Antidepressants has many biological applications such as the use

Antidepressants drugs are widely used for the treatment of
psychiatric disorders and therefore their monitoring in biological fluids is
important considering that they need to be accurately monitored. Several
conventional techniques such as adsorption, electrochemical, chemical, and
biological methods have been developed for separation and extraction of
antidepressants, however they have several limitations such as requirement of
post-treatment, less efficiency, and high installation costs. Nanotechnology
has observed tremendous growth in the past and has many biological applications
such as the use of nanomaterials for antitumor, antibacterial, biosensors, and in
medicine. Recently, nanotechnology has emerged as an excellent alternative for extraction
of antidepressants over conventional techniques. Nanomaterials due to their
small size have large surface area and thus have high reactivity which, enables
them to be used as adsorbents. This review focuses on the use of different
nanomaterials especially nanoparticles, nanotubes, nanofibers, nanoshells, nanocomposites,
nanorods and polymer-based nanosorbents for antidepressants extraction from
biological species. The limitations of using such nanomaterials for extraction
of antidepressants and possible techniques to overcome these limitations have
been discussed as well.




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Over the last decade, major depressive disorder (MDD) is the
leading cause of sadness and/or a loss of interest in activities once enjoyed.
It is estimated by The World Health Organization (WHO) to affect 350 million
people globally, and hence has a huge impact on both the affected individuals
and the society 1,2. Pharmaceutical
development and production is a major issue with several consequences on life
on earth. Especially in research and development as well as in all aspects of
the strongly growing biopharmaceutical sector 3,4. There is now increasing
mobility and availability of drugs monitoring. Apart from this,
antidepressants, an
increase in antidepressant drug consumption has occurred and consequently,
treatments with antidepressants need to be accurately monitored 5–7. The clinical
monitoring to ensure patient’s adherence to antidepressants therapy and/or to
individualize the dosage regimens is highly recommended 8–10. So, the
antidepressants drugs have several adverse effects on the patient’s body (Figure
1).The main classifications of antidepressants are the selective serotonin reuptake
inhibitors (SSRIs) (e.g. fluoxetine and citalopram), serotonin-norepinephrine reuptake
inhibitors (SNRIs) (e.g. venlafaxine and duloxetine), tricyclic antidepressants
(TCAs) (e.g. imipramine and desipramine), monoamine oxidase inhibitors (MAOIs)
(e.g. tranylcypromine and phenelzine), reversible inhibitors of monoamine
oxidase A (RIMAs) (e.g. moclobemide and toloxatone), tetracyclic
antidepressants (TeCAs) (e.g. mirtazapine and setiptiline), and noradrenergic
and specific serotonergic antidepressant (NaSSAs) (e.g. aptazapine and
mianserin) 11. 

Antidepressants concentrations in biological fluids above acceptable limit, as
given in international standards, in various biological species such as blood,
serum, urine, saliva and human milk is a major medical concern all over the
world. For these drugs,
distinct ranges of optimum plasma concentration for therapy are required
(100–300 g L?1 for most of the TCAs) 12. In clinical practice,
conventional monitoring is usually based on biological sampling methods using
different approaches for sample treatments, such as liquid-liquid
microextraction (LLME) 13,14, solid phase
extraction (SPE) 15,16, magnetic solid
phase extraction (MSPE) 17, stir bar sorptive
extraction (SBSE) 18, pressurized
liquid extraction (PLE) 19 or
microwave-assisted extraction (MAE) 20.

With regard to the quantitative analysis of the selected drugs,
these have been quantified in different biological matrices using several
techniques  such as thin-layer
chromatography (TLC) 21, gas
chromatography-mass spectrometry (GC-MS) 22, liquid
chromatography using UV diode array (LC-DAD) 23, fluorescence 24, chemiluminescence
25, electrochemical
detection (ECD) 26, gas
chromatography-flame ionization detection (GC-FID) 27 and liquid
chromatography-mass spectrometry (LC-MS) 28. However, these
techniques have several limitations. Conventional extraction techniques require
proper selection of the sorbent such that it is robust and can work under
variable conditions. Estimation of the extraction efficiency, reusability, and
disposal of the sorbents with antidepressants are also some of the major
issues.  Also, installation of such
techniques can be difficult and expensive. Nanotechnology can serve as an
alternative for these conventional techniques.

Nanotechnology is field conducted at the nanoscale objects
(10-9 m), which is about 1 to 100 nanometer (nm). The prefix “nano” is a key to open many
“doors” 29. It has various
applications in medicine, electronics, food, cosmetic industries, space, solar
cell and water treatment. The nanomaterials have excellent thermal, mechanical,
optical, structural, and morphological properties which enable them to be used
in different applications.

In this review, antidepressants extraction using nanotechnology
has been discussed. It is a comprehensive compilation of papers that have used nanotechnology
for antidepressants extraction in biological species. They have been accessed
through ScienceDirect, Google Scholar and other. The criteria for the selection
of the papers was such that they reported the use of different nanomaterial,
either with or without modification, for the antidepressants extraction in biological
species. The nanomaterial used for antidepressants extraction possessed
different extracting and adsorbing capabilities for antidepressants. This
review is novel and such kind of work, which only focuses on the use of nanotechnology
for antidepressants extraction in biological species has not been reported

Mechanisms of
antidepressants extraction

The mechanism of action of these drugs work by increasing levels
of a set of chemical substances within the brain called neurotransmitters. Some
neurotransmitters, including serotonin and noradrenaline, can improve mood and
emotion, although this process isn’t always fully understood 30–32.

Nanomaterials, due to their small surface area have high
catalytic properties. The common mechanism in antidepressants extraction is
adsorption. In adsorption method, antidepressant molecule is attached on the
surface either through chemisorption
or physisorption. Nanomaterials that have excellent adsorption
properties possess two main properties: their innate surface area and external
functionalization 33. High surface
area, adsorption activity, location of atoms on surface, lack of internal
diffusion resistance, and high surface binding energy are also some of the factors
that determine the adsorption capability of the nanomaterial 34,35. The adsorption capability of a
nanomaterial is found through different isotherm and kinetic models. Table 1
shows the different nanomaterials used for antidepressants extraction, along
with the isotherm and kinetic models used. The nanomaterials that have
been used for antidepressants extraction are nanoparticles, nanotubes,
nanofibers, nanoshells, nanocomposites, nanorods and polymer-based nanosorbents
(Figure 2). The adsorption efficiency may vary with each nanomaterial. Figure 3
shows the extraction mechanism of antidepressants through different


for antidepressants extraction

Nanomaterials used till date for extraction of antidepressants
are nanoparticles, nanotubes, nanofibers, nanoshells, nanocomposites, nanorods
and polymer-based nanosorbents. Figure 4 gives a classification of the
nanomaterials used for antidepressants extraction. Table 1 shows the different
nanomaterials used for antidepressants extraction along with parameters such as
extraction, linear range, LOD, pH, instrumentation, analysis time and antidepressants
extraction recovery.



Nanoparticles are in the range of 1–100 nm and can be metallic,
semiconductor, or polymeric. They have various biological applications such as in
medicine, electronics, food, cosmetic industries, space, solar cell and water
treatment. They can effectively extract a wide variety of drugs as well 36. They can be used as
adsorbents for various drugs in biological species. Due to their small size,
large surface area and excellent catalytic activity, nanoparticles are emerging
as an alternative to conventional treatments for extraction of antidepressants
from biological species.





Nanotubes are one dimensional nanostructures with a hollow cylindrical
tubes. Carbon nanotubes (CNTs) have been widely used in pharmacy and medicine
due to their variable chemical, physical, electrical, and structural
properties. They can be used as adsorbents for extraction of drugs 37.

Their interesting properties as adsorbents are the high surface
area, high ability for ?-? interactions, relatively lower price, wider
accessibility, and easy functionalization 38. CNTs due to their
high adsorption rates and efficiency, have been commonly used as adsorbents for
extraction of antidepressants, and other types of drugs 37. These advantages
have made CNTs one of the most used sorbents in the recent years 39–41. However, the
surface of CNTs is highly hydrophobic and requires surface modification. With
surface modification, CNTs can be very efficiently used for extraction of

In one such case, combined use of CNTs and ionic liquid to
improve the determination of nine antidepressants in urine samples. Multiwall
carbon nanotubes (MWCNTs) used as novel SPE sorbent for antidepressants
(imipramine, desipramine, amitryptiline, nortryptiline, clomipramine,
trimipramine, trazodone, fluoxetine, and mianserine) preconcentration in urine samples
has been developed. In addition, the use of an ionic liquid as silanol
suppressor additive is proposed to improve the chromatographic behavior of the
antidepressants, avoiding band tailing of chromatographic peaks. The target antidepressants
were then monitored by HPLC-UV. The study showed extraction recoveries of 72.4-97%
for extraction of target antidepressants from urine. The LODs were determined
to be in range 12.3-90.1 ng mL-1. Overall, the results that the
developed method is an effective, useful extraction for the determination of
nine antidepressants in urine samples 42.


Magnetic adsorption techniques are widely employed for extraction
of antidepressants from biological species 43,44. Magnetic
multi-walled carbon nanotubes (MMWCNTs) thus can be easily used as a cleaner
alternative for antidepressants extraction 42. The magnetic
nature of the nanotubes enables them to be easily separated magnetically, thus interesting
properties as sorbents. Magnetic CNTs have been synthesized through chemical
deposition of Fe3O4 on the CNTs surface.


Here, CNTs were modified with magnetic nanoparticles, and 1,4
diazabicyclo2.2.2octane (DABCO). The resulting material is shown to be a selective
sorbent for the determination and extraction of four types of antidepressants (citalopram,
sertraline, fluvoxamine and fluoxetine) in human plasma samples with
ultrasound-assisted magnetic solid phase extraction (UA-MSPE). The selected
antidepressants were quantified by HPLC-UV instrument. The linear dynamic range
and LOD are 1–1000 ng mL?1 and 0.2– 0.5 ng mL?1,
respectively. The method was applied to the determination and extraction of the
selected antidepressants in plasma samples and gave recoveries of >91% DOI:

CNTs also have high mechanical strength, large surface area,
high aspect ratios and excellent electrical properties 45,46. Due to this, they
can be used as electrodes 47–49. For example, The
MWCNT-modified glassy carbon electrode (MWCNT/GCE) was constructed and the
electrochemical behavior of trazodone was investigated. The GCE electrode was
coated by casting 15 µL of the black suspension of MWCNTs and dried in air. The
electroactive areas of the MWCNT/GCE and the bare GCE were obtained by cyclic
voltammetry (CV) using 1.0 mM of K3Fe(CN)6. The MWCNT/GCE
showed much better performance than the bare GCE (without MWCNT). The
analytical performance of MWCNT/GCE has been evaluated for detection of trazodone
in urine as a real sample. Under optimized conditions, the concentration range
and LOD are 0.2–10 µM and 24 nM, respectively for trazodone. The recovery
determined was in the range of 99.15–103.2% for detection of trazodone from
urine samples 49.

Practically, CNTs are the most widely used nanotube for extraction
of antidepressants. However further insights on antidepressants
extraction using other nanotubes can been gained through molecular dynamic
simulations. A study had run molecular dynamic simulations technique using
boron nitride and silicon carbide (SiC) nanotubes to study the effect of these nanotubes
on antidepressants extraction. In the case of armchair boron nitride nanotubes,
the entry or non-entry of water and nitrate was studied for 6 types of boron
nitride nanotubes. The (4,4) boron nitride nanotubes didn’t allow any water or
nitrate to pass through due to its small diameter. Water passed through (5,5)
and (6,6) but nitrate ions could not pass through. In larger nanotubes, (7,7),
(8,8), (9,9) both nitrate and water molecules easily passed through. This
simulation study showed the optimal size of nanotubes that could be used for
nitrate removal from water 78. In a separate study, (7,7), and (8,8) silicon
carbide nanotubes were immobilized in a silicon nitride membrane and immersed in
a sodium nitrate solution. Along the Z axis, electric field was applied and ion
current, retention time of ions, radial distribution function of water nanotube
and nitrate containing water and autocorrelation function of hydrogen bond was
calculated as well. It was found that nitrate ions passed most successfully through
the (8,8) silicon carbide nanotube 79.K2 



Nanofibers have diameter less than 100 nm and have been used in
various medical applications. They are safe due to their extremely long length,
and can easily be incorporated onto any media or support. They also have high
surface-to-volume ratio, adjustable functionality, and large porosity. Due to
these properties, they have been used in filtration of particulates, airborne
nanoscale particles, and other 50.

Polymer nanofibers have been widely used for extraction of
antidepressants. In one study, polymer nanofibers had been utilized to prepare
electrospun polystyrene nanofibers and these nanofibers were used as a SPE
sorbent to directly extract trazodone from human plasma. SPE has been widely
used for its high selectivity and good reproducibility in sample preparation of
biological matrixes. These electrospun polystyrene nanofibers were utilized in
the treatment of human plasma for the extraction of antidepressants. The target
compound was then monitored by HPLC-UV, the study showed extraction recoveries
of 58.3-75.2% and the relative recoveries of 94.6-105.5% for extraction of
trazodone from human plasma. The linear response for trazodone over the range
of 20-2000 ng mL-1 and the LOD was determined to be 8.0 ng mL-1.
Overall, the results that the developed electrospun polystyrene nanofibers and
the analysis procedure is an effective extraction method in pharmaceutical
analysis of trazodone from human plasma. It provides a number of advantages in
simplifying sample preparation and reducing the cost and time of the analysis
with acceptable reliability, selectivity, and sensitivity 51.

Hollow fiber-based liquid phase microextraction (HF-LPME) was
applied for the extraction and preconcentration of three antidepressant drugs
including amitriptyline, imipramine and sertraline in the biological samples.
The antidepressants adsorption experiments were carried out using an accurel
Q3/2 polypropylene hollow fiber membrane (Wuppertal, Germany) with a 0.2µm pore
size, 600µm internal diameter and 200µm wall thickness have been used as
adsorbent for antidepressants extraction. The target drugs were then monitored
by HPLC-UV, the calibration curves were obtained in the range of 5-500 µg L-1
and the LODs ranged between 0.5 and 0.7 µg L-1. The study showed extraction
recoveries of 65-68%. Overall, the study exhibited the excellent performance of
the HF-LPME technique for the extraction of antidepressant drugs from
biological samples prior to HPLC analysis 52.



Nanoshells are made of a dielectric core and are covered by a
thin metallic film. The core-shell nanoparticles of the type [email protected]@N-cetylpyridinium
have been used for MSPE of amitriptyline and nortriptyline. [email protected]
cores were used to immobilize the N-cetylpyridinium through adsorption of
amitriptyline and nortriptyline from plasma samples. The study showed antidepressants
extraction relative recoveries in the range from 89 to 105 %. The detection
limits are 0.04 and 0.08 ng mL-1. Overall, the MSPE method exhibited
selective and efficient and preconcentration of tricyclic antidepressant amine
containing groups’ drugs using core-shell nanoparticles of the type [email protected]@N-cetylpyridinium



Nanocomposites such as polymer 54,55, graphene based 56,57, and magnetic
polymer 58,59 have been widely
used in medical applications such as in for the extraction of drugs.
Nanocomposites consist of a combination of nanomaterials, which enhance its
overall antidepressants adsorbing capability. In one such case, a sensitive
MSPE method based on Fe3O4–MgSiO3 magnetic
nanocomposites was developed for extraction of some antidepressants drugs (venlafaxine,
escitalopram, paroxetine, sertraline and fluoxetine) in serum and urine samples
by using LC-UV. The LOD and LOQ for the target antidepressant were found to be
in the range of 1.73–2.83 and 5.21–8.53 ng mL-1, respectively. The
obtained recoveries in the range of 72–115 % with RSD < 4.75%. Overall, this material (Fe3O4–MgSiO3) has been employed as an SPE adsorbent for separating and extracting trace amounts of antidepressant drugs from serum and urine samples 60. 3.6.         Nanorods Nanorods are morphology of nanoscale objects (10-9 m), in the range of 1–100 nm. They may be synthesized from metals such as gold 61, silver 62 or semiconducting materials 63. Nanorods are synthesized by using direct chemical synthesis. In one such case, SnO2 nanorods with SPME method was developed for determination of some types of SSRIs drugs (citalopram and fluoxetine) in human urine and plasma samples coupled with HPLC instrument. The reproducibility for the extraction (RSD < 10%) was obtained. The calibration curve was obtained in the range of 1–500000 ng mL-1 with LOD in the range of 0.2–0.5 ng mL?1 for citalopram and fluoxetine. The obtained recoveries in the range of 79–94 %. Overall, SnO2 nanorods were successfully used as sorbent on SPME for determination and extraction of fluoxetine and citalopram in human plasma and urine samples and determined by HPLC 64.   3.7.         Polymer-based nanosorbents Polymer-based nanosorbents such as organic polymers 65,66, inorganic and hybrid polymers 67,68, and molecularly imprinted polymers (MIPs) 69,70 have been widely used in medical applications such as, for the extraction of drugs 71. In one such case, a selective and sensitive molecular-imprinted polymer based on magnetic chitosan/graphene oxide method was developed for determination of fluoxetine in water, pharmaceutical formulation and urine samples. The target compound was then monitored by spectrophotometry. The method exhibited a linear range of 0.8–10 µg L-1 with LOD of 0.03 µg L-1. The achieved recoveries are satisfactory (95.7–104 %). Overall, a novel method based on imprinted polymer was synthesized using magnetic chitosan/graphene oxide. The developed method was applied to determine fluoxetine drug in various samples 72. Another selective method was developed for determination and extraction of amitriptyline drug from water and plasma samples using nano-sized molecularly imprinted polymer (MIP) with ultrasound-assisted extraction (UAE). A linear range of 20–200 µg mL-1 with LOD in the range of 0.7–1.2 µg mL-1. The relative recovery in the range of 82.4–92.3%. Overall, the developed method (nano-sized MIP with UAE) was applied to determine amitriptyline drug in water and plasma samples 73.   4.    Future perspectives Most of the studies have been performed at a laboratory without using green synthetic materials, therefore, newer methods need to be developed for using green synthetic materials and methods such as, supercritical carbon dioxide (scCO2) process for the preparation of the nanomaterials may be further developed and encouraged. Naturally occurring nanomaterial such as halloysite nanotubes, which are clay based nanomaterials can be used for antidepressants extraction from biological species 74–76. They are highly suitable for biological applications as they are eco-friendly, cheap, and possess great extraction capacity along with excellent tunable surface chemistry 77–79. Such properties also enable them to be excellent adsorbents for antidepressants.   5.    Conclusion Antidepressants drugs are widely used for the treatment of psychiatric disorders and therefore their monitoring in biological species is important considering that they need to be accurately monitored. Antidepressants extraction does not occur through common processes for biological species. Conventional techniques used for Antidepressants extraction include adsorption, and other biological and chemical techniques. However, these techniques have several limitations. Nanotechnology is a suitable alternative to extract the antidepressants over the conventional techniques, as it is a cleaner and energy efficient method. Nanomaterials such as nanoparticles, nanotubes, nanofibers, nanoshells, nanocomposites, nanorods and polymer-based nanosorbents have been used for antidepressants extraction. Many advantages associated with these materials are high surface area, easy synthetic routes, high catalytic activity, and good optical, electrical and mechanical properties. The nanomaterials have either been used as sorbents due to their large surface areas. The nanoparticles were used without any modification, or immobilized on a support. Efficient antidepressants extraction rates have been achieved using these nanomaterials at differing modification, extraction type, biological species, linear range, LOD, instrumentation and extraction recovery. The concentration of antidepressants extracted have been determined through different techniques such as, spectrophotometry, and chromatography techniques. Antidepressants extraction recoveries as high as 100% have been achieved using different nanomaterials. However, these nanomaterials have several limitations such as toxicity and particle agglomeration. The nanomaterials may also become unstable at varying conditions. Use of novel and eco-friendly materials such as nanotubes and its composites for antidepressants extraction may lead to an improvement in antidepressants extraction efficiency. With development of further techniques that overcome the limitations of nanomaterials may become the silver bullet needed for efficient antidepressants extraction from biological species.  K1Add more data here.  K2Look for another nanotubes used for extraction of AD. Instead of CNTs.