Microchemical Journal 184 (2023) 108136

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Microchemical Journal
journal homepage: www.elsevier.com/locate/microc

Review Article

Nanomaterials-modified electrochemical sensors for sensitive

determination of alkaloids: Recent trends in the application to biological,
pharmaceutical and agri-food samples
Judith Gañán , Gonzalo Martínez-García , Sonia Morante-Zarcero , Damián Pérez-Quintanilla ,
Isabel Sierra *
Departamento Tecnología Química y Ambiental, ESCET, Universidad Rey Juan Carlos, C/Tulipán s/n, 28933 Móstoles, Madrid, Spain

A R T I C L E I N F O A B S T R A C T

Keywords: Alkaloids are a widespread group of secondary metabolites that occur naturally in a wide range of plant families.
Chemically modified electrodes Many of them exhibit significant biological activity and therefore have numerous pharmacological applications.
Nanomaterials However, there is a great concern about the adverse effects (acute hepatotoxicity, genotoxicity and neurological
Electrochemical sensors
damage) they may cause on consumers, as some of them are present in food. So, it is crucial to develop sensitive,
Pharmaceutical and food applications
Alkaloids
selective and convenient sensors for alkaloids screening in different matrices. In this sense, the electrochemical
detection platforms provide a promising analytical approach as it is economical, efficient, eco-friendly and easy
to operate. Recently, some researchers have proposed electrochemical sensors based on nanomaterials as one of
the powerful alternatives or complementary analytical tools to conventional time-consuming detection pro­
cedures, as they have shown high performance in terms of sensitivity and selectivity. Nanomaterials are
fundamental for developing electrochemical sensors in different applications, such as biomedical, pharmaceu­
tical, environmental and food analysis. In this sense, this work presents a study on the applying different
nanomaterials in detection platforms of alkaloids in agri-food, pharmaceutical and biological samples. Special
attention has been paid to sensors developed with nanomaterials such as carbon-based materials, metal nano­
particles, silica-based materials and imprinted molecular materials. Synthetical and technological aspects in
developing sensors for alkaloids detection, current challenges and futures perspectives are included to provide an
overview and suggestions for future research directions.

1. Introduction environmental pollutants, organic and pharmaceutical compounds and

Electrochemical sensors are devices that use an electrode as a
transducer element to determine an analyte [1]. Since the development
of the first electrochemical oxygen sensor in the 1950s, many of them
were developed, providing the ability to detect different analytes, such
as toxic gases, fuels in confined areas or different organic, inorganic and
biological samples in different matrices. These sensors are based on the
employment of noble metals covered with semipermeable membranes.
The so-called traditional electrodes are then metal wires on which sur­
face occurs a redox reaction that involves the analyte. The most common
are mercury, gold, platinum, and most recently graphite electrodes. The
development of these conventional sensors was a revolution during the
first decades due to their unique characteristics like easy-to-use, rela­
tively low cost and wide range of analytes measurable like gases,
biological substances. However, today it is well-known that conven­
tional electrodes have some serious limitations due to their slow surface
kinetics, which severely affects the sensitivity and selectivity of the
procedures [2]. Slows reactions require high overpotentials to proceed
with the reaction at appreciable kinetics and obtain measurable signals,
but they limit good selectivity.
Nowadays, efforts to solve these problems are focused on the
development and employment of nanomaterials. Nanomaterials (NMs)
play an important role in the development of analytical techniques
needed for pharmaceutical, environmental and food safety control.
Particularly, NMs are getting a lot of attention in the development of
electrochemical sensors [1–6]. In this sense, NMs can play a crucial role
in the construction of high-performance sensors, as they exhibit excel­
lent chemical, physical, mechanical and electronic properties. The

* Corresponding author.
E-mail address: isabel.sierra@urjc.es (I. Sierra).

https://doi.org/10.1016/j.microc.2022.108136
Received 4 July 2022; Received in revised form 31 October 2022; Accepted 1 November 2022
Available online 5 November 2022
0026-265X/© 2022 Elsevier B.V. All rights reserved.
J. Gañán et al.
Fig. 1. Alkaloids classification based on the starting molecule in the biosynthetic pathway.
principal advantages that can be achieved through the employ of NMs as
electrodes modifiers are: (i) increased electroactive area, (ii) enhanced
surface kinetics, (iii) allowed to improve the selectivity of the electrode
since NMs make available stable support for functionalization with
specific groups, and (iv) improved the adsorption of the analytes on the
surfaces of the electrodes which enhance the sensitivity [6].
Chemically modified electrodes (CMEs) have been widely used as
they offer the ability to tailor the physicochemical properties of the
electrode to facilitate electrochemical reaction of the target analytes that
may not display desirable properties with the base electrode materials.
Recent advances in nanomaterials as new modifiers electrodes have had
a positive impact on electroanalytical techniques. Moreover, using
combinations of different types of materials to modify electrodes can
further improve the analytical performance of the electrodes, including
their stability, sensitivity and selectivity performance [6,7].
This review will focus on the recent advances in the nanomaterials
used to desing and fabricate CMEs for the electrochemical detection of
alkaloids. Alkaloids are secondary metabolites produced by many
plants. Due to the distinctive bioactivity of many of them, they have
received increasing attention in the food and pharmaceutical industries.
Some alkaloids may occur naturally in some foods or form part of food or
beverage ingredients, and because of their pharmacological properties,
many of them are used in pharmaceutical preparations. Excessive
ingestion of some of these alkaloids can cause many unwanted side ef­
fects and lead to symptoms ranging from tremors, [8] tachycardia [9],
gastrointestinal difficulties, [10] convulsions, seizures and even death
[11]. Therefore, it is very important to develop rapid and simple
analytical methods to accurately determine the content of these alka­
loids in various foods, pharmaceutical preparations, and human fluids to
estimate a person’s daily intake and to monitor overexposure.
To this end, the current state of efforts to develop this sensing
technique is described in the context of how different nanomaterials can
be employed in designing electrochemical sensors for the efficient
determination of alkaloids in diverse matrices with special emphasis on
the resulting advantages and contributing factors. Due to the highly
productive publication records in the field, the scope of the review is
limited to nanomaterial-based electrochemical sensors to determine
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Microchemical Journal 184 (2023) 108136
alkaloids with interest in agri-food and pharmacological applications.
2. Alkaloids: An overview
Alkaloids are one of the widest groups of secondary metabolites
found in a living organism. Alkaloids have been traditionally isolated
from plants like Papaver somniferum, Atropa belladonna, Coffee arabica or
Conium maculatum, i.e., but in recent years an increasing number are to
be found in animals, insects and marine invertebrates [12]. Since
chemical overview, alkaloids are defined by Pelletier as “a cyclic com­
pound containing nitrogen in a negative oxidation state which is of
limited distribution in living organisms”. Alkaloids are characterized by
great structural diversity, and there is no uniform classification of them
it could be classified in terms of their chemical structure, biological
activity, the pathway of their biosynthesis and occurrence into hetero­
cyclic and nonheterocyclic alkaloids. In the present paper, classification
is used based on the starting molecule in the biosynthetic pathway:
ornithine, lysine, tyrosine, tryptophan, or a non-amino acid precursor
such as purine analogues, focusing in particular on those alkaloids with
the most important biological, pharmaceutical and agri-food interest for
which electrochemical sensors based on nanomaterials have been
developed to date (Fig. 1).
The most active representative alkaloids according to this classifi­
cation are [8,13–14]:
• Alkaloids derived from purine: caffeine, theobromine and theoph­
ylline are included in the group of methylxanthine alkaloids derived
from an adenine/guanine.
• Alkaloids derived from tyrosine: isoquinoline alkaloids are derived
from tyrosine. Morphine, codeine and thebaine are the most well-
known in this group.
• Alkaloids derived from ornithine: tropane (e.g. atropine, scopol­
amine) and pyrrolizidine (e.g. senecionine, echemidine) alkaloids
belong to this group.
• Alkaloids derived from lysine: piperidine alkaloids (piperine) and
quinolizidine alkaloids (sparteine and lupanine) are alkaloids
derived from the amino acid lysine.
J. Gañán et al. Microchemical Journal 184 (2023) 108136

Table 1 • Alkaloids derived from tryptophan: of the great group of the indole
Distribution, pharmacological activity and adverse effects of the most relevant alkaloids derived from tryptophan occur three subgroups: simple
alkaloids with biological, pharmaceutical and agri-food interest for which indole (carboline), quinoline alkaloids (quinine) and ergot alkaloids
electrochemical sensors based on nanomaterials have been developed to date. (ergometrine, ergotamine).
Chemical group Distribution Pharmacological Adverse Effects • Glycoalkaloids: e.g. solanine and tomatine are alkaloids corre­
activity sponding to the glycosides alkaloids group.
Purine alkaloids
Methylxantines Sterculiaceae, Central Nervous Elevated Most of these compounds are of great relevance to medicine, due to
(caffeine, Thenaceae, System stimulants, breathing, their important pharmacological effects [15–18], which are listed in
theobromine, Runiaceae, bronchodilators, gastrointestinal
theophyline) Aquifoliaceae, coronary dilators, disturbances,
Table 1. So, for example, morphine is used as a potent analgesic and to
Sapindeaceae diuretics, anti- agitation, treat chronic severe pains [19], codeine is a well-known antitussive
cancer adjuvant insomnia, [20], and theophylline is applied in various pharmacological treatments
treatments headache, such as asthma, apneas and chronic obstructive pulmonary diseases
tachycardia,
[21]. Although alkaloid drugs are generally very safe at therapeutic
arrhythmia,
nausea, seizures doses, overexposure can cause severe adverse effects (Table 1), for
example is demonstrated that the limited safe dose of crude alkaloids is
1.25 g/kg body weight in mice [22]. Some alkaloids like thebaine are
Derived from tyrosine
Opiate alkaloids Papaveraceae, Analgesic, Nausea, vomiting, not directly unhealthy for humans, but their liver metabolism produces
(morphine, Berberidaceae, antitussive, constipation, other alkaloids like noscapine, codeine or morphine [23], whose toxicity
codeine, Fumariaceae, spasmolytic, drowsiness, are well-known for a long time [24]. Drug doses are usually well regu­
papaverine, Magnoliaceae, coronary euphoria,
lated, however, overexposure can occur through diet, as many of these
thebaine) Convolvulaceae vasodilator sedation,
depression,
alkaloids can be found naturally in foods. For example, methylxanthines
headache, such as caffeine, theobromine and theophylline are in abundance in teas
gastrointestinal and cocoa beans and are frequently present in chocolates, biscuits, and
disorders, energy drinks [25]. Likewise, lysine-derived alkaloids such as piperine
tachycardia,
or capsaicin can be found in foods like peppers and black pepper [13].
sweating,
dizziness Moreover, other plant-derived alkaloids may occur as contaminants in
different food products. Indeed, natural toxins like opium, tropane,
Derived from ornithine
pyrrolizidine or ergot alkaloids are appearing in different food products.
Tropane Solanaceae, Anticolic, Cardiac disorders, For this reason, recently, the European Food Safety Authority (EFSA) has
alkaloids Erythroxylaceae, spasmolytic, mainly related to focused its attention on these plant-derived alkaloids as an emerging
(atropine, Convolvulaceae, enlarge pupil’s heart rate food safety risk. These alkaloids can grow in fields as weeds and
scopolamine) Brassicaceae, agent disturbances,
contaminate food crops, thus entering the food chain [26–31]. While it is
Euphorbiaceae disorientation,
depressive true that the alkaloids described previously are commonly administered
activity, dryness to patients and their therapeutic doses are perfectly defined, it should
of mucous not be forgotten that they are often very potent in their action and any
membranes unintentional ingestion can produce serious adverse effects. As can be
seen in Table 1, overexposure to these compounds can cause consider­
Derived from lysine able toxicological effects including, delirium, agitation and convulsions,
Piperidine Apiaceae, Antidiarrheal, Gastrointestinal
tachycardia, nausea and vomiting, etc., but also more serious diseases
alkaloids Solenaceae, antipyretic, irritation
(piperine, Fabaceae, analgesic, anti- such as neurological disorders, carcinogenic, teratogenic and/or muta­
capsaicin) Asteraceae inflamatory genic effects and may even be lethal [29,30,32,33]. For most alkaloids,
there is an affine safety line between the therapeutic and toxic dose that
Derived from tryptophan triggers these adverse effects. In fact, for someone such as theophylline,
Quinoline Cinchona Antitumor, Headache, the safe and effective use of this drug depends on careful dose adjust­
alkaloids officinalis antimalarial, ringing in the ment based on accurate measurements of drug concentration in blood
(quinine) antibacterial, ears, trouble
serum. For all the above, to prevent alkaloid overdose-induced intoxi­
antifungal, seeing, sweating
antiparasitic,
cation, it is necessary to sensitively monitor the concentration of the
antiviral, anti- different alkaloids in biological and pharmaceutical and even agri-food
inflammatory samples.
Ergot alkaloids Claviceps purpurea Anti-hypertension; Delirium, To date, numerous instrumental methods for the detection of alka­
(cabergoline) (fungus) migraine headache Hallucinations,
loids in different samples have been developed and are available such as
effects; Parkinsoń s convulsions,
disease; vasoconstriction high-pressure liquid chromatography (HPLC) or gas chromatography
Tranquilizing; (GC) coupled to mass spectrometry (MS) or fluorescence detection (FLD)
Analgesic [34–36]. Even though these methods are reliable highly sensitive and
selective, they are generally considered to be conventional and outdated
Glycoalkaloids options because of their several disadvantages, including expensive
Glycosides Solanaceaes anti-inflammatory, gastritis, hardware and their time-consuming and laborious operation. Addi­
alkaloids anti-cancer gastrointestinal
tionally, these analytical techniques normally require long and laborious
(solanine) disturbance,
nausea, vomiting, sample preparation steps before their determination, which can limit
diarrhea, fever, their application on-site detection, increasing the time and cost of
low blood methodologies. Therefore, developing accurate, fast, simple methods to
pressure. monitor these natural toxins in real samples can be an interesting
alternative. In this sense, new options based on nano-systems, such as
nanomaterials-chemically modified electrodes, as diagnostics and risk
assessment tools have become attractive options for researchers.

3
J. Gañán et al. Microchemical Journal 184 (2023) 108136

Table 2
Electrochemical sensors modified with nanomaterials for determination of the most relevant alkaloids with biological, pharmaceutical and agri-food interest.
Modifier Electrode Electrochemical Analyte Matrices Linear LOD Ref.
Technique range (μmol
(μmol L− 1)
L− 1 )

Carbon-based nanomaterials (Carbon nanotubes, graphene, graphene oxide and nanocomposites)

Carbon Nanotubes SWCNT CCE DPV Codeine Pharmaceutical preparation, CO: 0.2- CO: 0.11 [42]
Caffeine cola drinks, tea and urine 230 CF: 0.25
CF: 0.4-
300
MWCNTs GCE CV Thebaine Human urine 1.0-600 0.23 [44]
MWCNTs CPE DPV Atropine Pharmaceutical preparation 0.014- 0.0015 [45]
0.094
MWCNTs GCE CV Theophylline Pharmaceutical preparation 0.3-50 0.05 [46]
MWCNTs SPE CV Capsaicin Chilli peppers 0.5-60 0.45 [47]

MWCNTs GCE SWV Caffeine Tea leaves, coffee, cold drink, 10-500 0.0035 [48]
pharmaceutical preparations
and urine
CNTs-based CNTs/PBA GCE DPV Solanine Potatoes 1.0-28 0.3 [43]
nanocomposites MWCNTs/VF CPE SWV Morphine Urine and pharmaceutical 0.2-250 0.09 [49]
preparation
MWCNTs/La3+CuO CPE DPV Morphine Urine and pharmaceutical 0.05-325 0.008 [50]
preparation
MWCNTs/DNF-Co3O4 GCE DPV Thebaine Urine 0.01-900 0.0024 [51]
MWCNTs/ILs CPE CV Morphine Urine and pharmaceutical 0.6-600 0.02 [19]
preparation
MWCNTs/ILs CPE DPV Morphine Urine and pharmaceutical 0.45-450 0.14 [56]
preparation
CNTs/ILs/ZnO CPE CV Morphine Urine and pharmaceutical 0.1-700 0.06 [57]
preparation
CNTs/ILs/NiO CPE SWV Morphine Urine and pharmaceutical 0.05-520 0.01 [58]
preparation
MWCNTs/CMC Drop- LSV Theobromine Green tea, chocolate, and coffee 0.5-80 0.21 [59]
GCE
MWCNT/NF Drop- DPV Caffeine Cola, energy drinks and green 0.6-400 0.23 [60]
GCE tea
MWCNT/VTMS Drop- DPV Caffeine Coffee, instant coffee and energy 0.75-40 0.22 [61]
GCE drink
Graphene GR GCE SWV Cabergoline Pharmaceutical preparation 0.2-5.2 0.0054 [65]
GR GCE DPV Morphine - MP: 1-5 MP: 0.4 [66]
Noscapine NP: 1-35 NP: 0.2
Graphene-based N-GR/MWCNT GCE SWV Caffeine Cookies, chocolate and milk tea 0.06-50 0.02 [67]
nanocomposites GR/NF GCE DPV Caffeine Cola, energy drinks and coffee 0.4-40 0.12 [68]
GR/NF GCE SWV Codeine Urine and pharmaceutical 0.05-30 0.015 [69]
preparation
GR/NF SPE DPV Caffeine Coffee, energy drinks, cola 0.1-10 0.021 [70]
drinks, and iced tea
GR/NF GCE SWV Caffeine Pharmaceutical preparation 0.26-10 0.038 [71]
GR/AFW/NF GCE DPV Theophylline Black tea, urine and serum 0.1-160 0.0028 [21]
GR/CoFe2O4 CPE SWV Codeine Urine and pharmaceutical 0.03-12 0.011 [20]
preparation
GR/Zn2SnO4 CPE DPV Morphine Urine, serum and 0.02-15 MP: [72]
Codeine pharmaceutical preparation 0.011
CO:
0.009
GR/Co3O4 CPE DPV Atropine Urine, serum and 0.1-3.2 0.03 [73]
pharmaceutical preparation
GR/ MnO2/ IL GCE DPV Theophylline Pharmaceutical preparation 1.0-200 0.1 [74]
GR/PFA GCE DPV Theophylline Black tea, green tea, coca cola TP: 0.2- TP: 0.03 [75]
Caffeine drink and energy drink 100 CF: 0.08
CF: 1.0-
160
Graphene oxides rGO GCE DPV Caffeine Human blood plasma and urine 20-120 0.043 [76]
rGO GPE DPV Caffeine Coffee, tea, cola and energetic 50-300 - [77]
drinks
GO GCE CV Theophylline Green tea 0.8-60 0.1 [78]
Graphene oxide- GO/NF GCE DPV Caffeine Tea, cola and energy drink 0.04-80 0.2 [79]
based rGO/NF SPE Amperometry Caffeine Coffee 0.29-2.58 0.22 [80]
nanocomposites rGO/Pd GCE DPV Morphine Urine 0.34-12 0.013 [81]
rGO/Cu2O/Co(OH)2 GCE Amperometry Caffeine Beverages samples and coffee 0.83- 0.4 [82]
1200
GO/Fe3O4@SiO2 SPE DPV Morphine Urine and pharmaceutical 1.0-100 0.75 [83]
preparation
GQDS GQDs SPE DPV Theophylline Pharmaceutical preparation 1-700 0.2 [87]
Carbon nanofibres GCE DPV Theophylline Pharmaceutical preparation 0.6-137 0.2 [89]
(continued on next page)

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J. Gañán et al. Microchemical Journal 184 (2023) 108136

Table 2 (continued )
Modifier Electrode Electrochemical Analyte Matrices Linear LOD Ref.
Technique range (μmol
(μmol L− 1)
L− 1 )

Poly-sulfosalicylic acid
film-CNFs
Dy2O3@Eu2O3-CNF GCE SWV Papaverine Urine and pharmaceutical 0.1-2 0.01 [90]
preparation
OMC OMC GCE CV Morphine Urine 0.1-20 0.05 [92]
OMC/NF GCE DPV Theophylline Human blood serum and food TP: 0.8- TP: 0.37 [93]
Caffeine samples 180 CF: 0.47
CF: 1.3-
230

Metal, metal oxide nanoparticles and metal nanoparticles-based nanocomposites

Au NPs and AuNPs- AuNPs CPE DPV Morphine Urine 0.4-200 0.0042 [95]
based AuNPs GCE DPV Caffeine Cola drink 25-1000 2.49 [98]
nanocomposites AuNPs AuE DPV Caffeine Cola drinks, energy drink, and 2.0-5000 1.0 [99]
tea
AuNPs/NF CPE DPV Morphine Urine 0.4-200 0.0004 [96]
AuNPs/Ferrocene CPE DPV Morphine Urine 1.0-1800 0.0035 [97]
AuNPs/ Aminotriazole GCE DPV Theophylline Blood serum and urine 0.004- 0.0085 [100]
100
Other metal CdSe NPs GCE DPV Theophylline Tea, carbonated cola drink, fruit 1.0-700 0.41 [101]
nanoparticles juice drink, fermented milk
drink and preserved fruit
CuS NPs CPE DPV Caffeine Tea and coffee 2.0-120 0.018 [102]
Al2O3 film CPE SWV Morphine Urine and pharmaceutical 0.1-550 0.03 [104]
preparation
CeO2 NPs SPE DPV Codeine Serum CO: 0.09- CO: [105]
Caffeine 50 0.043
CF: 5-286 CF: 2.4
TiO2 NPs GCE SWV Theophylline Urine and pharmaceutical 1.0-20 0.023 [106]
preparation
MnO2/ILs GCE DPV Theophylline Pharmaceutical preparation 0.1-120 0.05 [107]
Co2O3 NPs CPE DPV Caffeine Tea bags, coffee powder, coffee 5-600 0.016 [108]
sachet, carbonated beverage,
energetic drink cans and
pharmaceutical preparation
Co3O4 NPs GCE DPV Atropine Urine 0.01-0.46 0.001 [109]
Fe3O4 NnFs CPE DPV Morphine Serum 0.003- 0.002 [110]
245
BaFe12O19 NPs SPE DPV Morphine Urine and pharmaceutical 0.06-600 0.02 [111]
preparation

Ordered mesoporous silica-based nanomaterials and nanocomposites

MPY-HMS-OMS CPE DPV Scopolamine Tea and herbal tea infusions 0.9-200 0.30 [120]
MSN@ZIF-MIP GCE DPV Atropine Eyedrop, human serum, human 0.005-9.5 0.00098 [121]
urine, beef, and cereals samples.
PPy-MIP-MS GCE DPV Theophylline Green tea, carbonated cola 0.005- 0.0007 [122]
drink, fermented milk drink and 1000
preserved fruit

Polymeric-based nanomaterials
MIP/DMTD/ AgNO3 CPE DPV Atropine Pharmaceutical preparation 0.6-9.0 0.046 [125]
MIP/AuNPs/f- MWCNT PGE SWV Papaverine Urine and serum 0.001-5 0.0004 [126]

MIC-AuNPs/MWCNT- PGE DPV Quinine Plasma and urine 0.001-1 0.0005 [127]
chitosan
o-PD-MIP/AuNPs GCE DPV Theophylline Serum 0.4-3400 0.1 [128]
NF/SWCNTs SPE DPV Morphine Untreated Human capillary, 0.5-10 0.48 [129]
whole blood
MIP-Sodium alginate/ GCE DPV Theophylline Plasma and pharmaceutical 0.01-60 0.0032 [130]
MWCNTs preparation
Crocein orange G-triethoxy GCE DPV Theophylline Pharmaceutical preparation 0.05-30 0.0014 [131]
(3-isocyanatopropyl)
silane-MIP/CNPs–SO3H

AFW: tungstate nanorods; AuE: gold electrode; AuNPs: Gold nanoparticles; CF: Caffeine; CMC: Carboxymethylcellulose; CNFs: Carbon Nanofibers; CO: Codeine; CPE:
Carbon paste electrode; CV: Cyclic voltammetry; DMTD: Dimercapto-1,3,4-thiadiazole; DNF: Dandelion nanoflowers; DPV: Differential-pulse voltammetry; f- MWCNT:
functionalized multiwall carbon nanotube; GCE: Glassy carbon electrode; GO: Graphene oxide; GPE: Graphite pencil electrode; GQDs: Graphene Quantum Dots; GR:
Graphene; HMS: Hollow mesoporous silica; ILs: Ionic Liquid; LSV: Linear sweep voltammetry; MIC: Molecular imprinted composite; MIP: Molecular imprinted
polymer; MP: Morphine; MPY: mercaptopyrimidine; MS: Mesoporous silica; MWCNT: Multiwalled carbon nanotubes; NF: Nafion; NnFs: NanoFibres; NP: Noscapine;
NPs: nanoparticles; NSs: nanosheets; OMC: Ordered Mesoporous Carbon; OMS: Ordered mesoporous silica; o-PD: ortho-phenildiamine; PBA: Phenylboronic Acid; PFA:
poly(folic acid); PGE: Pencil graphite electrode; PPy: Polypyrrole; rGO: Reduced graphene oxide; SPE: Screen printed electrode; SWV: Square wave voltammetric;
SWCNTs: Single wall carbon nanotubes; TF: Theophylline; VF: Vinylferrocene; VTMS: vinyltrimethoxysilane.

5
J. Gañán et al.
3. Critical overhaul of nanomaterial-modified electrochemical
sensors for alkaloids analysis
Due to their excellent physical and chemical properties, nano­
materials are considered the most interesting resource in designing
chemically modified electrodes. Factors such as type of nanomaterial,
chemical composition, quality of crystalline structure, crystallographic
axis orientation, morphology and dimensions of nanomaterial/s
employed to modify the electrode must be taken into account when
developing reliable electrochemical sensors for target analyte detection.
Many studies have been carried out to develop electrochemical sensors
that use diverse nanomaterials for the accurate analysis of alkaloids. The
most important systems in this context are based on nanomaterials such
as carbon-based nanomaterials, metal nanoparticles, ordered meso­
porous silica-based and polymeric materials. Table 2 lists all the studies
found in the literature on the determination of alkaloids in biological,
pharmacological and agri-food matrices by electrochemical techniques
using nanomaterials as chemical modifiers of the electrodes. Table 2 has
been organised according to the type of modifiers (carbon-based nano­
materials, metal nanoparticles, ordered mesoporous silica-based and
polymeric materials), and these from simpler to more complex
modifiers.
3.1. Carbon nanomaterials
Carbon-based nanomaterials have been widely studied as electrode
modifiers materials. Carbon nanomaterials exhibit interesting charac­
teristics such as (i) high electrical conductivity, (ii) large specific surface
area and (iii) good mechanical and chemical stability [37]. The
commonly employed materials are carbon nanotubes (CNTs), graphene,
and their derivates. Carbon nanomaterials can be used either alone or in
combination with other materials to achieve new composites deriving
Fig. 2. A) Schematic representation for the possible growth mechanism of proposed dandelion-like Co3O4 nanoflowers; B) SEM image of dandelion-like Co3O4
nanoflowers and C) DPVs of DNF-Co3O4/MWCNTs/GCE in 0.1 M (pH 7.0) at different concentrations of thebaine from 0.01 to 900.0 μmol/L of thebaine [51].
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Microchemical Journal 184 (2023) 108136
their properties synergically.
3.1.1. Carbon nanotubes
Since the discovery of multi-walled carbon nanotubes (MWCNTs) in
1991 [38] and single-walled carbon nanotubes (SWCNTs) in 1993 [39]
CNTs have attracted considerable interest reflecting their unique
behaviour, including their remarkable electrical, chemical, mechanical
and structural characteristic. There are two distinct structural families in
CNTs, SWCNTs [39] consist of a single hollow tube with diameters be­
tween 0.4 and 2 nm, while MWCNTs [38] are composed of multiple
concentric nanotubes 0.34 nm apart, where the final MWCNTs has di­
ameters of 2–100 nm [40].
The conductivity of tubes is a consequence of their electronic prop­
erties, which is important for the paper of these nanomaterials in elec­
trochemistry. MWCNTs are regarded as metallic conductors, a highly
attractive property in electrode design. However, the behaviour of the
SWCNTs is not clear, which can be metallic, semi-conductor or small
band gap semi-conductor depending on their diameter and chirality
[41]. Furthermore, of their excellent conductivity, as for sensing appli­
cations, CNTs have some interesting advantages such as small size with a
large surface, high sensitivity, fast response and good reversibility,
therefore, CNTs have been widely used as electrode modifiers [40]. As
will be discussed afterwards, CNTs were presented in several modified
electrodes combinate with other advanced nanomaterials to get the
advantage of synergistic properties. As can be seen in Table 2, CNTs have
been widely used for electrode modification to determine different types
of alkaloids [42–47].
Thus, for example, Rezaei and Damiri [43] modified a glassy carbon
electrode (GCE) with a MWCNT film. For this, the GCE previously
cleaned was coated by casting with the MWCNT suspension (0.1 % (p/v)
MWCNT in dimethylformamide) and dried in an oven at 60 ◦ C. The
electrochemical behaviour of thebaine, an opium alkaloid, was studied
J. Gañán et al.
employing the MWCNT-GCE and a bare GCE. Thebaine produced two
well-defined and pH-dependent oxidation peaks on the MWCNT-GCE,
and the oxidation peak current significantly increased as compared
with the bare GCE, which showed an ill-defined peak under the same
conditions. The sensor, under optimized conditions, showed thebaine
oxidation peak, two linear dynamic ranges of 1.0 – 80 and 100 – 600
µmol/L, with a detection limit of 0.23 µmol/L. To evaluate the appli­
cability of the proposed method, the recovery of thebaine was deter­
mined in the urine samples by standard addition, obtaining satisfactory
recoveries (92 – 99 %). A modified MWCNT carbon paste electrode
(CPE) was employed by Dar et al. [44] for the electrochemical deter­
mination of atropine. The MWCNT-CPE was prepared in the usual way
by hand-mixing graphite powder, carbon nanotube powder and mineral
oil in a (60:10:30) ratio, and the prepared paste was filled into the Teflon
well. Employing this electrode, the oxidation peak current was propor­
tional to the concentration of atropine over the range from 3.98 to 27.23
µg/L, and the detection limit was 0.449 µg/L after 2 min of accumula­
tion. This method was satisfactorily applied to determine atropine in
Indian traditional medicine (seeds and leaves of Datura Stramonium)
with recoveries between 99 and 101 %.
A versatile electrochemical sensor was developed using a GCE
modify with CNT/phenylboronic acid for the electrochemical determi­
nation of glycoalkaloids [48]. The sensor developed showed a linear
response to 1 µg/L from 28 µg/L, with a detection limit of 0.3 µg/L for
solanine. Mokhtari et al. [49] prepared a novel CPE modified with
MWCNTs/vinylferrocene. The paste was easily prepared by hand mixing
10.0 % (w/w) MWCNTs, 1.0 % (w/w) vinylferrocene and 89.0 % (w/w)
graphite. The electrode showed excellent electrocatalytic activity in the
oxidation of morphine. The results showed that the electrocatalytic
interaction occurs between the mediator (vinylferrocene) and morphine,
but the presence of MWCNT in the paste increased the sensibility. This
can be because electron transfer at carbon nanotube electrodes could be
better facilitated by edge-plane-like nanotube ends. The sensor was
applied to square wave voltammetric (SWV) measurement, observing
that the current peaks of morphine increased linearly with a concen­
tration in the range of 0.2 – 250 µmol/L with a limit of detection of 0.09
µmol/L. To demonstrate the capability of the modified electrode in the
determination of morphine in real samples, the sensor was applied to
determine morphine in pharmaceutical and urine samples.
The MWCNTs coupled with other nanomaterials have shown inter­
esting improvements in producing sensors. Metal oxides such as copper
oxide nanoparticles due to their physicochemical properties, including
high reactive surface morphology, high surface to volume ratio, good
thermal stability, numerous active sites and smaller particle size. In this
sense, Rajaei et al. [50] synthesized a CuO nanostructure doped with
lanthanum (La3+) used as a modifier in MWCNT-CPE. La3+ has
numerous benefits as a dopant, such as its ionic radius being bigger than
the Cu element, which affects several structural attributes and is easily
implemented in CuO crystal frameworks. The fern-like La3+-CuO
nanoleaves obtained were used to modify MWCNT-CPE. The electro­
chemical behaviour of morphine was studied employing unmodified and
modified CPE, observing that the morphine oxidation peak potential at
La3+-CuO/MWCNT-CPE was found at 330 mV, meaning about 260 mV
decrease of the overpotential than that of the unmodified CPE, and 4.9
times increase was observed for the oxidation peak current. The authors
attributed the enhancement in the electrochemical catalytic activity of
La3+-CuO/MWCNT-CPE to the enlarged surface area provided by
MWCNT and fern-like La3+-CuO nanoleaves and the out-standing elec­
tron-transfer ability of nanomaterials. In addition, fern-like La3+-CuO
nanoleaves show high conductivity and fast electron transfer ability. The
La3+-CuO/MWCNT-CPE showed excellent electrocatalytic activity to­
ward morphine and resulted in a linear range of 0.05–325 µmol/L and a
reasonably low detection limit of 0.008 µmol/L. Another example is the
combination of MWCNTs and Co3O4 nanoparticles as modifiers to
modify a GCE [51]. Transition-metal oxides with varied morphologies
have gained special attention in sensing applications. A solvothermal
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Microchemical Journal 184 (2023) 108136
route (Fig. 2A) is applied to form dandelion-like Co3O4 nanoflowers
(DNF-Co3O4) that can be applied for thebaine sensing. SEM micrographs
(Fig. 2B) show interconnected Co3O4 micro-dandelions with diameters
between 2 and 6 μm. This type of nanomaterial provides high porosity
and a great surface area to volume ratio, which makes it favourable for
sensing because it enhances surface reactions and thus, enhances sensor
response values. The fabricated modified electrode (DNF-Co3O4/
MWCNT-GCE) exhibited fast electron transfer and clear electrocatalytic
behaviour regarding thebaine electro-oxidation. At an optimal condi­
tion, the sensor displayed a linear response between the concentrations
and peak currents of thebaine across a 0.01 – 900 μmol/L range (Fig. 2C)
and 2.4 nmol/L detection limit.
MWCNTs have often been combined with ionic liquids (ILs) to design
novel electrodes. ILs are molten salt with a melting point close to or
below room temperature. They are formulated with two asymmetrical
ions of opposite charges that only loosely fit together (generally bulky
organic cations and smaller anions) [52]. The ILs possess unique prop­
erties such as negligible vapour pressure, wide potential window, high
thermal stability, viscosity and good conductivity and solubility. These
properties of ILs can be tailored by combining different cations and
anions. Moreover, their miscibility/immiscibility with other solvents
can also be easily controlled by interchanging anions and cations [53].
Due to their special characteristics, researchers have focused on using
ILs to develop novel electrochemical sensors [52–55]. Furthermore, the
synergistic combination of MWCNTs and ILs components results in
significant improvement for numerous electrochemical applications
[55]. Similarly, several authors have combined it for the electrochemical
determination of alkaloids [19,56–58].
Ensafi et al. [56] prepared a new MWCNT modified carbon IL elec­
trode (MWCNT/IL-CPE), employing 1-butyl-3methyl-imidazolium
hexafluoride phosphate as a binder. The electrochemical response of
morphine on the modified electrode was studied by cyclic voltammetry.
MWCNT/IL-CPE significantly exhibited an oxidation peak current (14.5
μA) in contrast with low redox activity that was observed at MWCNT-
CPE and bare CPE, with oxidation peaks current of 6.80 and 5.90 μA,
respectively. Also, at the surface bare IL-CPE, the morphine oxidation
peak current was improved (12.7 μA), which indicates that the presence
of ILs in CPE enhances the peak currents and decreases the oxidation
potential because the oxidation peak appeared at 0.43 V against 0.54 V
in the bare CPE. With the MWCNT/IL-CPE, the morphine could be
detected in a linear calibration range of 0.45–450 µmol/L with a
detection limit of 0.14 µmol/L. Finally, the electrochemical sensor
developed was examined to determine morphine in real samples such as
urine and drugs. Later, the same research group prepared a CPE modi­
fied with MWCNT and anionic room-temperature IL, n-hexyl-3-methyl­
imidazolium to detect morphine. In comparison to their previous work
[56], this new sensor has a longer dynamic range (0.6–600 µmol/L) and
has a better detection limit (0.02 µmol/L) [19].
A novel combination of MWCNT/ZnO and 1-methyl-3-butylimidazo­
lium bromide was reported by Afsharmanesh et al. [57] to be employed
as CPE modifiers for voltammetric determination of morphine. The au­
thors demonstrated that the presence of ZnO/MWCNT on the ZnO/
MWCNT/IL-CPE surface had great improvement in the electro­
chemical response, which was partly due to the excellent characteristics
of ZnO/MWCNT nanocomposite. The suitable electronic properties of
ZnO/MWCNT together with the IL gave the ability to promote charge
transfer reaction, and good anti-fouling properties, especially when
mixed with a higher conductive compound such as IL when used as an
electrode. Compared with previous reports for the determination of
morphine using IL/MWCNTS-CPE [19,56], this modified electrode has
the best dynamic range (0.1–700 µmol/L) and a similar detection limit
(0.06 µmol/L) for morphine analysis. Sanati et al. [58] fabricated an
interesting IL modified NiO/MWCNT-CPE (IL/NiO/MWCNT-CPE) using
hydrophilic IL 1- methyl-3-butylimidazolium chloride as a binder. The
IL/NiO/MWCNT-CPE was used for the voltammetric determination of
morphine by SWV. This modified electrode showed the best dynamic
J. Gañán et al.
range (0.05–520 µmol/L), limit detection of 0.01 µmol/L and sensitivity
compared with other modified electrodes employed in the morphine
determination.
Another interesting description is the use of polymers in combination
with MWCNTs [59–61]. The resulting MWCNTs-polymer hybrids
nanomaterials often exhibit unique properties with a large electroactive
area due to the three-dimensional nanostructure of the MWCNTs, as well
as high electrocatalytic activity and selectivity due to the properties of
the polymers. Thus, Peng et al. [59] developed a simple and sensitive
method for the voltammetric analysis of theobromine in green tea,
chocolate, and coffee samples using a nanobiohybrid sensor based on
GCE modified with MWCNTs and a biopolymer sodium salt of
carboxymethylcellulose (CMC). The GCE was modified by a drop-
coating method using 5 μL water-dispersible CMC/MWCNTs on the
electrode surface and dried in an infrared lamp. The authors demon­
strated that CMC/MWCNTs-GCE had electrocatalytic ability towards the
oxidation of theobromine, with a remarkable oxidation peak at
approximately 1.34 V. Also, the results provided show that CM/MWCNT
film could provide more effective active sites than bare GCE.
3.1.2. Graphene and derivates
Graphene was discovered in 2004 by Geiḿ s research group through
the so-called “scotch-tape” technique [62]. It is a two-dimensional sheet
of sp2 bonded carbon atoms, which looks like a honeycomb. This two-
dimensional disposition provides graphene with unique properties
such as ballistic conductivity, very high mechanical strength, high sur­
face area, and rapid heterogeneous electron transfer [63]. For all these
reasons, graphene is one of the most interesting materials to be
employed as an electrode modifier. Furthermore, doping or chemically
modifying graphene with other nanomaterials can provide electro­
catalytic properties and enhance the stability of doped graphene elec­
trodes, which has great potential for target analyte sensing [64].
Graphene was used by Jain and Sinha [65] to modify GCE for the
selective determination of Carbegoline (ergot alkaloids). The electro­
catalytic oxidation of cabergoline was studied by cyclic voltammetry
(CV) and SWV using the sensor developed. The results clearly showed
that the chemically modified GC surface makes it considerably more
sensitive to the electro-oxidation of cabergoline and confirms the
enhanced electrocatalytic performance of the graphene GCE sensor.
Likewise, Navaee et al. [66] used graphene nanosheets (GNSs) as a GCE
modifier, which was successfully employed for the determination of the
three major opium alkaloids: heroin, morphine and noscapine with
detection limits of 0.4 and 0.2 µmol/L, respectively. Simultaneous
detection of heroin, morphine and noscapine without any separation or
pretreatment step is one of the main achievements of this work.
As demonstrated, CNTs and graphene have been extensively studied
as both exhibit excellent electrochemical performance in the field of
alkaloid sensors. To go a step further, Jiang et al. [67] took advantage of
the properties of both to prepare a nanocomposite with nitrogen-doped
CNTs (NCNTs) and N-graphene. The electrochemical sensor N-gra­
phene/N-CNT-GCE was prepared via electrodeposition over a bare GCE.
The electrochemical behaviour of caffeine at graphene-NCNT-GCE was
qualitatively studied by CV, showing that this sensor exhibited the
largest current response with the most negatively shifted potential to
bare GCE, graphene-GCE or NCNT-GCE. The caffeine determination was
demonstrated by SWV, where under optimal conditions N-graphene/
NCNT-GCE exhibited a wide linearly of 0.06–50 μmol/L with detection
limits of 0.02 μmol/L.
To improve the detection performance the polymer Nafion (NF) have
been recurrently added to disperse graphene [21,68–71]. Thus, a new
electrochemical sensor for codeine was fabricated based on composite
graphene and NF film modified GCE (Gr/NF-GCE). The authors observed
that by employing graphene-NF GCE, a considerable increase in peak
current was observed compared with NF-GCE. These results were
attributed to the synergistic effect of NF and graphene. NF can act as a
preconcentration effect and graphene could accelerate the electron
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Microchemical Journal 184 (2023) 108136
transfer on the electrode surface to amplify the electrochemical signal
due to the excellent electric conductivity of graphene. The sensor had a
detection limit of 0.015 µmol/L over a wide linear range from 0.05
µmol/L to 30 µmol/L. The sensor developed was successfully applied to
detect codeine in human urine samples and cough syrup [69].
In addition, graphene combines with any other nanomaterial offer­
ing new characteristics due to obtaining synergic properties in the
nanohybrid [20,72–75]. Afkhami et al. [20] synthesized a nano­
composite of graphene and CoFe2O4 nanoparticles to use as a modifier in
CPE to determine codeine and acetaminophen in biological and phar­
maceutical samples. Authors use electrochemical impedance spectros­
copy (EIS) to demonstrate the diminish of the resistance to charge
transference (Rct) in presence of graphene sheets (respect bare CPE); in
addition, the presence of nanohybrid graphene-CoFe2O4 causes a much
bigger decrease in Rct value (respect graphene-CPE spectra), due to a
significant increase of charge transfer in presence of the nanohybrid.
Bagheri et al. [72] employed Zn2SnO4/graphene nanocomposite as a
modifier in a CPE for simultaneous determination of the opium alkaloids
morphine and codeine by differential pulse voltammetry (DPV).
Zn2SnO4 is a ternary oxide semiconductor, anchored onto a graphene
matrix, significantly enhancing the electrochemical properties of the
sensor. Using Zn2SnO4/graphene-CPE the peak current was about ten
times as great as that for the bare CPE and four times as great as that for
the graphene-CPE due to the more electrochemical active sites present
on the surface of Zn2SnO4/graphene CPE. The modified electrode pro­
vided detection limits of 0.011 and 0.009 μmol/L for morphine and
codeine, respectively. The sensing system had excellent selectivity
against foreign substances with recoveries between 97 and 104 % during
morphine and codeine detection using real samples, like biological
fluids and pharmaceutical samples. The same research team decorated
graphene with Co3O4 nanoparticles to be used as modifier CPE as a novel
strategy to carry out direct and sensitive determination of tropane
alkaloid atropine [73]. Co3O4 nanoparticles have recently gained in­
terest due to their low cost, biocompatibility, wide availability and great
electrocatalytic activity. To compare the performance of different pre­
pared electrodes (graphene-CPE and Co3O4/rGO-CPE), the electro­
chemical response of atropine was studied. An increase of 3 times was
observed in the peak current of atropine on the surface of Co3O4/rGO-
CPE relative to graphene CPE. The authors associated the enhanced
intensity of peak current can be due to the special structure and the large
surface areas of Co3O4/rGO-CPE. The sensor developed showed a good
electrochemical response over the linear range from 0.1 to 3.2 μmol/L
with a detection limit of 0.03 μmol/L. The sensor was successfully
applied to atropine detection in biological fluids and pharmaceutical
samples with recoveries from 98 to 104 %.
Some other materials that are also someway related to graphene are
graphene oxide (GO) and reduced graphene oxide (rGO). GO due to its
hydrophilic character is easier to disperse with numerous solvents
(including water), obtaining more homogenous modified electrodes that
with graphene. However, GO exhibit a significant loss of conductivity
compared with graphene. For these reasons, several methods have been
used to reduce the GO to graphene in rGO form.
However, the GO offers more reactive positions due to oxygenated
functional groups on its surface. It is a very interesting characteristic to
obtain functionalized graphene films with any organic molecules or with
other nanomaterials (like metallic nanoparticles, polymers or other
carbon allotropes like CNTs or graphene quantum dots) to obtain
nanohybrids strongly linked. Furthermore, the lower conductivity of GO
to graphene, could be partially, recovered through a (chemical or elec­
trochemical) reduction process obtaining rGO. Thus, the employ of GO
in electrode modification is a good alternative, because is more soluble
in most solvents (especially polar), is most reactive and, in addition, is
cheaper than graphene. For this reason, several authors have made use
of these to determine alkaloids [76–82].
Thus, for example, Khoo et al. [77] carried out a comparative study
employing different chemically modified graphene electrodes (graphite
J. Gañán et al.
oxide (GPO), GO and electrochemically reduced graphene oxide (ErGO))
for the detection of caffeine. The analytical performances were studied
by DPV and found that ErGO showed the most favourable analytical
parameters, such as lower oxidation potential, sensitivity, linearity and
reproducibility of the response. The authors comment that the best
performance exhibited by ErGO may be correlated to the lower content
of oxygen groups, which can have a negative effect on charge transfer
processes.
The large theoretical surface area of graphene (2630 m2 g− 1) facili­
tates the deposition of nanoparticles with low aggregation. In this sense,
Atta et al. [81] developed a hybrid of reduced rGO/palladium (rGO/Pd)
modified CGE and was employed in the determination of morphine.
Using rGO/Pd-GCE revealed that the oxidation-current response in­
creases nearly to double that obtained with GC- rGO and approximately-
five times that obtained with bare a GC electrode. rGO/Pd-GCE sensor
had high resistance to interferences when it was used to determine
morphine in human urine. Satisfactory results were obtained, with a low
detection limit of approximately 0.013 μmol/L and good recovery data
of 101.1–102.2 %. Also, Beitollahi et al. [83] have reported an attractive
method to determine morphine using a graphite screen printed electrode
(SPE) modified with the magnetic core shell GO, GO/Fe3O4@SiO2. For
modification of the Beitollahiś SPE, 1 mg of the GO/Fe3O4@SiO2
nanocomposite was dispersed in 1 mL of Milli-Q water by ultra­
sonication for 1 h, and then an aliquot (5 μL) of the suspension solution
was added on the carbon working electrode, then left until the solvent
was evaporated at room temperature. The sensor (GO/Fe3O4@SiO2-
SPE) was evaluated for morphine determination, showing a much higher
anodic peak current for oxidation of morphine at about 125 V more
negative potential than unmodified SPE. The stability of the sensor was
tested over a 3-week lapse, showing a decrease in the current signal
lower than 2.3 %. The sensor provided linear DPV responses in the range
of 1.0 – 100 μmol/L for morphine with a detection limit of 0.75 μmol/L.
Finally, the sensor was successfully applied to morphine monitoring in
biological fluids obtaining satisfactory recoveries (98–103 %). The SPE
integrates three electrodes on an insulating substrate (like ceramic or
polyvinyl chloride) making it portable, inexpensive and easy to operate.
On the other hand, the small electrode size allows a small sample vol­
ume, which is favourable to improve the signal-to-noise ratio and
enhancing the mass transmission rate. At the same time, it is beneficial
to encourage the miniaturization of electrochemical sensing devices
[84].
3.1.3. Carbon quantum dots and graphene quantum dots
Carbon quantum dots (CQDs), often just called carbon dots (CDs), are
small fluorescent carbon nanoparticles with sizes less than 10 nm in
diameter [85] included in so called zero-dimensional (0D) nano­
materials, their most relevant characteristics are high chemical stability,
good conductivity and luminescence, and also broadband optical
absorption.
Graphene quantum dots (GQDs) are a subgroup of CQDs consisting of
small graphene fragments characterized by their unique characteristics
produced by the fact that electronic transport is relied upon in the three
spatial dimensions [86]. The most harvested properties are those related
to their photoluminescent ones due to the non π → π* band gap. How­
ever, their electronic characteristics are also being exploited in prepar­
ing any electrochemical sensors. In this regard, [87] describe a DPV
sensor based on GQDs modified graphite SPE capable of determinate
theophylline in a linear range between 1 and 700 µmol⋅L− 1 with a limit
of detection of 0.2 µmol⋅L− 1, adequate to pharmaceutical analysis.
3.1.4. Carbon nanofibers
Carbon nanofibers (CNFs) are another carbon allotrope included in
the one-dimensional (1D) nanomaterials as well as CNTs. Despite the
similar structure, exist important differences such as that while CNTs are
a few graphite layers rolled up on themselves around a hollow parallel
nucleus; graphitic layers of CNFs usually form an angle with the inner
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Microchemical Journal 184 (2023) 108136
tube and their interior can be hollow or solid. Another important
structural difference is the diameter: typically, less than 100 nm in CNTs
and in the range of 10 to 500 nm for CNFs. These nanofibers are wild
employed in electrochemical sensors due to, principally, the very high
capacity of CNFs to form nanohybrids with different materials. This
ability comes from the angular organization of the graphite sheets,
which results in the presence of graphitic edges, which are more reactive
than the central areas of the sheets [88]. In that respect, Duan et al.
report an electrochemical sensor based on a poly-sulfosalicylic acid film
decorated CNFs electrode capable to detect theophylline in pharma­
ceutical tablets. These sensors show a linear range from 0.6 to 137 µmol/
L and a detection limit of 0.2 µmol/L obtaining a recovery rate in real
pharmaceutical samples between 98.6 and 103.4 %. [89]. In the same
way, Teker and Aslanoglu report square wave voltammetry (SWV)
sensors based on dysprosium oxide and europium oxide nanoparticles
linked to CNFs for the papaverine determination. This sensor achieves
the quantification of papaverine in the range from 0.1 to 2 µmol/L and
with a successfully limit of detection of 0.01 µmol/L In addition, the
developed sensor was successfully applied to determine papaverine in
pharmaceutical pills and human urine obtaining recoveries from 99.8 to
100.8 % [90].
3.1.5. Ordered mesoporous carbon
Ordered mesoporous carbon (OMC) materials are created using
mesoporous silicas as a template. Sucrose was used as the internal car­
bon source; after the carbonization of sucrose with sulfuric acid, the
silica was subsequently dissolved employing an aqueous sodium hy­
droxide solution. Transmission electron microscopy images of the
resulting material show a uniform pore distribution, and scanning
electron microscopy images permit seeing the nanoparticleś
morphology. On the other hand, X-ray diffraction exhibits the inverse
relation between silica and carbon nanostructure [91].
From the beginning, a great potential for the shape-selective,
sensing, adsorption, and catalysis of large species that were limited by
the micropores (typically less than 1 nm) of zeolites and just time was
required for the development of electrochemical sensors. Among them,
there are any worth mentioning. Li et al [92] proposed a morphine
electrochemical detection scheme utilizing OMC modified GCE.
Employing OMC, a decrease in the overpotential and an increase in the
peak current was achieved with respect to the bare GCE. The results of Li
show a high electrocatalytic effect in the oxidation of morphine and
permit the obtention of a wide linear response (from 0.1 to 20 µmol/L),
high sensitivity of 1.74 µA/µM and low detection limit of 0.1 µmol/L.
Other applications of OMC in alkaloid sensing were developed by
Gao et al. [93]. They developed a large mesoporous carbon/NF based
sensor over a GCE for simultaneous determination of theophylline and
caffeine in human blood serum and different food samples using the DPV
measurement technique after a preconcentration step. In the optimized
conditions, the authors report a linear range compressed between 0.8
and 180 µmol/L with a limit of detection of 0.37 µmol/L for theophylline
and a linear range compressed between 1.3 and 230 µmol/L and the
limit of detection is 0.47 µmol/L for caffeine. The validation of the
method was contrasted by the recoveries between 90.0 and 98.5 % in
human serum and between 91.2 and 104.8 %.
3.2. Metal and metal oxide nanoparticles
Metal nanoparticles (MNPs) and metal oxide nanoparticles (MONPs)
received extraordinary attention due to their exclusive physical, chem­
ical, and electronic properties that make them suitable transducer
components of an electrochemical sensor. This is due to their size, sta­
bility and high surface area. The main functions of MNPs in electro­
analysis involve the toughening of the conductive sensing interface and
the catalytic properties of nanoparticles. The fast electron transfer be­
tween the transducer and analyte molecule in presence of metal nano­
particles is considered “electronic-wires” and electrocatalysts because of
J. Gañán et al.
their nanosized structure [94]. The MNPs such as Au, Pd, Ag and Pt are
famous for electrochemical sensing applications, as can be seen in
Table 2. They can be used as a simple modifier, though are generally
used in combination with other materials and play a certain role in
enhancing the analytical detection of target analytes.
Gold nanoparticles (AuNPs) are the subject of intensive research due
to their ability to functionalize the surface of electrodes with self-
assembled monolayers, large particle surfaces, good bio-compatibility
and electrocatalytic activity, so they are used in many electrochemical
studies. In recent years, AuNPs have attracted significant interest in the
modification of electrodes for the analysis of alkaloids such as morphine
[95–97], caffeine [98,99] and theophylline [100]. Generally, the
modified electrodes based on AuNPs show high sensitivity towards the
detection of alkaloids compared with bare electrodes.
Au nanoparticles electrodepositing onto CPE (AuNP-CPE) were used
to construct a sensor to determine morphine. This electrode provides a
promising approach for highly sensitive morphine sensing that offers an
excellent response in the concentration range of 0.4–200 µmol/L, with a
detection limit of 0.0042 µmol/L. AuNP-CPE has also been successfully
applied to determine morphine in urine samples with satisfactory re­
covery [95]. As well, Ören and Anık [98] reported a GCE modified with
AuNPs to develop an electrochemical sensor for caffeine determination
in cola drink samples. A detection limit of 2.49 μmol/L for caffeine was
obtained in the linear range from 25 to 1000 μmol/L under optimized
conditions. In another example, Trani et al. [99] employed an AuNPs-
chitosan nanocomposite to modify a gold electrode for electro­
chemical analysis of caffeine in beverage samples. The sensor developed
showed a broader linear range of 2.0–5000 μmol/L with a detection
limit of 1 μmol/L. The sensor was successfully applied for the determi­
nation of caffeine in a series of commercial beverages and the results
were compared with those obtained with the HPLC-PDA method,
showing generally good agreement about the results.
MNPs combinate with different substrates have been used to get
enhanced electrocatalytic activity toward alkaloid detection. For
example, gold NPs were electrodeposited on an NF modified CPE for
electrochemical determination of morphine [96]. To prepare the NF-
CPE a mixture of NF solution, Nujol and graphite powder (10:15:75;
w/w, %) was hand mixed and the homogeneous composite was packed
in the electrode. Then the NF-CPE was immersed into 6 mmol/L of
HAuCl4 solution containing KNO3. A constant potential of − 0.4 V versus
Ag/AgCl was applied for 400 s. At the optimum conditions, the con­
centration of morphine was determined using DPV in a linear range of
0.2–260 μmol/L, and a detection limit of 0.0013 nmol/L. The modified
electrode was satisfactorily employed for the determination of morphine
spiked into urine samples, and excellent recoveries were obtained. Later,
Atta et al. [97] introduced a highly sensitive electrochemical sensor
based on Au nanoparticles/Ferrocene modified CPE (GNP/FM-CPE), to
be used to determine morphine. The modification of the surface with
ferrocene moieties proved to be effective as it adds a faradaic component
to the process of charge transfer. Therefore, it increases the rate of
charge transfer at the surface-electrolyte interface. The voltammetric
behaviour of morphine was studied by CV at GNP/FM-CPE. The results
showed that the electrodeposition of Au nanoparticles on ferrocene
modified CPE drive to an increase in the morphine peak current
regarding bare CPE, which indicates an improvement in the electrode
kinetics and a substantial decrease of oxidation potential. Under optimal
conditions, the morphine concentration could be measured in the con­
centration range of 1–1800 μmol/L with a detection limit of 0.0035
μmol/L. The limit of detection resulted lower than in their previous work
[95]. Also, AuNPs were functionalized with aminotriazole (AT-AuNPS)
to modify GCE through the electrodeposition method for electro­
chemical determination of theophylline. Using the AT-AuNPS film
modified electrode the current response of theophylline was linearly
increased while increasing their concentration from 0.004 to 100 μmol/
L and the detection limit was found to be 0.0085 μmol/L. The practical
application of this modified electrode was demonstrated by the
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Microchemical Journal 184 (2023) 108136
determination of theophylline concentration in human blood serum and
urine samples with good recoveries [100].
On the other hand, also other nanoparticles have been used to modify
electrodes for alkaloid determination. For example, Yin et al [101]
employed CdSe nanoparticles to modify a GCE and used to determine
theophylline. Theophylline showed a well-defined oxidation peak at the
CdSe-GCE and the oxidation peak current was much higher than that at
the bare GCE. It can be ascribed to the immobilized CdSe particles,
which showed higher accumulation efficiency to theophylline. Under
optimal conditions, theophylline showed a linear relationship in the
range of 1.0–700 μmol/L, with a detection limit of 0.4 μmol/L. The
sensor developed was successfully used to determine theophylline in tea,
cola drinks, fruit juice drink, fermented milk drink and preserved fruit
with acceptable recoveries (94–106 %). Also, CuS nanoparticles were
used to modify CPE to determine caffeine in food samples [102]. At CuS-
CPE, caffeine showed an oxidation peak with 1.7 times more current
signal than at bare CPE under identical conditions, which suggests that
CuS NPs improve the charge transfer capacity of CPE. Under experi­
mental conditions, the oxidation current of caffeine was proportional to
its concentration in the range of 2.0–120 μmol/L, with a detection limit
of 0.018 μmol/L. The sensor developed was successfully applied to
determine caffeine content in tea and coffee samples, obtaining re­
coveries in the range of 85–107 %.
The employment of metal oxides in electrode modification is
growing rapidly due to their sensitivity, chemical stability, non-toxicity,
cost-effectiveness and rapid response. These metal oxides can be tailored
into different nanostructures like nanotubes, nanorods, nanofibers, etc.
Due to the large aspect ratio, these nanostructured metal oxides provide
high sensing properties [103]. These nanomaterials present high
dielectric constant, thermal stability, uniform pore size, high pore den­
sity, low cost and relatively simple preparation. Different kinds of metal
oxides have been used in alkaloid sensing, such as AlO3 [104], CeO2
[105], TiO2 [106], MnO2 [107], and Co2O3 [108,109]. Thus, for
example, Arabali and Sadeghi [104] synthesized and applied Al2O3
nanoparticles as a modifier in CPE to develop a sensor to determine
morphine. Al2O3 showed good electron conductivity at the surface of
CPE. The peak current of morphine at Al2O3-CPE was 1.8 times larger
than at bare CPE using CV. The SWV shows that the relation of peak
current versus morphine concentration is linear for 0.1–550 μmol/L of
morphine, with a detection limit of 0.03 μmol/L. The developed sensor
was applied to determine morphine in urine and ampoule samples,
obtaining good recoveries. CeO2 NPs were used by Kairy et al. to modify
graphite SPE [105]. For this preparation, the CeO2 NPs solution was
prepared by mixing 80 % of dispersed CeO2 Np and 20 % of graphite in
deionized water. The mixture was sonicated and then 5 μL of the mixture
was dropped onto the SPE surface. The CeO2-SPE was employed to study
the electrochemical behaviours of codeine and caffeine alkaloids by
DPV. Under optimal conditions, the electrode showed low detection
limits of 0.043 and 2.4 μmol/L, for codeine and caffeine, respectively.
The CeO2-SPE exhibited practical analytical utility for the simultaneous
determination of codeine and caffeine in human serum samples with
excellent recoveries.
The electrochemical characteristic of nanomaterials is often influ­
enced by the shape of the nanostructure. Contrary to metals whose
surface energy is associated with the nature of crystal facets, metal ox­
ides tend to behave differently. The associated surface energy for metal
oxide is a complex combination of inherent surface area and shape
complexity. In regards, Soomro et al. [109] studied the shape-dependent
electrochemical response with the presence of certain functionalities at
the electrode. The as-synthetized Co3O4 nanostructures were grown
using amino acids such as cysteine (CYS), glutathione (GSH) and histi­
dine (HYS) as templates under hydrothermal action. The synthesized
Co3O4 nanomaterials were evaluated as modifiers in GCE electrodes to
determine atropine. Firstly, the behaviour of CYS/Co3O4-GCE, HYS/
Co3O4-GCE and GSH/Co3O4-GCE against atropine was studied. The
GSH/Co3O4-GCE produced a higher current density with a much lower
J. Gañán et al.
anodic potential compared with other electrodes. The peak shape for
GSH/Co3O4-GCE was also well-defined compared to its competitors. The
observed behaviour of GSH/Co3O4-GCE signifies both the enhanced
electron transfer kinetic and higher electrochemical reactivity associ­
ated with the unique structural features of flowers-like Co3O4 Further­
more, GSH/Co3O4-GCE possesses the greatest active area (0.575 cm2) in
comparison with CYS/Co3O4-GCE and HYS/Co3O4-GCE (0.154 and
0.230 cm2, respectively). The large exposed surface area provides many
more active sites, heavily influencing the electrocatalytic phenomena
occurring on the surface of the electrode. Herein, the observed signal
sensitivity is in complete agreement with the estimated active surface
area. The GSH-Co3O4 modified electrode was applied for the electro­
chemical sensing of atropine in a concentration range of 0.01–0.46
μmol/L, with a detection limit of 0.001 μmol/L. The developed sensor
demonstrated excellent capability when used for atropine detection in
human urine samples with strong anti-interference potential against
common co-existing species.
Recently, a sensitive electrochemical sensor to determine morphine
at the surface of an electrode modified with Fe3O4 nanofibers was pre­
pared [110]. Fe3O4 or magnetic NP presented special attention as they
can increase electron transfer reaction from kinetic and thermodynamic
viewpoints. On the other hand, nanostructures like nanofibers are
widely used to elaborate electrodes owing to their best electrical con­
ductivity, unique and idiosyncratic structure, and high mechanical
strength. Magnetic electrospun nanofibers were made by electro­
spinning and then the thermal processing method. The modified sensor
was used for morphine analysis using CV and DPV. A broad linearity
range was observed in a concentration range of 0.0033–245 μmol/L with
a very low detection limit of 0.002 μmol/L toward morphine. The sensor
exhibited good selectivity, sensitivity, and acceptable recoveries
(ranging within 98 – 105 %) to undergo morphine detection under
serum samples [110].
A simple, reliable, and sensitive method was developed utilizing
BaFe12O19 nanoparticles as a modifier on graphite SPE (BaFe12O19-
GSPE) to determine morphine in real samples [111]. The M− type
barium hexaferrite has a hexagonal molecular structure with interesting
properties. Further to the mentioned benefits regarding nanomaterials,
larger sizes of atoms (atomic radius is approximately 2.78 Å), and higher
chemical ability of reaction of barium, barium hexaferrite has wide­
spread application in electrochemical sensors. The BaFe12O19 nano­
particles were obtained using the sol–gel auto-combustion method. The
nanoparticleś mean size was 76 nm, and their morphology was hexag­
onal. To modify SPE 5 μL of aliquots of the BaFe12O19 nanoparticles/
H2O suspension solution was cast on the GSPE surface and dried at room
temperature. BaFe12O19-GSPE and bare GSPE were compared, obtaining
that the modified electrode takes advantage of higher sensitivities and
selectivities with a lower detection limit. DPV procedure has been used
to analyze morphine. The results indicated that the linear response
range and detection limit were 0.06–600 μmol/L and 0.02 μmol/L
respectively [111].
3.3. Ordered mesoporous silica-based materials
Ordered mesoporous silica (OMS)-based materials were first
described in 1992 [112]. OMS-based materials have gained strong in­
terest from the analytical community due to their unique properties,
such as high thermal and mechanical stability, high specific surface and
large pore volume. A special issue with this type of materials is the
possibility to design made-to-order, since then, depending on the prep­
aration conditions (pH, temperature, type of surfactant, and concen­
tration of the reagents, etc.) it is possible to obtain materials with
different structures, pore diameters, specific surface area, particles sizes
and shape, depending on the desired application requirements [113].
In recent years, OMS has been used in electrochemical applications
due to their highly porous and regularly ordered structure, which pro­
vides good accessibility and fast mass transport to active centers. In
11
Microchemical Journal 184 (2023) 108136
addition, the surface of these nanomaterials can be easily modifiable
through its functionalization with organic groups, which can enhance
sensitivity and selectivity. Over the last decade, OMS-based materials
have been successfully applied as CPE modifiers for the determination of
many inorganic and organic contaminants [114–119]. For electro­
chemical determination of alkaloids, in particular tropane alkaloids,
Gañán et al. [120] synthesized three different types of OMS (MSU-2,
HMS and SBA-15) and functionalized them with 2-mercaptopyrimidine
(MPY) to be evaluated as CPE modifiers. The influence of the silica type
on the electrochemical behaviour of the OMS-CPE was studied using
ferrocyanide and scopolamine as probes. The results showed that the
electrochemical behaviour of scopolamine was highly influenced by the
morphology and the channel structure of the OMS. The best results were
obtained employing HMS nanomaterial, which presented pseudo-
spherical morphology and 3D wormhole like channels. In addition, the
presence of MPY over the HMS surface significantly improved the
scopolamine peak current. Under optimum conditions, HMS-MPY-CPE
exhibited a broader linearity range from 0.9 to 200 µmol/L, with a
detection limit of 0.3 µmol/L by DPV. The developed sensor was suc­
cessfully applied for a rapid determination of scopolamine in tea and
herbal tea infusion samples with good recoveries (between 82 and 102
%). Sun et al. [121] also employed mesoporous silica nanomaterials as a
modifier for to determine tropane alkaloids. Herein, a novel flower-like
core–shell mesoporous silica nanospheres@zeolitic imidazolate
framework-8 (MS@ZIF-8) was synthesized and used to preparation of
molecularly imprinted MSN@ZIF-8 modified GCE. The molecularly
imprinted electrochemical sensor based on MSN@ZIF-8 nanocomposite
was prepared with p-aminophenol as functional monomer, Au nano­
particles as cross-linker, and atropine as template molecule via elec­
tropolymerization technique. The electrochemical behaviour of atropine
was studied employing MIP-atropine/GCE and MIP-atropine/
MSN@ZIF-8/GCE by DPV, showing the highest intensity of the anodic
peak with MIP-atropine/MSN@ZIF-8/GCE. According to the authors,
the presence of MSN@ZIF-8 on the electrode surface increased the
effective electrode reaction area for the formation of more atropine
imprinted sites on the sensor, so the current response of atropine
enhance significantly. Under optimized conditions, the sensor devel­
oped showed a wide linear range (0.005–9.5 µmol/L) and subnanomolar
detection limit (0.00098 µmol/L) and was successfully applied for
atropine determination in eyedrops, human serum, human urine, beef,
and cereals samples. Gan et al. [122] also took advantage of the excel­
lent properties of OMS to use it as supporting material to develop a novel
molecularly imprinted electrochemical sensor to determine theophyl­
line. The prepared theophylline-imprinted sensor exhibits a wide linear
dynamic concentration range (0.005–1000 μmol/L), low detection limit
(0.0007 μmol/L) and excellent selectivity when used in coexisting with
other structurally related substances such as caffeine, theobromine,
xanthine, guanine, adenine, and paraxanthine. Finally, The method
developed was applied to recognize and detect theophylline in different
food samples such as green tea, carbonated cola drink, fermented milk
drink and preserved fruit, obtaining recoveries within an acceptable
range of 92.3–110 %.The authors attribute these excellent results to the
introduction of OMS with high pore volume and large surface area into
the sensing system, as this has enabled the formation of an enormous
amount of imprinting cavities that matched theophylline, which gua­
rantees the specific recognition towards theophylline, addition to the
high conductivity and electrotransfer ability of the prepared sensor
thanks to used pyrrole as a functional monomer in the electro­
polymerization procedure.
3.4. Polymeric-based nanomaterials
Molecularly imprinted sensors have attained special attention due to
the presence of specific sites towards target analytes molecules. Several
organic polymers, including chelating and conducting polymers (CP),
have been used to fabricate electrochemical sensors. The CP have
J. Gañán et al.
extended the π-conjugated system with alternating single and double
bonds across the polymeric chain. In contrast to conventional organic
polymers, CP have a high electron affinity and redox activity. In CP, the
selective properties of the conventional polymer and electronic prop­
erties of the metals or semiconductors are combined [123]. CPs consist
of a wide group of organic compounds (such as polypyrrole (PPy),
polyaniline (PANI), polythiophene, and their derivatives) with specific
properties, which have been used in many electrochemical applications.
However, simple CPE presented a few limitations, such as low sensi­
tivity, surface poisoning due to adsorbed intermediates, and in­
terferences from other species. Thus, recently, CP have been combined
with other nanomaterials to obtain hybrid nanocomposites with
enhanced properties [124]. As is shown in Table 2, this combination has
also been widely applied for the electrochemical analysis of alkaloids
[125–131]. In this context, Tiwari et al. proposed the synthesis of a
nanoporous network of DMTD-AG coordination polymer derived from
2,5-dimercapto-1,2,4-thiadiazole and AgNO3 [125]. This nanomaterial
was tested as a modifier in CPE for the electrochemical assay of atropine
using the DPV technique. The sensor developed demonstrates high
effectiveness due to the favourable structure of DMTD-Ag favours the
channelling of the electron by providing a large surface area and
effective support for the proficient oxidation of atropine. Under the
optimal conditions, the anodic peak current increased linearly with the
concentration of atropine in the range from 0.6 to 9.0 μmol/L at an R2
value of 0.98, with a detection limit of 0.0046 μmol/L. To show its
applicability, the proposed sensor was used for atropine analysis in a
clinical formulation obtaining satisfactory recovery. Also, Rezaei et al.
proposed a hybrid nanomaterial synthesized combining molecularly
imprinted polymer, a carbon-based material, and metal nanoparticles to
be used as modifier surface of a pencil graphite electrode (PGE) [126].
PGE is a relatively new type of carbon electrode, it was having been
satisfactorily applied for its electrochemical reactivity, good mechanical
rigidity, low cost, low technology, and easy modification. For the sensor
fabrication, firstly, the pretreated bare PGE was immersed in a sus­
pended solution of MWCNT. Then MWCNT/PGE was modified with
uniform electropolymerization of the MIP layer on the surface of the
electrode by using the CV method using papaverine as a template
molecule. Finally, the potenciostatic deposition method was used for the
electrodeposition of AuNPs by applying a constant potential to prepare
AuNP/MIP/MWCNT-PGE. SWV measurement was performed for the
quantitative determination of papaverine. Under the optimal conditions,
the sensor showed a linear response with the concentration of papav­
erine in the range from 0.001 to 5.0 μmol/L, with a detection limit of
0.0004 μmol/L. To investigate the selectivity of the fabricated sensor,
different substances (morphine, oxycodone, thebaine and codeine),
which have similar behaviour and structure to papaverine were tested as
interfering substances, and the application ratio of these substances to
papaverine resulted in 15 times. Finally, to demonstrate the ability of
the suggested method for the determination of papaverine in biological
samples (urine and serum). The result was sufficient, accurate and
precise which showed satisfactory recovery for papaverine.
4. Most relevant applications of nanomaterial-modified
electrochemical sensors for alkaloids analysis in biological,
pharmacological and agri-food samples
In this section, we will discuss the most relevant applications of these
electrochemical devices for alkaloid determination. To this end, the
bibliography analyzed in this review has been organized according to
the samples to which the methods developed are applied, mainly bio­
logical fluids, pharmaceutical preparations, or agri-food samples.
Due to the complexity of these samples, the use of the standard
addition methodology is so frequent. It is worth mentioning that the use
of some electroanalytical techniques permits the application of standard
addition calibrations on the same measuring cell by adding aliquots of a
standard of increasing concentration onto the sample. This procedure
12
Microchemical Journal 184 (2023) 108136
greatly facilitates the elaboration of this type of methodology compared
to other techniques, such as chromatographic ones, which require the
preparation and measurement of each of the calibration points with
increasing concentration of the standard. Besides that, the employ of
sensors, especially electrochemical ones, offers the important advantage
of diminishing the sample pretreatment, due to their high selectivity.
4.1. Determination in biological fluids
The most extended samples in which analyzed alkaloids are biolog­
ical ones, due to this compoundś family can be utilized such poison,
analgesic, sedative, anaesthetic or dopant considering its action on the
central nervous system. Alkaloids determination in biological samples
such as serum, urine, blood, etc. is a very important topic for applica­
tions like clinical or forensic science.
The following are the most representative examples of alkaloid
electrochemical sensors applied to biological samples
[19–21,42,44,48,49,50,51,56–58,68,71,72,75,80,82,90,92,93,95–97,
100,104–106,109–111,123,126–130]. There are sensors useful to
determine different kinds of alkaloids. Most of the sensors developed
have been applied to determine opiate alkaloids such as morphine
[19,49,50,56–58,71,80,82,92,95–97,104,110,111,129], codeine [20,
42,68,71,105], papaverine [90,126] and thebaine [44,51]. As can be
seen in Fig. 3, morphine is the target more studied, followed by codeine,
in biological samples (mainly urine). These opium alkaloids are widely
used in medicine because of their important pharmacological properties,
but it is also frequently used as a drug of abuse. For these reasons, the
most common uses of opium alkaloids in biological samples are moni­
toring therapeutic levels in patients and for epidemiological purposes of
drug-abuse control [80].
A particularly remarkable work is the one published by Atta et al.
[96] who developed a CPE modified with Au nanoparticles and NF was
used for the electrochemical determination of morphine. The authors
combined the advantages of NF, such as good ion-exchange and pre­
concentration features and the high electrocatalytic activity of Au
nanoparticles achieved a simple and sensitive method for morphine
determination in human urine with a very low detection limit (0.00013
μmol/L). Also, the determination of morphine in blood serum was, after
simple protein precipitation, centrifugation and filtration of the sample,
the goal of Bahrami et al. [110], who used magnetic nanofiber modified
CPEs to determine the analyte concentration by DPV. The developed
methodology offers well results to precision and detection limit, com­
parable with the HPLC-MS reference method, but with a great saving of
time and effort in sample pre-treatment, as well as a large volume of
solvents; In addition, HPLC coupled to mass spectrometer is expensive
equipment and requires specific installations, which can be dispensed by
using electroanalytical techniques. In that case, serum samples were
stored frozen until analysis in the 10 mL centrifuge tubes, the proteins
were precipitated by the addition of 1 mL saturated ammonium sulfate
solution and vortexing for 15 min, after centrifugation, the clear su­
pernatant layer was filtrated with a pore-size of 0.45 μm Milli-pore filter
obtaining a protein-free human blood serum. This solution was trans­
ferred into a 10 mL flask and diluted with PBS after measurement.
However, Verrinder et al. [129] improve the goals by [110] employing a
sensor based on SWCNTs and the polymer NF that allows them to
measure whole blood serum collected by capillarity without any pre­
treatment (Fig. 4). The analytical characteristics are a few worse (linear
range from 0.5 to 10 µmol L− 1, and limit of detection of 0.48 µmol L− 1),
but detectable in whole blood, a very complex sample. This type of SPEs
offers important advantages, such as the possibility of miniaturization of
the measuring system, allowing point-of-care determination. In addi­
tion, the development of nanomaterial-based inks is a very easy and
robust way to prepare nanomaterial-modified electrodes, that can be,
then modified by other nanomaterials obtaining nanohybrids with
synergic properties. Furthermore, the employ of these strips electrodes
permits allows the three electrodes required for electrochemical analysis
J. Gañán et al. Microchemical Journal 184 (2023) 108136

Fig. 3. Sample distribution of the electrochemical sensors into the applications of interest for this review purpose.

Fig. 4. (a) Miniaturized electrode panel, (b) single electrode with the amount of blood sample required and (c) schematic illustration of electrodes preparation [129].
Adapted with permission of ACS Omega 2021, 6, 17, 11563–11569; https://pubs.acs.org/doi/https://doi.org/10.1021/acsomega.1c00773.

13
J. Gañán et al.
to be combined in a minimum surface area, minimizing both the sample
volume (only a few microliters are necessary). In that case, the SPE is
composed of SWCNTs ink in the working and counter electrode and
silver ink for the reference electrode and the three connections. In
addition, NF modification provides a cation exchange membrane
maintaining all cationic species out of the electrode surface, without loss
of electrical conductivity. An interference study compares the sensor
response of morphine 2,5 µmol L− 1 in the absence and presence of 10
µmol/L of codeine, tramadol, O-desmethyltramadol, dextromethorphan,
nicotine, 2.5 μmol/L fentanyl, 20 μmol/L caffeine, and 950 μmol/L
salicylic acid. The study shows that any potential interference provokes
a response variation higher than the tolerance limits of RSD for the
morphine 2.5 µmol/L.
Using the synergic properties obtained from the combination of
magnetic core graphene oxide and silica nanocomposite, Beitollahi et al.
[82] design an electrochemical capable of the quantification of
morphine in urine employing the standard addition methodology. In this
regard, ten millilitres of centrifugated and filtered urine were trans­
ferred into different 25 mL flasks, adding different volumes of a
morphine standard solution and finally diluted to the mark with PBS. An
interference study was carried out to demonstrate that common con­
centration of glucose, sucrose, lactose, fructose, citric acid, methanol,
ethanol, Mg2+, Al3+, Fe2+, Fe3+, Cl− or F− , alanine, methionine,
phenylalanine, glycine, folic acid (vitamin B9) and urea did not interfere
with the determination of morphine. However, ascorbic acid in an equal
molar ratio causes an appreciable interference in morphine quantifica­
tion. This interference could be removed by using an ascorbic oxidase
enzyme in spite of removing the reduced form of ascorbic acid.
A method for other opium alkaloids, papaverine, was developed by
Teker and Aslanoglu [90]. In this, the employ of carbon nanofibers
combined with dysprosium and europium oxide nanoparticles permits
the quantification of papaverine in human urine just filtered and diluted
in a buffer solution. It is remarkable that in this case is not necessary to
use the standard addition calibration methodology. The selectivity of the
response obtained with this device was carried out by analyzing the
response of 2.0 µmol/L papaverine in presence of 30 µmol/L ascorbic
acid, 4.8 µmol/L dopamine, 1.5 µmol/L paracetamol and 12 µmol/L
salbutamol. It clearly shows that the voltammetric response of each of
these possible interferents appears at different potentials to papaverine.
Other groups of alkaloids extensively studied in biological samples
are methylxanthines such as theophylline [21,93,100,106,128,130] and
caffeine [42,48,75,93,105]. Theophylline and caffeine have very similar
chemical structures, and both display multiple pharmacological effects
(Table 1). Additionally, caffeine due to its effects as a central nervous
system and metabolic stimulant is commonly used recreationally to
reduce physical fatigue and restore mental alertness when somnolence
occurs [93]. These are some of those such natural alkaloids that have
been shown to possess a variety of bioactivities at low-dose but can
cause frequent adverse reactions at elevated serum levels, so monitoring
of these targets in biological fluids is necessary to confirm the suspicion
of recent use in forensic toxicology and to assist in overdose treatment in
medical emergency settings.
One of the most interesting advantages of electroanalytical methods
is their capacity to obtain the determination of a few compounds
simultaneously, without the need for separation or pretreatment pro­
cedures. Gao et al. [93] describe an electrochemical sensor based on a
GCE modified with large mesoporous carbon al NF composites for
simultaneous determination of theophylline and caffeine. The results
show that the DPV peaks of the two analytes can be distinguished at the
modified electrode with peak-to-peak separation of about 150 mV, this
means that the sensor is suitable for the simultaneous determination of
the analytes. So, this sensor was applied for simultaneous determination
of theophylline and caffeine in human blood serum without any labo­
rious sample pretreatment, but only a simple dilution (1:50, v/v) with
the supporting electrolyte, with satisfactory results. The employ of
electrochemically rGO for simultaneous determination of some purine
14
Microchemical Journal 184 (2023) 108136
alkaloid derivates (caffeine, xanthine, hypoxanthine and uric acid) was
reported by Raj and John [75]. In this paper, GCE was modified with
GO, which is then, reduced electrochemically by the application of 15
cycles from 0 to − 1.4 V in PBS. Over this surface, a DPV analysis permits
simultaneous determination of the four purine alkaloid derivates in
human serum and real urine samples at the same DPV measurement;
thanks to the electrocatalytic effect offered by the rGO electrogenerated
over the GCE, which causes the narrowing of the voltammetric signals
and, consequently, the separation of the four signals. Thus, in addition to
not requiring sample purification or any other pretreatment excluding
the dilution to 10 times for serum and in 25 times for urine in phosphate
measurement buffer, the concentration of the four analytes can be ob­
tained simultaneously with good results, and these were confirmed by
recoveries studies. Concerning the potential interferences, ascorbic acid
is usually present in these samples in very high concentrations (much
higher than analytes ones) and an evaluation of the interference pro­
duced by this acid was carried out at 25 and 750 µmol/L, showing no
interference in the signal of any four analytes. Likewise, Kesavan and
John [100] describe an electrochemical sensor based on aminotriazole
grafted AuNP electrodes for the simultaneous determination of
theophylline and uric acid in human biological fluids. Authors applied
this sensor to determine uric acid and theophylline in human blood
serum and real urine samples without any complex pretreatment, except
dilution 20 times in phosphate buffer solution (PBS), obtaining good
results, not worse than a reference HPLC method. In addition, the au­
thors carried out an interference assay in which the modified electrode
was tested for the detection of theophylline and uric acid from common
potential interferents that could be present in the biological samples
such as Na+, Ca2+, Mg2+, K+, NH+ 2− 2−
4 , Cl , F , CO3 , SO4 , glucose, urea
− −
and oxalate by DPV. The presence of 30 µmol/L of these substances does
not change the current response observed for 40 nmol/L theophylline
and 30 nmol⋅L− 1 uric acid. Another application of the electrocatalytic
properties of some nanomaterials like graphene is the capacity for
quantification of one analyte in presence of very high levels of a po­
tential interferent.
4.2. Determination in pharmacological samples
Due to alkaloids are very useful as drugs, the analysis of these
compounds in pharmacology preparations is very extended and there
are lots of papers describing electrochemical methodologies using
different types of nanomaterials to determine different alkaloids in
pharmaceutical samples [19,20,42,45,46,48,49,50,56–58,65,66,68,70,
71,72,73,81,82,87,89,90,104,106–108,111,125,130,131]. As shown in
Fig. 3 the most usual alkaloids present in this kind of sample are opioids
such as morphine [19,49,50,56–58,66,71,72,104,111], codeine
[20,42,68,71], noscapine [66] or papaverine [90] and methylxanthines
like theophylline [46,73,87,89,106,107,130,131] or caffeine
[42,48,70,81,108]. But several sensors have also been developed to
determine atropine [45,72,123,125] or cabergoline [65]. As shown
above (Table 1) all of these alkaloids present important pharmacological
properties and are marketed as both a single-ingredient and in combi­
nation preparation drugs. Therefore, is necessary and of great impor­
tance to develop simple, rapid and accurate methods that allow the
determination, either individually or simultaneously, of trace amounts
of different alkaloids in pharmaceutical samples.
Reviewing Table 2, it can be seen that several studies have achieved
the simultaneous determination of alkaloids in pharmaceutical prepa­
rations. So, for example, Habibi et al [42] developed a sensor capable to
detect simultaneously codeine and caffeine alkaloids in pharmaceutical
samples using an SWCNT modified CCE, achieving a detection limit of
0.11 and 0.25 μmol/L for codeine and caffeine respectively. To study the
applicability of the sensor developed, two different commercial phar­
maceutical samples (tablets) were analyzed. For this purpose, ten tablets
for each were completely ground and homogenized. The powdered
tablet was dissolved in distilled water and the as-prepared suspension
J. Gañán et al.
Fig. 5. Schematic representation of a surface modification of GCE (left) and voltammograms obtained for different concentrations of the three analytes (right) [71].
was stirred and centrifuged. Then, an aliquot of the supernatant was
diluted 50-times with 0.01 M H2SO4 solution. A portion of the resultant
solution was then taken for determination of drug concentrations,
achieving satisfactory results and recoveries (98.3–102.1 %).
Itś important to note that can often find pharmaceutical preparations
containing several active ingredients. In this sense, the ability for
simultaneous determination of a few analytes without separation
methods is one of the most interesting properties of electrochemical
sensors, such as the device developed by Yigrit et al. [70], who describe
a sensor capable of determining specifically paracetamol, acetylsalicylic
acid, and caffeine obtaining limits of detection of 1.2, 0.65 and 0.00038
μmol/L, respectively without applying any separation technique thanks
to the difference into the oxidation potential of the three compounds
applying these sensors 0.62, 1.06, and 1.44 V for paracetamol, ace­
tylsalicylic acid and caffeine, respectively using an SWV optimized at 75
Hz frequency, 14 mV of scan increment and 50 mV of pulse amplitude,
after an accumulation time of 60 s at 0.1 V (Fig. 5). The sample treat­
ment was boiling in sodium hydroxide to obtain the hydrolysis of ace­
tylsalicylic acid and simply dilution in pH 2.5 PBS. In addition, the
authors apply the sensor to a dilution of a commercial pharmaceutical
tablet comparing the obtained results with an HPLC method described in
the bibliography and there are no significate differences (α = 0,05)
between the results for de determination of any of the three analytes
measured by the two techniques in relation to precision and accuracy.
On the other hand, in spite to demonstrate the selectivity of that device,
some potentially interfering substances (chosen among the substances
commonly found with the analytes in pharmaceuticals and/or in bio­
logical samples) were added into the measurement cell with and without
analytes. It was found that K+, Na+, Ca2+, Zn2+, Mg2+, SO2− 4 , NO3 ,
−
glucose, fructose, sucrose, ascorbic acid and dopamine did not interfere
with the determination of these compounds.
Dar et al. [45] describe a method to determine atropine based on its
voltammetric oxidation consisting of an electrochemical sensor con­
structed by immobilization of MWCNTs onto a CPE. Next, an accumu­
lation of analyte was carried out by electrochemical reduction of
atropine applying − 0.2 V for 2 min; finally, a DPV scan is used as an
electroanalytical technique. Dar et al. apply this method in pharma­
ceutical samples (both traditional medicine and clinical) to obtain good
recoveries. For traditional medicine (leaves of Datura strammonium) was
necessary a double (chloroform and sulfuric acid) successive extraction
before buffer dilution, however, for determining atropine in commercial
eye drops was not necessary any pretreatment, except buffer dilution
and degasification. In addition, an interference study to estimate the
interference of similar structure molecules like ascorbic acid, ofloxacin,
norfloxacin, gatifloxacin, glucose and lactose, the presence of any of
them produces a signal variation higher than 5 %. At this point can be
interesting to compare the results obtained in [45] with others obtained
some years later by Chauhan et al. [132] using an HPLC methodology, in
which obtaining a worse linear range (50 to 150 µg mL− 1), and a slight
improvement with respect to the LOD (0.15 µg mL− 1) but paying a high
15
Microchemical Journal 184 (2023) 108136
price: the requirements of longer analysis times and high-volume
organic solvents consumption.
Employing nano-porous coordinating polymers based on silver
metallic atoms and 2,5-dimercapto-3,4-thiadiazole (DMTD) as coordi­
nating organic ligands on a CPE, [125] achieved the voltammetric
determination of ultra-trace atropine levels and its application to eye
drops pharmaceutical product. This paper reports a very high increase of
the signal at 0.9 V to atropine oxidation in presence of the proposed
nanomaterial. The determination was carried out by DPV in PBS pH 10
standard solutions, and just diluted and buffered pharmaceutical prod­
ucts and real samples were analyzed with good results.
4.3. Determination in agri-food samples
Electrochemical sensor development for alkaloids quantification is
now trending in the analysis of agri-food samples and is possible that this
trend continues at least, during the next years. The high complexity of
agri-food samples must be taken into account, making it even more
interesting (and more complicated) the development of chemical and
electrochemical sensors capable of determinate alkaloids with minimal
need for sample pretreatment. However, some papers describe the
development of electroanalytical devices for the determination of al­
kaloids in agri-food samples [21,42,43,47,48,59–61,67,69,74,
76–79,81,84,93,98,99,101,102,108,120,123,122]. As shown in Fig. 3
the most common alkaloid analyzed in agri-food samples are methyl­
xanthines as caffeine [42,48,60,61,67,69,74,76,78,79,84,93,98,
99,102,108], theophylline [21,74,77,93,101,122] or theobromine [59]
due to its natural presence in many food products such a coffee, tea,
yerbamate, guarana berries, cola nuts and cacao beans, and conse­
quently in their derivate products as teas, chocolates, biscuit, etc.
Moreover, caffeine is used extensively as a food additive, especially in
beverage as cola drinks and energy drinks.
Amongst the above, the following is worth mentioning the method
developed by Shu et al. [74] for simultaneous determination of
theophylline and caffeine in a wide linear range and with detection
limits of 0.03 μmol/L and 0.08 μmol/L for theophylline and caffeine,
respectively, using a poly (folic acid)/graphene modified glassy carbon
electrode by DPV technique. In addition, the authors verified the
absence of interference by a 20-fold excess of xanthine, cysteine and
dopamine, a 60-fold excess of uric acid, acetaminophen and ascorbic
acid, a 300-fold excess of histidine and phenylalanine, a 500-fold excess
of sodium citrate, glutamic acid and glucose in the response of
theophylline and caffeine. The sensor developed was applied for quan­
tification of theophylline and caffeine in extracts of black tea, green tea
drink, Coca Cola drink and Red Bull drink, without previous sample
treatment obtaining well recoveries (97–102 %). Another notable work
is that of Gan et al. [122], who developed an electrochemical method
using an MNSs@PPy modified GCE for theophylline determination with
a linear dynamic concentration range of more than six orders of
magnitude and low detection limit (0.66 nmol/L). The method was
J. Gañán et al.
applied for theophylline quantification in green tea, carbonated cola
drink, fermented milk drink and preserved fruit with a simpler sample
treatment. The concentration of theophylline found was 0.156, 0.371,
0.285 and 0.522 μmol/L in green tea, carbonated cola drink, fermented
milk drink and preserved fruit samples, respectively. These results were
confirmed using an HPLC method, and the results showed that both
methods were in good agreement with a relative error lower than 4 %.
It is remarkable that the analysis of liquid samples is usually easy and
even automated with these sensors, by using standard addition when it is
necessary through successive addition of standard aliquots over the
same measurement cell.
Finally, another of the most common methylxanthines present in
some agri-food samples like cacao or chocolate is theobromine. In [59],
was described the development of a method for the determination of this
alkaloid using a nanohybrid of MWCNTs and CMC sensor by direct CV in
coffee, tea and chocolate by just boiling and dilution. In addition, the
selectivity of the sensor by measurement of theobromine in presence of
elevated concentrations of some amino acids, organic acids, vitamins,
saccharides, and ions, shows that all these species did not modify the
signal of theobromine in more than 4,5%. This sensor was applied to
determine theobromine in water extracted from different food samples
(coffee, chocolate, and tea) obtaining good results. linear ranges be­
tween 0.5 and 80 µmol/L, a limit of detection of 0.21 µmol/L and well
recoveries values (93,5–109,7%).
In addition, sensors have also been developed to analyse other al­
kaloids in agri-food samples, such glycoalkaloids in potatoes [43],
capsaicin in peppers [47] or tropane alkaloids like scopolamine in tea
and herbal infusions [120] and atropine in beef and cereal samples
[123].
A methodology for the determination of glycoalkaloids in potatoes
using MWCNTs grafted with phenylboronic acid (PBA) immobilized
GCE was described by Wang et al. [43]. For this, the sample, previously
washed and peeled, was ground to collect the resulting liquid. From this,
analytes (solanine and chaconine) were extracted with methanol:formic
acid 1:1 (v/v) and the resultant solution were homogenized by ultra­
sound at 10 kHz for 1 h. Finally, it is centrifuged at 10.000 rpm for 10
min and filtered through a membrane filter before analysis. Five potato
samples were analyzed to obtain a concentration of solanine in all
samples in a range from 4.54 to 6.98 μmol/L. Finally, the results ob­
tained with this sensor were compared with another HPLC methodology,
showing satisfactory results with a relative error between both meth­
odologies of 3.25 %.
Kachoosangi et al. [47] developed an interesting application of these
devices for capsaicin determination in commercial pepper spicy sauces
and chilli peppers. This sensor consists of an SPE modified with
MWCNTs. The electroanalytical measurement was carried out through
stripping voltammetry, applying one minute of open potential accu­
mulation, and recording its adsorptive stripping voltammogram at 0.1 V
s− 1. The sensor developed shows a linear range between 0.5 and 35
μmol/L and a detection limit of 0.45 μmol/L for capsaicin. The method
was successfully applied for the determination of capsaicin in six com­
mercial hot pepper sauces with a very simpler sample treatment. For the
capsaicin, the sample treatment consisted of a simple dilution of an
aliquot of sample in ethanol, sonicated for 10 min, stirred magnetically
for 2 h, and centrifugated to discard solid material. After aliquots of 50
μL of standard solution with increasing concentrations of capsaicin were
dropped onto the surface of the electrode and the cyclic voltammetry of
capsaicin was recorded directly. The results obtained were highly
satisfactory and agreed with those obtained with a confirmative HPLC
method.
5. Conclusion, challenges, and future perspective.
This review has provided an overview of recent advances in the
design of electrochemical sensors, which are strengthened by the unique
physicochemical and electrochemical properties of nanomaterials,
16
Microchemical Journal 184 (2023) 108136
leading to improved development of advanced applications for the
analysis of alkaloids in real samples. Table 2 provides a comparative
study of the linearity range and detection limit of modified electrodes
with several nanomaterials for alkaloid sensing. In the last years, most of
the work was focused on synthezising new functional materials that
greatly enhance over-potential reduction, sensitivity, selectivity, and
stability. Of these functional nanomaterials, carbon-based nano­
materials, metal nanoparticles, ordered mesoporous silica materials,
polymers and their combinate composites have been extensively
employed as electrode modifiers to develop sensing interfaces. As the
review has shown carbon nanomaterials have been more investigated
compared to other nanomaterials. This is probably due to their great
properties, such as high surface area, electrochemical stability and
excellent electrical conductivity. In addition, the carbon nanomaterials
such as CNTs can efficiently promote electron-transfer reactions. Sig­
nificant advances have been achieved in the controlled size and
morphology of nanomaterials for the development of electrochemical
sensors. The nanoscale materials are being designed in nanoflowers,
nanowires, nanorods, nanofibers, etc., which can improve the properties
of the electrochemical sensors. On the other hand, the combination of
different advanced nanomaterials can allow the design of a tailor-made
sensor. So, great results have been achieved by integrating carbon-based
nanomaterials with metal nanoparticles, quantum dots or conductive
polymers to achieve synergetic effects to enhance catalytic reactions
with target analytes. As shown above, also the use of metal and metal
oxide nanoparticles as chemical modifiers has been another strategy to
improve sensor sensitivity. Thanks to their surface area, high conduc­
tivity and electrocatalysis characteristics, they have been widely used to
improve detection limits in electrochemical studies. However, this field
of research needs to be further developed to address the main obstacles
in this area of research, which are (i) controlled synthesis (in terms of
size, shape and surface area), (ii) the understanding of the relationships
between the structure, composition and reactivity of nanomaterials, (iii)
the development of new functional nanometric interfaces, and (iv) the
eco-degradability of nanomaterials.
As noted above, at certain levels, alkaloids can cause multiple serious
adverse effects, such as anxiety, restlessness, diarrhoea, nausea, palpi­
tations, hallucinations, and convulsions, and some are even associated
with genotoxic and carcinogenic effects. This is probably the reason why
multiple nanomaterial-based sensors have been developed to date for
monitoring alkaloids in pharmacological and biological samples. How­
ever, only a few electroanalytical devices are designed for the deter­
mination of alkaloids in agri-food samples. Most of the sensors described
have proven useful for the determination of alkaloids in food samples,
with caffeine being the most analyzed alkaloid due to its presence in
many beverages such as teas, coffee, cola, and energy drinks. In most
cases, the results were comparable to those obtained with HPLC-MS
reference methods, but with a great saving of time and effort in the
sample pre-treatment, as well as a large volume of solvents which has a
great advantage over conventional techniques and conforms to the
principles of green chemistry.
Electrochemical sensors based on nanomaterials could be excellent
devices for health and food safety monitoring, as detection platforms can
be adapted to point-of-care testing. Point-of-care testing offers many
advantages, such as simplicity, speed of detection, reliability of results
and sensitivity. As shown throughout the review, electrochemical sen­
sors based on nanomaterials have shown great potential and perfor­
mance for the detection of alkaloids, however, there is still a great need
for more powerful sensors for alkaloids in the future. This demand can
be met by focusing on the development of (i) a single sensor platform for
the detection of multiple important alkaloids, (ii) robust sensors that can
be used under all experimental conditions, (iii) highly selective sensors
for alkaloids, and in particular (iv) portable/miniaturised sensors for
alkaloids.
J. Gañán et al.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Data availability
No data was used for the research described in the article.
Acknowledgments
Authors thank financial support to MCIU/AEI/FEDER, UE for
RTI2018-094558-B-I00, EVALKALIM project and to the Comunidad of
Madrid and European funding from FSE and FEDER programs for
financial support for S2018/BAA-4393, AVANSECAL-II-CM project.
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