CLONAZEPAM

ABSTRACT
The usage of drug-based compounds to prevent mild steel corrosion has considerably
increased in recent years. Regarding other drug-based substances used as potential anti-
corrosion agents clonazepam distinguishes out. This work uses diminished weight,
thermometry, and electronic impedance spectroscopy to evaluate both the experimental and
statistical features of the pharmacological molecule clonazepam as a mild steel corrosion
inhibitor in chloride solution , surface image processing, molecular dynamical simulations,
density functional theory, and potentiodynamics polarisation.The results show that the efficacy
of inhibition increases with increasing clonazepam drug concentration, peaking at 90.1% for
weight loss, 89.2% for thermometric studies, 91.4% for the technique of electrochemical
impedance spectroscopy, and 85.1% for (potentiodynamics polarisation) methods at 500 ppm.
The potentiodynamic polarisation method has shown that the medication clonaze-
pam acts as a mixed-type corrosion inhibitor. The Langmuir adsorption isotherm was followed
during the clonazepam medication adsorption.The surface characterisation experiments using
SEM and AFM demonstrate that the mild steel surface has barrier layers surrounding it. For the
form with no charge and hydrogenated forms, the energy of the highest occupied molecular
orbital (EHOMO), the energy of the lowest unoccupied molecular orbital (ELUMO), the energy
gap (E), chemical toughness, softness, polarity moment, and electron emission were all
assessed. The results of the molecular dynamic simulations showed that the Fe surface had an
almost flat adsorbed direction.

INTRODUCTION
A benzodiazepine medication called clonazepam is used to treat non-convulsive epileptic
seizures, epilepsy, and anxiety disorders acutely. In addition, it has a wide range of off-label
uses, including restless legs syndrome, acute mania, insomnia, and tardive dyskinesia. In order
to help members of the collaboration of professionals treating those suffering from panic and
seizure disorders, this activity will emphasise the indications, mode of action, administration,
negative side effect profile, contraindications, tracking, and toxicity of clonazepam in clinical
contexts.
A benzodiazepine with a lengthy half-life and strong potency is clonazepam. It has GABA-A
receptor agonist properties. By boosting serotonin production, it also has serotonergic effects.[1]
Anxiolytic and anticonvulsant properties describe clonazepam. It has FDA approval for the
treatment of panic and seizure disorders.[2][3] In addition, it is used off-label to treat
schizophrenia, restless legs syndrome, insomnia, tardive dyskinesia, and REM sleep behaviour
disorder as a monotherapy or adjuvant
therapy.[4]
The usage of inexpensive and environmentally benign organic corrosion inhibitors with
heteroatoms like N, S, and O has recently increased concerns in the global economy. When
corrosion inhibitors and meta2surface come into contact with each other more frequently
through an electron substitution, heteroatoms that are found in organic chemicals serve as the
centre for adsorption [5]
The efficacy of inhibitors to prevent corrosion is enhanced by the existence of vanderWaals
force. Over the years, a variety of organic corrosion inhibitors have been utilised, including
imidazoline, amide, amines, acetylenic alcohols, dimeric and trimeric acids, the quaternary
amines, and surfactants. However, these compounds have a number of drawbacks, such as
high costs and a difficult synthesis process [6].

.
Fig.1 Structure of Clonazepam

The development of innovative, more affordable, and environmentally friendly corrosion

inhibitors to replace conventional or existing inhibitors has recently been the subject of research
[7].The usage of amino acids, natural extracts, carb polymers, ionising liquids, pharmaceutical
medicines, and MOF-based anti-corrosion agents are among the best and safest solutions to
these problems [8]. The ability to develop drug-based anticorrosion agents on a large scale and
lower the prevalence of expired medications in society are their main advantages [9].
Drug molecules are also biodegradable and created to dissolve effortlessly in the watery
environs of the human body because they are made for human ingestion [10].certain
characteristics essentially ensure that certain medications, such as cefixime , cefadroxil ,
cefpodoxime , nicotinic acid and nicotinamide , thiamine hydrochloride , sulfamethoxazole , and
tro- bramycin , can be used as possible corrosion inhibitors. To the best of our knowledge,
however, clonazepam (CLONA) hasn't been utilised for any type of metal shielding.
Fig. 2 depicts the chemical composition, molecular formula, and molar weight.
 Fig.2 Molecular structure of clonazepam drug , Molecular formula=C15ClH10N3O3 ,
Molar mass = 315.711 g/mol.
The pharmaceutical medicine clonazepam is non-harmful, reasonably priced, and ecologically
friendly. It is frequently used to treat seizures, panic disorder, anxiety, and the movement
disorder akathisia. It belongs to the benzodiazepine class of tranquillizers. Heteratoms of
nitrogen and oxygen make up the substance. The p electrons of aromatic rings and the lone
electron pair of nitrogen and oxygen heteroatoms in clonazepam significantly increase the
adsorption of inhibitory molecules on the steel's mild interface in sodium chloride the solution
[11]. Adsorption of a substance that inhibits on the outermost layer of metal depends on the
properties of the metal's outermost layer, the adsorption process, the electro-chemical potential
at the interface, and the characteristics of the surrounding atmosphere [12].
This study's objective is to use weight loss, thermometric, and electrophysiological
measures to examine how well the drug clonazepam (CLONA) inhibits mild steel corrosion in
3.5 weight percent solution of sodium chloride (NaCl). The steel's coating of protection layer
was evaluated using scanning electron microscopy (SEM). Clonazepam (CLONA) drug's ability
to suppress rust on the outermost layer of steel is better understood thanks to studies in the
fields of density functional theory and molecule dynamical modelling.

References
[1].Chouinard G, Labonte A, Fontaine R, Annable L. New concepts in benzodiazepine therapy
rebound anxiety and new indications for the more potent benzodiazepines. Prog
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antipsychotic and anticonvulsant drugs. J Psychiatry Neurosci. 2006 May;31(3):168-76
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Affect Disord. 2004 Mar;78(3):2018
[5] M. Zunita, Y.J. Kevin, Ionic liquids as corrosion inhibitor: from research and
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Corrosion inhibition of A36 mild steel in 0.5 M acid medium using waste citrus
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Inhibitors: Sustainable Corrosion Inhibitors II: Synthesis, Design, and Practical
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[12] F.E. Abeng, V.C. Anadebe, V.D. Idim, M.M. Edim, Anti-corrosion behaviour of
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(2020) 125–130.

RECENT ADVANCEMENT OF CLONAZEPAM

Now a days clonazepam is used in treatment of various disorders and diseases like in Panic
disorder , Acute mania , seizures disorder etc.

Seizure disorder
The extensive variety of actions of clonazepam against various seizure diseases. The
management of acute epilepsy and the treatment of acute non-convulsive epileptic disorder
(complex partial seizures or absence seizures) are its main indications. Additionally, it works
well for reducing childhood small motor seizures, including petit mal absences, Lennox-Gastaut
syndrome, and infantile spasm.[13] Additionally effective in treating psychomotor, myoclonic,
grand mal, and focal motor seizures is clonazepam. It is not, however, the first-line treatment for
these ailments. Patients who are resistant to conventional treatment can utilise it.
Fig.3 Chemical and Molecular structure of Clonazepam

Panic disorder
Individuals with panic disorders, whether or not they also have agoraphobia, experience a
considerable improvement after taking clonazepam. Due to the possibility of experiencing
discontinuation symptoms and abuse, it is effective in the short-term management of panic
disorder. However, it is also less likely to cause rebounding anxiousness upon quitting than
other benzodiazepines because of its prolonged half-life. Specialists also use it for the acute
therapy of fear attacks.[14]

Acute Mania
Serotonin agonists and analgesic properties of clonazepam are linked to its antimanic action. As
a result, it can occasionally be useful in the management of acute mania. According to the
study, clonazepam was found to be much more effective than lithium at suppressing manic
symptoms. Fewer individuals also required haloperidol PRN therapy, and the amount of days
they required it decreased while taking clonazepam. In doing so, clonazepam lessens the
requirement for antipsychotic medications in the treatment of acute mania and lowers the
likelihood of side effects in these individuals.A benzodiazepine and the antipsychotic haloperidol
are currently thought to work best together to treat acute agitation in emergency rooms are
common.[15]

Miscellaneous uses
It is also used to treat akathisia , restless leg syndrome , rapid movement of the eye , bruxim ,
behaviour disorder etc.

References
[13]Pinder RM, Brogden RN, Speight TM, Avery GS. Clonazepam: a review of its
pharmacological properties and therapeutic efficacy in epilepsy. Drugs. 1976 Nov;12(5):321-61.
[14]Marchesi C. Pharmacological management of panic disorder. Neuropsychiatr Dis Treat.
2008 Feb;4(1):93-106.
[15]Garza-Treviño ES, Hollister LE, Overall JE, Alexander WF. Efficacy of combinations of
intramuscular antipsychotics and sedative-hypnotics for control of psychotic agitation. Am J
Psychiatry. 1989 Dec;146(12):1598-601.

PHYSIOCHEMICAL CHARACTERIZATION

Physical properties
● State - solid
● Appearance - white powder
● Melting point - 238-240degree celcius
● Solubility - 100mg/L at 25degree celcius, insoluble in water , slightly soluble in alcohol
● Molecular weight - 315.71
● Odour - faint odour
● Density - 1.4592 gm/ml

Chemical properties
● The hydrogens at positions 5 and 7 of the drug clonazepam are replaced with 2-
chlorophenyl and nitro groups, respectively.
● Clonazepam is 1,3-Dihydro-2H-1,4-benzodiazepin-2-one.
● All forms of epilepsy and seizures, myoclonus and related aberrant movements, panic
disorders, and epilepsy are all treated with it.
● Molecular formula=C15H10ClN3O3

A benzodiazepine derivative called clonazepam (CLZ) should benefit from cyclodextrin

complexation to increase its their bioavailability which is currently hindered by its extremely low
water miscibility. However, selecting the best cyclodextrin to utilise is an important step in
maximising its possible beneficial effects on the medicine. As a result, the efficacy of a few
unstructured cyclodextrin (CD) derivatives in terms of their ability to combination with, dissolve,
and amorphize CLZ was thoroughly assessed and compared to that of native CDs. The capacity
of the CD cavity to produce efficient interactions with the medication has been explored in
relation to its size, amorphous or crystalline nature, presence, and kind of substituted elements.
By mixing, kneading, co-grinding, and co-evaporation, equimolar CLZ-CD solid systems were
produced. Phase-solubility analysis, differential scanning calorimetry, and X-ray powder
diffractometry were used to examine drug-CD correlations.
The natural CD with the best complexing ability was -CD, indicating that the size of its
cavity is ideal for hosting a therapeutic molecule. The efficiency of -CD and -CD was negatively
impacted by the existence of substituents, although -CD's complexing and solubilizing power
was improved. The methylated derivative performed better than the hydroxypropylated one.[16]
Solid-state research showed that methylated - CD (Me-CD) was the best carrier and that
amorphous CDs had higher amorphizing power than the corresponding naturally crystalline
ones. Co-grinding was the most effective preparation technique for fostering the development of
effective drug-CD solid-state interactions. Me-CD was found to be the best companion for CLZ
in dissolving rate trials, and co-grinding was found to be the most effective way to maximise the
drug's dissolution qualities. Co-ground products with Me-CD may therefore be the ideal
approach for developing CLZ formulations in the future with increased therapeutic efficacy.

References
[16]Mennini Natascia , Bragagni Macro , Maestrelli Francesca Maestrelli , Mua Paola "Journal
of Pharmaceutical and Biomedical Analysis " , volume 89 , 15 February 2014 , p 142-149

SAR OF CLONAZEPAM
● The amide moiety's nitrogen atoms shouldn't be replaced.
● For effective schistosomicidal action, the carbonyl carbon atom of 1,4-benzodiazepines
should have low density of electrons.
● To bind with variants of 5-phenyl-1,4-benzodiazepin-2-one, Ring A should include an
aromatic or heteroaromatic ring.
● The functional anxiolytic effect of ring A is enhanced by an electronegative group at
position 7.
● The pharmacological action of the medication is poor if heterocycles are utilised as ring
A.
● Ring B must have a proton-accepting the group in order to bind to GABAA.
● Peak activity is shown when the proton receiving group is located on the 2-position of
ring B and is in coplanar spatial orientation with ring A.
● The preference for binding with GABA BZR subpopulations changes when the oxygen in
ring B is replaced with sulphur, but the anxiolytic characteristics are still present.
● The antagonist action reduces when the methylene 3-position or imine nitrogen of the
ring B is substituted, but the one acting as the agonist action is unaffected.
● The 3-hydroxy moiety-containing derivatives are quickly eliminated.
● The receptor occupancy and in vivo activity are decreased by structurally large
substituents on ring B, such as the tert-butyl group.
● Nitrogen in the 4-position and the 4,5-double bond are not necessary for anxiolytic
action.
 ● If a C-N bond is used in place of a C=N bond, BZR affinity is reduced.
● The 5-phenyl ring C is not required for BZR binding.
● The agonist action of the medication is decreased by substitution at the para location of
ring C.
● When a drug is substituted in the ortho location, there is no discernible difference in the
agonist characteristic of the drug.
● The affinity of the BZR increases when the 1,2-bond of the carbon ring is annealed with
a second electron-rich ring, such as the imidazole.[17]

MODE OF SYNTHESIS

Fig.4 Synthesis of Clonazepam

Steps--

i. Hydrogen over Raney nickel reduces to 2-chloro-2'nitrobenzophenone to 2-chloro-2'-

aminobenzophenone.

ii. Bromoacetamide is created by amidating the amino group of the previously produced
molecule with 2-bromoacetyl bromide.

iii.By reacting with ammonia, bromoacetamide is transformed into aminoacetamide.

iv. The above-mentioned chemical changed into 5-(2-chlorophenyl)-2,3-dihydro-1H-1,4-
benzodiazepine-2-one during interaction with pyridine.

v. After nitration, clonazepam is produced.[18]

MECHANISM OF ACTION

The GABA occupancy for the GABA receptors is increased by clonazepam. As a result, the
neuronal cell membrane allows influx of more chloride ions, which causes the neurons to
become hyperpolarized and get relaxed.Because of this, the neurons are less excited and have
a harder time firing action potentials.[19]

ADVERSE EFFECTS

Here are some Clonazepam side effects:

● Dizziness
● Drowsiness
● increased production of saliva
● inability to coordinate
● Tiredness
● Depression
● Mood shifts
● Suicidal ideas
● Allergic responses

Reference
[17][18][19] Vardanyan R, Hruby V. Synthesis of essential drugs. Elsevier; 2006 Mar 10.

PHARMACEUTICAL APPLICATION OF 1,4 BENZODIAZEPINES

Pharmacokinetics and drug interactions

Clonazepam is quickly absorbed following oral administration, and peak serum concentrations
are typically reached in 1 to 3 hours, occasionally beyond 9 hours. Average bioavailability
ranges from 80% to 90%. Approximately 82% of the serum's protein is bound. The body quickly
distributes clonazepam to many organs and tissues.For clonazepam, the connection between
dosages and levels in the blood varies greatly, just like it does for other medications that are
extensively metabolised. Clonazepam has a half-life of 20–60 h. Most of the time, clonazepam
is broken down into 7-aminoclonazepam and 7-acetamidoclonazepam through reduction and
acetylation, respectively.As with diazepam, the metabolism follows first-order kinetics.
Additionally, hydroxymetabolites have been discovered.
 All of the metabolites don't seem to have any antiepileptic properties.
Unaltered clonazepam typically excretes less than 1% of the prescribed dose in urine, but the
aforementioned metabolites make up roughly 25% as free or conjugated molecules.As for
clonazepam, it can be stimulated by a number of AEDs, including phenytoin, phenobarbital,
primidone, and carbamazepine, leading to reduced serum concentrations and a diminished
clinical effect. It is not completely known how benzodiazepines affect the metabolism of other
AEDs. Phenytoin, phenobarbital, and carbamazepine serum concentrations don't appear to be
affected by clonazepam.[20]

References
[20]Landmark Johannessen Cecili ,Johannessen I Svein "in Handbook of Analytical
Separations"2020.

METABOLISM OF CLONAZEPAM

Fig.5 Metablism of Clomazepam

The liver's CYP3A4 and CYP3A4 enzymes metabolise clonazepam, which has an 86% affinity
for plasma proteins, mostly by reducing the nitro group to produce 7-amino clonazepam, which
is then changed into 7-acetamido clonazepam by N-acetyl transferase 2 (NAT2) .
The parent molecule and its metabolites undergo minor metabolic route hydroxylation at the C3
position to produce the matching 3-hydroxy metabolites (Tokola & Neuvonen, 1983; Tóth et al.,
2016).
Despite being known to be pharmacologically inactive, 7-amino clonazepam species had the
greatest concentration in plasma compared to the other metabolites.
However, a mouse in vivo investigation showed that the 7-amino metabolite could outcompete
the parent medication for benzodiazepine-binding sites, which resulted in a rapid loss of
clonazepam attachment to the GABA receptors when treatment ended (Munakata & Tsuchiya,
(2008)[21]

References
[21]Nikfarjam Zahra , Brown W Ronald , in "Benzodiazepine-based drug discovery 2022.

CONCLUSION
There was no evidence of neonatal toxicity or withdrawal syndromes in babies born to women
who took clonazepam during pregnancy, and clonazepam use did not appear to be causally
connected to any obstetric difficulties during pregnancy, labour, or delivery. A benzodiazepine
medication called clonazepam is used to treat non-convulsive status epilepticus, epilepsy, and
panic disorder acutely. In addition, it has a wide range of off-label uses, including restless legs
syndrome, acute mania, insomnia, and tardive dyskinesia. Stopping clonazepam suddenly can
worsen your condition and cause withdrawal symptoms that may last for several weeks to more
than 12 months. Do not take herbal remedies for anxiety or insomnia, such as valerian or
passionflower, with clonazepam. They can increase the drowsy effects of clonazepam and may
also have other side effects. In the present study the newly investigated clonazepam drug
compound as corrosion inhibitor was evaluated for it anticorrosion performance against mild
steel in 3.5 wt % NaCl solution and we concluded that.The mechanism of adsorption of
clonazepam on mild steel surface in 3.5 wt % NaCl obeyed Langmuir adsorption isotherm and
the values of free energy of adsorption ΔGads revealed that the adsorption mechanism of this
inhibitor is mainly dominated by physical adsorption .

References
[22]Abeng F.E. , Ita B.I , Anadebe V.C…..” Multidimensional insight into the corrosion mitigation
of clozapen drug molecule on mild steel in chloride environment:Empirical and computer
simulation explorations” , Results in Engineering , Volume 17 , March 2023 , 100924