pH 4 and pH 5 | DPAdSV | Human serum | [87] | |
| Pinazepam, camazepam, bromazepam, and BrTDO | Hanging mercury drop electrode | Pinazepam 100–700 ng/mL, camazepam 100–1000 ng/mL, bromazepam 100–1000 ng/mL, and BrTDO 100–1000 ng/mL | Pinazepam 15 ng/mL, camazepam 10 ng/mL, bromazepam 20 ng/mL, and BrTDO 20 ng/mL | Britton–Robinson pH 4 buffer for Pinazepam and pH 5 for bromazepam and BrTDO; Acetate pH 5 buffer for camazepam | DPAdSV | Urine after solid-phase extraction with C18 Sep-pak | [88] |
| Timelotem | Dropping mercury electrode | - | 2.5 × 10−6 | Britton–Robinson buffers containing 10% methanol | - | - | [89] |
| Tetrazepam, nortetrazepam, and menitrazepam | Hanging and dropping mercury electrodes | 5 × 10−7 to 5 × 10−6 tetrazepam | 10−7 | 0.1 M sulphuric acid, containing 1% dimethylacetamide | Polarography and DPP | - | [90] |
| Clotiazepam | Dropping mercury electrode | 6.5 × 10−7 to 1.10 × 10−5 | - | 0.1 M sulphuric acid | Polarography and DPP | Distensan tablets | [91] |
| Estazolam | Dropping mercury electrode | 1 × 10−7 to 9.0 × 10−6 | 5 × 10−8 | 0.1 M NH3–NH4Cl pH 9.2 buffer | Polarography | - | [92] |
| Camazepam | Dropping mercury electrode | 1.3 × 10−6 to 1.0 × 10−5 by DPP | 1.7 × 10−8 by DPP | 0.2 M phosphate pH 6.0 buffer | Current sampled polarography, CV, and DPP | Urine, with and without solid phase extraction (Sep-Pak C18) and Albego dragees (sugar-coated) 10 and 20 mg tablets | [93] |
| Metaclazepam | DC tast, DPP and DPAdSV at dropping mercury, hanging mercury electrodes; CV at hanging mercury electrode; coulometry at mercury pool | 1.8 × 10−9 to 3.2 × 10−7 by DPAdSV | 4.4 × 10−10 by DPAdSV | Polarography: Britton-Robinson buffer; coulometry: 4% ethanol/Britton-Robinson buffer | DC tast and DPP, CV, microcoulometry, and DPAdSV | Human urine, 2 mL diluted with 1 mL of 0.04 M pH 9.2 borate buffer; extracted with 1 mL of diethyl ether Evaporated to dryness and reconstituted in ethanol; diluted with 25 mL 0.04 M Britton-Robinson buffer pH 9.1 | [94] |
| Triazolam and clotiazepam | Hanging mercury drop electrode | Up to 2.2 × 10−7 for both triazolam and clotiazepam | 6 × 10−10 for triazolam and clotiazepam with accumulation times of 4 and 10 min by DPAdSV | 10−2 M carbonate pH 10 buffer | DPAdSV | - | [95] |
| Diazepam and nitrazepam | Hanging mercury drop electrode | 1 × 10−9 to 1 × 10−6 | - | Acetate pH 4.6 buffer | DPAdSV | - | [96] |