Determination of Packaging Efficiency of Norflu (Fluphenazine-Nortriptyline) in Case of Normal Packaging

ABSTRACT
This research program was conducted for the determination of packaging efficiency of Norflu
(Fluphenazine-Nortriptyline) products. We have done this experiment in various conditions
(sunlight, dark, 25 watt & 40 watt bulb) exposure. It was observed that the concentration of
Fluphenazine hydrochloride was decreased 65.41%, 8.77%, 9.19% and 20.55% and Nortriptyline
hydrochloride was decreased 51.59%, 21.35%, 21.71%, and 3.03% for sunlight, dark, 25 watt
and 40 watt light exposure respectively. The results showed degradation of the sample. One
reason for this could be for transparent packaging. However, because of contradictory results the
reason could be other than packaging.
Keywords: Fluphenazine hydrochloride, Nortriptyline hydrochloride, Norflu, Batch, Potency.
Chapter One
INTRODUCTION
1.1 About antipsychotic medications

Antipsychotics (also known as neuroleptics or major tranquilizers) (Harvey et al., 2009) are a
class of psychiatric medication, which are helpful to people (in pediatric and adult populations)
with schizophrenia, schizoaffective disorder and some forms of manic depression (bipolar
disorder). They are able to reduce, or sometimes eliminate, the distressing and disabling
symptoms of psychosis, such as paranoia, confused thinking, delusions and hallucinations, so
that the person taking them feels better (Sane Australia, 2014a). They can also be used to help
severe anxiety or depression (Timms, 2014a).
These medications help with:
The experience of hearing voices (hallucinations).

Ideas that distress the patient and don't seem to be based in reality (delusions).
Difficulty in thinking clearly (thought disorder).
The extreme mood swings of manic depression/bipolar disorder.
Some can help with severe depression (Timms, 2014a).
People with schizophrenia and other psychotic illnesses often have an imbalance in certain
natural chemicals in the brain, especially dopamine. Antipsychotic medications help the brain to
restore its usual chemical balance and so reduce symptoms (Sane Australia, 2014a).
They dont change the patients personality. While the patient might notice changes in his/her
mood and the way he/she cope with stress, antipsychotics will not change the personality.
Antipsychotics can relieve the symptoms of psychosis-related disorders; they do not stop people
from feeling the normal ups and downs of life. People may find it easier to think more clearly
(Sane Australia, 2014).These medications can help to control symptoms, but they do not cure the
underlying condition (Centre for Addiction and Mental Health, 2009).
Antipsychotics, like many medications, change the way one feels. This means that if a person
stops taking the medication he/she may start to feel the way he/she did before the treatment.
However, antipsychotic medications are not addictive, and one will not become dependent on
them (one does not need to take higher and higher doses to get the same benefits) (Sane
Australia, 2014a).
While antipsychotic medications can help some people with psychosis and mood disorders, at the
same time these drugs can have serious side-effects. The aim of medication treatment is to
reduce and control symptoms while keeping side-effects at a minimum. Taking antipsychotic
medication is one important step in getting better but is rarely enough on its own. As well as
medication, effective treatment for schizophrenia and related disorders usually includes ongoing
clinical support in the community, psychological therapies, education about the illness and how
to deal with it, psychosocial rehabilitation, and accommodation and employment support (Sane
Australia, 2014a).
1.1.2 Types of antipsychotics

Antipsychotics are commonly categorized into two drug classes, first-generation antipsychotics
(FGAs) and second-generation antipsychotics (SGAs), marking two waves of historical
development. FGAs were developed in the 1950s. Although FGAs provide treatment for
psychotic symptoms, use of these drugs can result in extrapyramidal symptoms, which are
various movement disorders characterized by repetitive, involuntary muscle movements,
restlessness, or an inability to initiate movement. Other common side effects are dry mouth and
sedation. Neuroleptic malignant syndrome and tardive dyskinesia are rare but serious side
effects. SGAs emerged in the 1980s. They generally have lower risk of motor side effects, but are
associated with significant weight gain, lipid and prolactin elevation, and the development of
type 2 diabetes (Seida et al., 2012).
While both are effective, the atypical medications have advantages over the typical ones. These
advantages include:
fewer side-effects such as trembling or stiffening of muscles

less risk of developing tardive dyskinesia: movement of the mouth, tongue and
sometimes other parts of the body over which the person has no control
Some evidence suggests that the newer medications may be effective in improving
overall mood, thinking and motivation (Sane Australia, 2014a).
While the atypical antipsychotic medications are used more than the typical, some people find
that the typical medications suit them better (Sane Australia, 2014a).
Table 1: Food and Drug Administration-approved first-generation antipsychotics (Seida et

al., 2012)
Generic Name
Indications
Age Group for Which

Approved
Chlorpromazine
Schizophrenia
Bipolar disorder (mania)
Hyperactivity
Adults and children (112 years)
Severe behavioral problems

Droperidol
Fluphenazine
Haloperidol
Loxapine
Perphenazine
Pimozide
Prochlorperazine
Thiothixene
Thioridazine
Trifluoperazine
Agitation
Psychotic disorders
Schizophrenia
Tourette syndrome
Hyperactivity
Severe childhood behavioral problems
Schizophrenia
Schizophrenia
Tourette syndrome
Schizophrenia
Adults and children

Adults
Adults
Adults and children 12 years

Adults and children >2 years and
Generalized nonpsychotic anxiety

Schizophrenia
Schizophrenia
Schizophrenia
Generalized nonpsychotic anxiety
>20 pounds
Adults
Adults and children
Adults
Table 2: Food and Drug Administration-approved second-generation antipsychotics (Seida

et al., 2012)
Generic Name
Indications
Age Group for Which
Aripiprazole
Schizophrenia
Approved
Adults and adolescents (13
5
Generic Name
Indications
Age Group for Which
Bipolar disorder (manic/mixed)
Approved
17years)
Adults and children (1017 years)
monotherapy or adjunctive to lithium or

valproate
Adjunctive treatment of major
Adults
depressive disorder
Irritability associated with autistic
Children (617 years)
disorder
Acute treatment of agitation
Adults
Asenapine
Acute schizophrenia
Bipolar disorder type 1 (manic/mixed)
Adults
Clozapine
Treatment resistant schizophrenia

Reduce risk of suicidal behavior in
Adults
younger patients with schizophrenia

Acute schizophrenia
Adults
IIoperidone
Olanzapine
Paliperidone
Schizophrenia
Bipolar disorder (depressive episode)
Treatment-resistant depression
Agitation associated with schizophrenia
and bipolar I mania
Schizophrenia
Schizoaffective disorder
Schizophrenia
Quetiapine
Bipolar disorder (acute manic)

Bipolar disorder (depression)
Bipolar disorder (maintenance)

years)
Adults
Adults
years)
Adults, children and adolescents
(1017 years)
Adults
Major depressive disorder

Schizophrenia
Risperidone

years)
Adults, children and adolescents
(1017 years)
6
Generic Name
Indications
Age Group for Which

Approved
Irritability associated with autism
Children (516 years)
Schizophrenia
Ziprasidone
Bipolar disorder (maintenance)
Adults
Acute agitation in patients with

schizophrenia
1.1.3 Mechanism of action of antidepressants

All antipsychotic drugs tend to block D 2 receptors in the dopamine pathways of the brain. This
means that dopamine released in these pathways has less effect. Excess release of dopamine in
the mesolimbic pathway has been linked to psychotic experiences. Various neuroleptics such as
haloperidol and chlorpromazine suppress dopamine chemicals throughout its pathways, in order
for dopamine receptors to function normally (McDonald and Murphy, 2003).
In addition of the antagonistic effects of dopamine, antipsychotics (in particular atypical
neuroleptics) also antagonize 5-HT2A receptors. Different alleles of the 5-HT2A receptor have
been associated with schizophrenia and other psychoses, including depression. Higher
concentrations of 5-HT2A receptors in cortical and subcortical areas, in particular in the right
caudate nucleus have been historically recorded. This is the same receptor that psychedelic drugs
agonize to various degrees, which explains the correlation between psychedelic drugs and
schizophrenia (McDonald and Murphy, 2003; Schmidt et al., 1995).
Typical antipsychotics are not particularly selective and also block dopamine receptors in the
mesocortical pathway, tuberoinfundibular pathway, and the nigrostriatal pathway. Blocking
D2receptors in these other pathways is thought to produce some unwanted side effects that the
typical antipsychotics can produce. They were commonly classified on a spectrum of low
potency to high potency, where potency referred to the ability of the drug to bind to dopamine
receptors, and not to the effectiveness of the drug. High-potency antipsychotics such as
haloperidol, in general, have doses of a few milligrams and cause less sleepiness and calming
effects than low-potency antipsychotics such as chlorpromazine and thioridazine, which have
7
dosages of several hundred milligrams. The latter have a greater degree of anticholinergic and
antihistaminergic activity, which can counteract dopamine-related side-effects (Stahl, 2003).
Atypical antipsychotic drugs have a similar blocking effect on D2 receptors, however, most also
act on serotonin receptors, especially 5-HT2A and 5-HT2C receptors. Both clozapine and
quetiapine appear to bind just long enough to elicit antipsychotic effects but not long enough to
induce extrapyramidal side effects and prolactin hypersecretion. 5-HT 2A antagonism increases
dopaminergic activity in the nigrostriatal pathway, leading to a lowered extrapyramidal side
effect liability among the atypical antipsychotics (Stahl, 2003).
1.1.4 Dosage of antipsychotic medications

Some drugs are very potent and the doctor may prescribe a low dose. Other drugs are not as
potent and a higher dose may be prescribed (Mental Health Care, 2014).
Unlike some prescription drugs, which must be taken several times during the day, some
antipsychotic medications can be taken just once a day. In order to reduce daytime side effects
such as sleepiness, some medications can be taken at bedtime. Some antipsychotic medications
are available in "depot" forms that can be injected once or twice a month (Education Medicaid
Integrity Contractor, 2013).
1.1.5 Side-effects of antipsychotic medications (Mental Health Care, 2014)

The different antipsychotic medicines can have different types of side-effects. Also, sometimes
one medicine causes side-effects in some people and not in others. Therefore, it is not unusual to
try two or more different medicines before one is found that is best suited to an individual.
Common side-effects include:
Dry mouth, blurred vision, flushing and constipation. These may ease off when you get used
to the medicine.
Drowsiness (sedation), which is also common but may be an indication that the dose is too
high. A reduced dose may be an option.
Weight gain which some people develop. Weight gain may increase the risk of developing
diabetes and heart problems in the longer term. This appears to be a particular problem with
the atypical antipsychotics - notably, clozapine and olanzapine (ok and Gaebel, 2008).
Movement disorders which develop in some cases. These include:
Parkinsonism - this can cause symptoms similar to those that occur in people with
Parkinson's disease - for example, tremor and muscle stiffness.

Akathisia - this is like a restlessness of the legs.
Dystonia - this means abnormal movements of the face and body.
Tardive dyskinesia (TD) - this is a movement disorder that can occur if you take
antipsychotics for several years. It causes rhythmical, involuntary movements. These
are usually lip-smacking and tongue-rotating movements, although it can affect the
arms and legs too. About 1 in 5 people treated with typical antipsychotics eventually
develops TD.
All antipsychotics can make people put on weight, although not everyone does. The older
'typical' antipsychotics cause a rise in the level of the hormone prolactin, which can lead to a
lowered sex drive and breast tissue growth in both men and women, and affect womens periods.
Atypical antipsychotic medicines are thought to be less likely to cause movement disorder sideeffects than typical antipsychotic medicines. This reduced incidence of movement disorder is the
main reason why an atypical antipsychotic is often used first-line. Being on antipsychotic
medication increases the risk of developing diabetes, and that risk is greater in younger people.
There is also the risk of cardiovascular problems and high blood pressure. People who are on
antipsychotics should have regular physical health checks and doctors should monitor for
diabetes and cardiovascular disease at least once a year.
The higher the dose of antipsychotic medication, the more severe the side effects seem to be.
1.2 Antidepressant medications (Timms, 2012b, Sane Australia, 2014b)

Antidepressants are drugs used for the treatment of major depressive disorder and other
conditions, including dysthymia, anxiety disorders, obsessive compulsive disorder, eating
disorders, chronic pain, neuropathic pain and, in some cases, dysmenorrhoea, snoring, migraines,
attention-deficit hyperactivity disorder (ADHD), substance abuse and sleep disorders. They can
be used alone or in combination with other medications.
9
Antidepressants help relieve the symptoms of depression and associated anxiety. They do not
make the patient euphoric, but simply help the patient to react more realistically in his/her
emotional responses. Taking antidepressant medication is one important step in getting better but
is rarely enough on its own. As well as medication, effective treatment for depression and
anxiety-related disorders may include education about the illness and how to deal with it, and
psychological therapies such as Cognitive Behavioral Therapy (CBT).
1.2.1 Types of antidepressant medications (Mayo Clinic Staff, 2011)

There are almost thirty different kinds of antidepressants available today and there are five main
types. The different classes of antidepressant medications are:
1) Tricyclics:
o
o
o
o
o
o
o
o
o
o
Amitriptyline
Clomipramine (Anafranil)
Doxepin (Silenor, Zonalon)
Imipramine (Tofranil, Tofranil-PM)
Trimipramine (Surmontil)
Desipramine (Norpramin)
Nortriptyline (Pamelor, Aventyl)
Protriptyline (Vivactil)
Amoxapine
Maprotiline
2) MAOIs (Monoamine oxidase inhibitors):

o
o
o
o
Isocarboxazid (Marplan)
Phenelzine (Nardil)
Tranylcypromine (Parnate)
Selegiline (Emsam, Eldepryl, Zelapar)
3) SSRIs (Selective Serotonin Reuptake Inhibitors):

o
o
o
o
o
o
Citalopram (Celexa)
Escitalopram (Lexapro)
Fluoxetine (Prozac, Prozac Weekly, Sarafem)
Fluvoxamine (Luvox, Luvox CR)
Paroxetine (Paxil, Paxil CR, Pexeva)
Sertraline (Zoloft)
4) SNRIs (Serotonin and Noradrenaline Reuptake Inhibitors):

o Venlafaxine (Effexor XR)
o Desvenlafaxine (Pristiq)
10
o Duloxetine (Cymbalta)
5) NaSSAs (Noradrenaline and Specific Serotoninergic Antidepressants):
o
o
o
o
o
Aptazapine (CGS-7525A)
Esmirtazapine (ORG-50,081)
Mianserin (Bolvidon, Norval, Tolvon)
Mirtazapine (Remeron, Avanza, Zispin)
Setiptiline (Tecipul)
1.2.2 Mechanism of action of antidepressants (Yldz et al., 2002, Stimmel et al., 1997)
MAOIs were the first class of antidepressants to be developed. They fell out of favor because of
concerns about interactions with certain foods and numerous drug interactions. MAOIs elevate
the levels of norepinephrine, serotonin, and dopamine by inhibiting an enzyme called
monoamine oxidase. Monoamine oxidase breaks down norepinephrine, serotonin, and dopamine.
When monoamine oxidase is inhibited, norepinephrine, serotonin, and dopamine are not broken
down, increasing the concentration of all three neurotransmitters in the brain.
TCAs have been in use since the 1950s when imipramine (Tofranil) was shown to be effective
for treating depression. TCAs primarily work by increasing the level of norepinephrine in the
brain and to a lesser extent serotonin levels. Some TCAs also are antihistamines (block the action
of histamine) or anticholinergic (block the action of acetylcholine, a neurotransmitter), and these
additional actions allow for uses of TCAs other than for treating depression as well as additional
side effects.
SSRIs were developed after TCAs and are the most widely used class of antidepressants. They
work by increasing the level of serotonin in the brain. Unlike MAOIs and TCAs, they do not
significantly affect norepinephrine levels in the brain. SSRIs also have fewer and milder side
effects, fewer drug interactions, and are much less likely to be effective for committing suicide
than TCAs.
SNRIs are the newest class of antidepressants. SNRIs work by increasing the levels of serotonin
and norepinephrine in the brain. Drug interactions and side effects associated with SNRIs are
similar to those seen with SSRIs.
11
NaSSAs act by antagonizing the 2-adrenergic receptor and certain serotonin receptors such as
5-HT2A and 5-HT2C, but also 5-HT3, 5-HT6, and/or 5-HT7 in some cases. By blocking 2adrenergic autoreceptors and heteroreceptors, NaSSAs enhance adrenergic and serotonergic
neurotransmission in the brain involved in mood regulation, notably 5-HT1A-mediated
transmission. In addition, due to their blockade of certain serotonin receptors, serotonergic
neurotransmission is not facilitated in unwanted areas, which prevents the incidence of many
side effects often associated with selective serotonin reuptake inhibitor (SSRI) antidepressants;
hence, in part, the "specific serotonergic" label of NaSSAs.
1.2.3 Dosage of antidepressant medications (National Health Service, 2013)

When prescribing antidepressants the lowest possible dose necessary to improve the symptoms is
selected. This approach is intended to reduce the risk of side effects. If this dose proves
ineffective, it can be gradually increased. Antidepressants are usually taken in tablet form.
Depending on the type of antidepressant prescribed and the severity of the patients depression,
he/she will usually have to take one to three tablets a day.
1.2.4 Common side effects of antidepressants (Allen, 2011)

Antidepressants can sometimes cause a wide range of unpleasant side effects, including:
i) nausea increased
ii) appetite and weight gain
iii) loss of sexual desire and other sexual problems, such as erectile dysfunction and decreased
orgasm
iv) fatigue and drowsiness
v) insomnia
vi) dry mouth
vii) blurred vision
viii) constipation
ix) dizziness
x) agitation
xi) irritability
xii) anxiety
Antidepressants may cause withdrawal symptoms if abruptly discontinued. Withdrawal
symptoms include nausea, vomiting, dizziness, headache, irritability, sleep disturbance,
nightmares, psychosis, and seizures. All antidepressants have a warning about use in children and
12
adolescents. Antidepressants increased the risk of suicidal thinking, and suicidal behavior in
short-term studies in children and adolescents with depression and other psychiatric disorders.
Anyone considering the use of antidepressant in a child or adolescent must balance this risk of
suicide with the clinical need for the drug. Patients who are started on therapy should be closely
observed for clinical worsening, suicidal thoughts or unusual changes in behavior.
1.3 Fluphenazine (College of Psychiatric and Neurologic Pharmacists, 2013)

Fluphenazine is a first generation antipsychotic (FGA) or typical antipsychotic drug. It used to
treat psychotic disorders (such as schizophrenia), agitation, and dementia (College of Psychiatric
and Neurologic Pharmacists, 2013).It is a phenothiazine with a piperazine side-chain. It works by
antagonizing the dopamine D2 receptors in the brain. It is a short-acting piperazine
phenothiazine.
Figure: Fluphenazine structure

Phenothiazines work by inhibiting the actions of the brain chemicals, dopamine and
norepinephrine, which are overproduced in individuals with psychosis.Compared to other
phenothiazines, fluphenazine has weak anticholinergic, sedative and hypotensive activity, weak
anti-emetic effects and strong extrapyramidal effects. It is the most potent of the phenothiazine
antipsychotics.
Fluphenazine rebalances dopamine to improve thinking, mood, and behavior. It is available in 1
mg, 2.5 mg, 5 mg, and 10 mg tablets, a liquid concentrate containing 5 mg per 1 mL, a rapidonset injectable form containing 2.5 mg per 1 mL, and a long-acting injectable form containing
25 mg per 1 mL.
1.3.1 Fluphenazine synthesis (Cusic, 1956; Yale and Sowinski, 1960; Merrilland Yale, 1968)
13
Fluphenazine
(4-[3-[2-(trifluoromethyl)phenothiazin-10-yl]propyl]-1-piperazineethanol),
is
synthesized by any of the methods described already for the preparation of trifluoperazine and
related antipsychotics. Alkylation of 2-trifluoromethylphenothiazine using 4-formyl-1piperazineylpropylchloride in the presence of sodamide synthesizes 2-trifluoromethyl-10-[3-(4formyl-1-piperazinyl)propyl]phenothiazine. Further alkaline hydrolysis removes the N-formyl
group, giving 2-trifluoromethyl-10-[3-(1-piperazinyl)propyl]phenothiazine. This is alkylated by
2-bromoethanol-1 acetate, which upon further acidic hydrolysis removes the protecting acetyl
group, yielding fluphenazine.
Figure: Synthesis of Fluphenazine
1.3.2 Fluphenazine hydrochloride (U.S. National Library of Medicine, 2011)

Fluphenazine hydrochloride is a trifluoromethyl phenothiazine derivative intended for the
management of schizophrenia. Chemically it is 4-[3-[2-(Trifluoromethyl) phenothiazin-10yl]propyl]-1-piperazineethanol dihydrochloride which may be represented by the following
structural formula:
Figure: Structure of Fluphenazine hydrochloride

14
Molecular
formula
of
Fluphenazine
is
C22H26F3N3OS2HCL.
Molecular
weight
of
FluphenazineHydrochloride is 510.44. Fluphenazine hydrochloride tablets are indicated in the

management of manifestations of psychotic disorders. Fluphenazine hydrochloride has not been
shown effective in the management of behavioral complications in patients with mental
retardation. Fluphenazine hydrochloride has activity at all levels of the central nervous system as
well as on multiple organ systems. The mechanism whereby its therapeutic action is exerted is
unknown.
1.4 Nortriptyline (U.S. National Library of Medicine, 2014)

Nortriptyline is in the class of drugs called tricyclic antidepressants (TCAs) and is used for
treating depression. Like all TCAs, nortriptyline increases levels of norepinephrine and
serotonin,
two
neurotransmitters,
and
blocks
the
action
of
acetylcholine,
another
neurotransmitter. It is believed that by restoring the balance of these different neurotransmitters

in the brain depression is alleviated. Nortriptyline was approved by the FDA in November 1964.
Figure: Nortriptyline structure
1.4.1 Nortriptyline synthesis (Vardanyan and Hruby, 2006)

Nortriptyline
is
5-(3-methylaminopropyliden)-10,11-dihydrodibenzcycloheptene.
In
nortriptyline, the nitrogen atom in the central part of the tricyclic system of desipramine is
replaced by a carbon atom, which is bound to a side chain by a double bond. Two suggested
methods of nortriptyline synthesis are based on the N-demethylation of amitriptyline. The third
15
way utilizes the reaction of methaylamine with 5-(3-bromopropyliden)-10,11-dihyadro-5Hdibenmz[a,d]cycloheptene.

According to the first scheme, demethylation takes places by the reaction of amitriptyline with
methyliodide, which leads to the formation of a quartanary ammonium salt, the reaction of which
with methylamine at a relatively high temperature gives the desired nortriptyline.
Figure: First method of nortriptyline synthesis

In the second scheme, the specified reaction of amitriptyline with ethtylahloroformate leads to
the substitution of a methyl group on the amino group with an ethoxycarbonyl group. Hydrolysis
of the product leads to nortiptyline.
Figure: Second method of nortriptyline synthesis

According to the third scheme, Nortriptyline is synthesized by reacting methylamine with 5-(3bromoptopyliden)-10,11-dihydro-5H-dibenz[a,d]cycloheptene.
16
Figure: Third method of nortriptyline synthesis

Nortriptyline is a drug with a relatively short latent period of action. It is practically devoid of
sedative effects. It is used in manic-depressive psychoses, in all forms.
1.4.2 Nortriptyline hydrochloride (U.S. National Library of Medicine, 2014)

Nortriptyline hydrochloride, USP is 1-propanamine, 3-(10,11-dihydro-5H dibenzo[a,d]cyclohep
ten-5-ylidene)-N-methyl-, hydrochloride.
Figure: Structure of Nortriptyline hydrochloride

Nortriptyline hydrochloride structural formula C19H21NHCl.Molecular weight is 299.8. It is a
white to off-white powder, having a slight, characteristic odor. It is soluble in water and in
chloroform; sparingly soluble in methanol; and practically insoluble in most organic solvents.
Each capsule, for oral administration, contains nortriptyline hydrochloride, USP equivalent to 10
mg, 25 mg, 50 mg or 75 mg nortriptyline.
1.5 Fluphenazine-Nortriptyline combination

Fluphenazine-Nortriptyline is a combination preparation of two well-known and time tested
molecules: Fluphenazine and Nortriptyline. Fluphenazine is a typical antipsychotic drug used for
the treatment of psychosis such schizophrenia, manic phases of bipolar disorder, agitation, and
dementia. Nortriptyline is a second-generation tricyclic antidepressant (TCA) used in the
treatment of major depression. In combination the compound renders a preparation with
17
antidepressant, anxiolytic and activating properties and mutually neutralizes side effects. A chart
is given showing the brand names and corresponding price of each combination FluphenazineNortriptyline drug that is sold by the pharmaceutical companies in Bangladesh (Square
Pharmaceuticals Ltd., 2014).
Table: Showing different Fluphenazine-Nortriptyline combination drugs sold by various

pharmaceuticals in Bangladesh (Health Prior 21, 2014).
Trade
Name
Amival
Generic Name Pharmaceuticals
Dosage
Fluphenazine
Amico
Formulation
Tablet
0.5mg+10
hydrochloride
Pharmaceuticals
+ nortriptyline
Ltd.
hydrochloride
Amival-f Fluphenazine
Anflu
Apresin
Ateval
Euphor
Amico
hydrochloride
Pharmaceuticals
+ nortriptyline
Ltd.
hydrochloride
Fluphenazine
Alco
hydrochloride
Pharmaceuticals
+ nortriptyline
Ltd.
hydrochloride
Fluphenazine
Beximco
hydrochloride
Pharmaceuticals
+ nortriptyline
Ltd.
hydrochloride
Fluphenazine
Ziska
hydrochloride
Pharmaceuticals
+ nortriptyline
Ltd.
hydrochloride
Fluphenazine
Bio-
Quantity
Packaging Price
100's pack
mg/Tab
Tablet
0.5mg+10
BDT
100's pack
mg/Tab
Tablet
0.5mg+10
0.5mg+10
100's pack
0.5mg+10
100's pack
0.5mg+10
105
BDT
100's pack
mg/Tab
Tablet
75
BDT
mg/Tab
Tablet
201
BDT
mg/Tab
Tablet
80
100
BDT
100's pack
80
18
Flutrip
hydrochloride
Pharmaceuticals
+ nortriptyline
Ltd.
hydrochloride
Fluphenazine
General
hydrochloride
Pharmaceuticals
Ltd.
mg/Tab
Tablet
0.5mg+10
BDT
100's pack
mg/Tab
71
BDT
nortriptylinehy
Fresh
Moodon
Norflu
Norz1n
drochloride
Fluphenazine
Nipa
hydrochloride
Pharmaceuticals
+ nortriptyline
Ltd.
hydrochloride
Fluphenazine
IbnSina
hydrochloride
Pharmaceuticals
+ nortriptyline
Ltd.
hydrochloride
Fluphenazine
Acme
hydrochloride
Pharmaceuticals
+ nortriptyline
Ltd.
hydrochloride
Fluphenazine
Aristo
hydrochloride
Pharmaceuticals
+ nortriptyline
Ltd.
hydrochloride
Permival Fluphenazine
Sanit
Tripnor
Opsonin
hydrochloride
Pharmaceuticals
+ nortriptyline
Ltd.
hydrochloride
Fluphenazine
Square
hydrochloride
Pharmaceuticals
+ nortriptyline
Ltd.
hydrochloride
Fluphenazine
Somatec
hydrochloride
Pharmaceuticals
Tablet
0.5mg+10
100's pack
mg/Tab
Tablet
0.5mg+10
BDT
200's pack
mg/Tab
Tablet
0.5mg+10
0.5mg+10
100's pack
0.5mg+10
250's pack
0.5mg+10
200's pack
0.5mg+10
mg/Tab
150
BDT
100's pack
mg/Tab
Tablet
200
BDT
mg/Tab
Tablet
80
BDT
mg/Tab
Tablet
170
BDT
mg/Tab
Tablet
80
79
BDT
100's pack
75
BDT
19
+ nortriptyline
Ltd.
hydrochloride
In this research project experiment conducted on sample which was manufactured by ACME
Pharmaceuticals (Trade name: Noflu).
1.5.1 Pharmacology (Square Pharmaceuticals, 2014)

Nortriptyline hydrochloride is a tricyclic antidepressant. Nortriptyline inhibits the uptake of
norepinephrine and serotonin at nerve terminals. In contrast to its parent compound amitriptyline
which is equally potent in inhibiting the uptake of norepinephrine and serotonin, Nortriptyline
has a greater effect on norepinephrine reuptake than on serotonin reuptake. Fluphenazine is a
tranquilizer of the phenothiazine type with piperazine side chain. Fluphenazine primarily acts as
a neuroleptic drug whose main therapeutic effect is believed to reside in potent dopamine
(especially D2) receptor antagonism. Due to the nature of the two active constituents and the
larger inter and intra subject variability seen in trials, accurate and consistent pharmacokinetic
data are not available. This can be illustrated by the fact that studies of nortriptyline
hydrochloride have produced half life values ranging from 16 to 38 hours. In the case of
Fluphenazine hydrochloride these values have been 10 to 16 hours.
1.5.2 Indications (Square Pharmaceuticals, 2014)

This medicine provides effective therapy in the management of patients exhibiting mild to
moderate anxiety; tension and/or agitation with or without co-existing depression.Various forms
of neurosis (anxiety, hysteria, depression, neurasthenia), disorder of sleep are amenable to treat
with this tablet. In addition, patients exhibiting general neurotic feelings, fear, mild to moderate
depression and mild to moderate anxiety have responded well to this tablet.
1.5.3 Dosage and administration (Square Pharmaceuticals, 2014)

Adult: One tablet three times daily. The course of the treatment should be limited to three
months. If the patient does not respond after 4weeks, an alternative treatment should be given.
Children: Not indicated for the treatment of children.
20
1.5.4 Contraindication and precaution (Ineson, 1996)

Phenothiazines and tricyclic antidepressants have been shown to lower the threshold for
electrically induced convulsions in animals; hence, this combination is not recommended for
patients with a history of epilepsy or brain damage. This combination is further contraindicated
in patients with blood dyscrasias, severe cardiac insufficiency, renal or liver damage. It is not
advisable to give monoamine oxidase inhibitors (MAOIs) with this combination, nor should they
be given in two weeks after cessation of treatment with MAOIs. This combination should be
given with caution to patients with glaucoma and to those who have a propensity for urinary
retention. This combination should be used with caution in patients with cardiac failure,
especially when there is evidence of rhythm disturbance and in patients with recent myocardial
infarction.
1.5.5 Side effects (Ineson, 1996)

Tardive dyskinesias have been reported in phenothiazine therapy, usually after prolonged courses
given at doses adequate to control psychotic illness. Consequently, treatment with this drug
should be limited to three months. Dryness of mouth, drowsiness, faintness and constipation.
Occasionally tachycardia, nasal congestion, blurred vision and excitement are seen.
Extrapyramidal reactions are unlikely to occur with this dose of Fluphenazine alone, and it is
probable that the anticholinergic activity of Nortriptyline affords protection against such effects.
As with all neuroleptic drugs the presence of unexplained hyperthermia could indicate
neuroleptic malignant syndrome. In this event, this combination and associated neuroleptic
treatment should be discontinued until the origin of the fever has been determined.
1.5.6 Drug interaction (Square Pharmaceuticals, 2014)

Interaction with barbiturates, alcohol and narcotic drugs may occur, so central nervous
depressants should be administered with caution. This combination may diminish the anti-
21
hypertensive effect of an adrenergic blocking agent and could potentiate the pressor response to
locally injected sympathomimetic agents.
1.5.7 Use in pregnancy and lactation (Ineson, 1996)

Do not use during pregnancy, especially in the first and last trimesters unless there are
compelling reasons. There is no evidence as to drug safety in human pregnancy, nor are the
results of animal studies conclusive. Breast feeding is not recommended for women receiving
this combination.
1.5.8 Overdose (Square Pharmaceuticals, 2014)

Over dosage should be treated symptomatically and supportively. If the patient is conscious,
prompt gastric lavage, dilution of the stomach contents to delay absorption, or stimulation of
vomiting should be attempted. An open airway should be maintained. Extrapyramidal symptoms
are amenable to anti-parkinsonian drugs. In severe hypotension, all the standard procedures for
the management of circulatory shock should be substituted.e.g. vasoconstrictors and/or
intravenous fluids. If vasoconstrictors are required, metaraminol, mephentermine or
noradrenaline should be administered but not adrenaline, as this will further lower the blood
pressure through interaction with the phenothiazine.
22
Chapter Two
LITERATURE REVIEW
23
2.1 Determination and analysis of nortriptyline and fluphenazine combinations

A rapid, simple, and highly sensitive second-derivative synchronous fluorimetric (SDSF) method
has been developed for the simultaneous analysis of binary mixtures of fluphenazine
hydrochloride (FLZ) and nortriptyline hydrochloride (NTP) in their co-formulated tablets. The
method is based upon measurement of the native fluorescence of these drugs at constant
wavelength difference (Deltalambda) = 120 nm in acetic acid. The different experimental
parameters affecting the fluorescence intensity of the studied drugs were carefully studied and
optimized. The fluorescence-concentration plots were rectilinear over the range of 0.25-3.0 and
1-10 microg/ml for FLZ and NTP respectively, with lower detection limits (LOD) of 0.05 and
0.18 microg/ml and quantitation limits of 0.15 and 0.53 microg/ml for FLZ and NTP
respectively. The proposed method was successfully applied for the determination of the studied
compounds in their synthetic mixtures and in commercial co-formulated tablets. The results
obtained were in good agreement with those obtained by the reference methods (Walash et al.,
2009).
The construction and electrochemical response characteristics of polyvinylchloride (PVC),
membrane sensors for determination of fluphenazine hydrochloride and nortriptyline
hydrochloride are described. The method is based on the formation of the ion-pair complexes
between the two drugs cations and sodium tetraphenylborate (NaTPB) or tetrakis (4chlorophenyl) borate (KtpClPB). Four polyvinylchloride sensors were fabricated. For
FluphenazineHCl sensors 1 and 3 were prepared using NaTPB and KtpClPB, respectively. For
NortriptylineHCl sensors 2 and 4 were prepared using NaTPB and KtpClPB, respectively. They
show linear responses for both drugs over the concentration ranges of 103105, 102105,
103105 and 102105 M with cationic slopes of 58.9, 52.5, 59.3 and 54.3 mV per
concentration decade, for sensors 14, respectively. The direct potentiometric determination of
fluphenazine and nortriptyline hydrochlorides in their pure forms using the proposed sensors
gave recoveries of 98.80.9, 99.00.9, 98.70.8 and 99.40.8% for sensors 14, respectively.
This is compared reasonably with the data obtained using the British Pharmacopoeial method
24
(1993). Sensors 14 were also used for determination of both drugs in their pharmaceutical
dosage forms and in the presence of their degrades. It is noteworthy to mention that tetrakis (4chlorophenyl) borate affects significantly the life time of the fabricated sensors of both drugs (ElRagehya et al., 2000).
A simple, fast, robust, and accurate high-performance liquid chromatography (HPLC) method is
described for simultaneous quantification of nortriptyline and fluphenazine in bulk powder and
dosage forms. The chromatographic separation was carried out in less than one minute on
Chromolith Performance RP-18e column, which consists of monolithic rods of highly porous
silica, using isocratic binary mobile phase of MeOH and 25 mM KH 2PO4 pH 4.5 in the ratio of
70:30 at 5 mL min1 flow rate and 40C. The high porosity of stationary phase enables it to be
used at high flow rates without problems concerning backpressure, these high flow rates in turn
lead to strong reduction of analysis time. A diode array detector was used at 254 nm for
detection. The method was validated for system suitability, linearity, precision, limits of
detection and quantitation, specificity, and robustness. LOD were found to be 0.40 and 0.78 g
mL1 for nortriptyline and fluphenazine, respectively. LOQ was 3.125 g mL 1 for both analytes.
Recovery values of this method were 98.50 and 98.00% for nortriptyline and fluphenazine,
respectively, and reproducibility was within 2.36%. Robustness study was done for small
changes in KH2PO4 concentration and pH, temperature, flow rate, wavelength of detection, % of
MeOH in mobile phase, and injection volume (Hashemab and Jirac, 2013).
Spectrophotometric and high performance liquid chromatographic procedures are described for
determination of nortriptyline hydrochloride and fluphenazine hydrochloride. The first procedure
is based on application of first derivative of ratio spectra ( 1DD) for quantitative determination of
nortriptyline hydrochloride in presence of fluphenazine hydrochloride. Secondly, an accurate,
sensitive and stability indicating method has been introduced for determination of nortriptyline
hydrochloride and fluphenazine hydrochloride in both bulk powder and in dosage form. In the
derivative ratio method, Beer's law is obeyed in the concentration ranges of 832 g mL 1 and 4
32 g mL1 of nortriptyline hydrochloride at wavelengths 271.4 and 284.2 nm, respectively. In
high performance liquid chromatographic method, linear relationship in the range of 0.63.6 g
mL1 and 1.24.2 g mL1 for nortriptyline hydrochloride and fluphenazine hydrochloride,
respectively, was obtained. The mobile phase used was 0.05 M ammonium acetate : methanol :
25
acetonitrile (4 : 1 : 5 v/v/v), and detection was done spectrophotometrically at 254 nm. Results
were statistically analyzed and compared with those obtained by applying the British
Pharmacopoeia (2000) method (El-Ragehya et al., 2002).
A novel method for the simultaneous high-performance liquid chromatographic determination of
nortriptyline hydrochloride and fluphenazine hydrochloride was developed and validated.
Fluvastatin sodium was used as internal standard. The determination was performed on a
Hypersil Gold C8 column (250 mm 4.6 mm i.d., 5 m particle size) at 25C; the mobile phase,
consisting of a mixture of formic acid (0.1 M, pH 2.16)-methanol (33:67, v/v), was delivered at a
flow rate of 1.1 mL/min and detector wavelength at 251 nm. The retention time of nortriptyline,
fluphenazine and fluvastatin was found to be 5.11, 8.05 and 11.38 min, respectively. Linearity
ranges were 5.01350.0 and 10.01350.0 g/mL with limit of detection values of 0.72 and 0.31
g/mL, for nortriptyline and fluphenazine, respectively. Results of assay and recovery studies
were statistically evaluated for its accuracy and precision. Correlation coefficients (r2) of the
regression equations were greater than 0.999 in all cases. According to the validation results, the
proposed method was found to be specific, accurate, precise and could be applied to the
simultaneous quantitative analysis of nortriptyline and fluphenazine (Ashour and Kattan, 2012).
A controlled clinical trial on the efficacy of a nortriptyline-fluphenazine combination was carried
out in patients with painful diabetic polyneuropathy. A visual analog scale was used to evaluate
the relief of pain or paresthesia. Significant relief of both pain and paresthesia was obtained with
this combination. The differences were statistically significant. Side effects were frequent but not
usually severe enough to lead to cessation of these medications. (Gomez-Perez et al., 1985)
A novel method for the simultaneous high-performance liquid chromatographic determination of
nortriptyline hydrochloride and fluphenazine hydrochloride was developed and validated.
Fluvastatin sodium was used as internal standard. Results of assay and recovery studies were
statistically evaluated for its accuracy and precision. According to the validation results, the
proposed method was found to be specific, accurate, precise and could be applied to the
simultaneous quantitative analysis of nortriptyline and fluphenazine (Nuha and Safwan, 2012).
26
2.2 Determination and analysis of fluphenazine as a single drug or in combination with

other drugs
A simple, stability-indicating liquid chromatographic method has been developed for the assay of
flunarizinedihydrochloride in the presence of its acid-induced degradation product. A BondapakC18 column was used with a mobile phase consisting of methanol-water (75:25, v/v) containing
0.5% w/v sodium chloride and 0.2% v/v triethanolamine adjusted to pH 6.6 with 30%
hydrochloric acid at a flow rate 2 ml min-1. Quantitation was achieved with UV detection at 254
nm based on peak area or peak height ratios. The proposed method was successfully applied to
the determination of the drug in laboratory-prepared mixtures in the presence of its degradation
product and in capsules. Moreover, the method was utilized to investigate the kinetics of the
degradation process at different temperatures and the apparent first-order rate constant, half-life
and activation energy calculated (Wahbi et al., 1995).
A simple, stability-indicating, reversed phase liquid chromatographic method has been developed
for the determination of fluphenazine hydrochloride in the presence of its oxidative and
ultraviolet degradation products. Reversed phase chromatography was conducted using an ODS
C18 (150 4.6 mm id) column at ambient temperature with UV-detection at 250 nm. A mobile
phase consisting of 0.03 M potassium dihydrogen phosphate bufferacetonitrile (40:60, v/v)
adjusted to pH 4 was used for the separation of the studied drug and its degradation products at a
flow rate of 1 mL min1. The method showed a good linearity over the concentration range of
2.020.0 g mL1 with a detection limit (LOD) of 0.8 g mL 1 and a quantification limit (LOQ)
of 1.5 g mL1. The proposed method was successfully validated and applied for the analysis of
the drug in its commercial dosage forms; the obtained results were favorably compared with
those obtained by the official and comparison methods. Moreover, the method was utilized to
investigate the kinetics of the oxidative degradation of the drug. The first-order rate constant,
half-life time, and activation energy of the degradation were calculated (Walasha and Wahba,
2014).
A simple, rapid, precise, sensitive, specific and accurate instrumental planar chromatographic
method for quantification of fluphenazine hydrochloride in injections has been developed and
validated. Chromatographic separation was on precoated silica gel F 254 HPTLC plates. The
mobile phase was methanol-purified water 9:1 (v/v). Densitometric analysis was performed at
27
306 nm. The calibration plots were linear in the range 100 to 500 ng L 1 with a correlation
coefficient of 0.998. The limits of detection (LOD) and quantification (LOQ) were 1.45 and 4.40
ng, respectively. Intra-assay and inter-assay precision, expressed as relative standard deviation
(RSD), were in the range 0.731.77% (n = 3) and 1.181.86% (n = 9), respectively. Recovery of
fluphenazine hydrochloride was between 98.29 and 101.53%, with RSD no higher than 1.87%.
The method was selective for fluphenazine hydrochloride and the preservatives in the injections.
Drug content was within the prescribed limits (95110% of the labeled content of the
formulations) when the method was used to quantify fluphenazine hydrochloride in real
pharmaceutical samples. Because the method is sensitive, precise, accurate, and selective for the
compound tested, it can be used for routine quality control testing of fluphenazine hydrochloride
in injections (Mennickent et al., 2010).
The electrochemical behaviour of fluphenazine based on its oxidation at platinum and glassy
carbon electrodes was investigated by linear sweep and cyclic voltammetry. The influence of pH,
concentration, nature of the buffer and scan rate was carefully examined. At both electrodes,
three anodic steps (representing an irreversible oxidation) were obtained. The method was
applied to the determination of fluphenazine in sugar-coated tablets (Sentrk et al., 1996).
Amber-coloured syringes designed for the distribution of unit-doses of oral drops were studied
for the efficiency of the photoprotectiveness and the possible binding of eleven phenothiazine
neuroleptics: alimemazine, chlorpromazine, cyamemazine, fluphenazine, levomepromazine,
periciazine, pipotiazine, prochlorperazine, thioproperazine, thioridazine, and trifluoperazine, all
very easily oxidized in solution in daylight. Spectrofluorimetry made it possible, in one
operation, to determine the remaining concentrations of drugs after storage and to verify the
absence of photo-oxidation. The storage was performed up to 13 days at 25 +/- 3 degrees C and
without any precaution from daylight. All the drugs studied were stable and none bound on the
syringes. However, the stability appeared to be due to the antioxidants in the drug preparations,
and not to the coloured material, since oral drops were also stable in uncoloured syringes
designed for injection. Nevertheless, the amber-coloured syringes efficiently protect the active
principles in pure aqueous solutions, without preservative, and thus this physical protection
reinforces the chemical one of the galenical formulation (Airaudo et al., 1995).
28
The coupling of end-column tris (2,2'-bipyridyl) ruthenium (II) electrochemiluminescence (ECL)

detection with capillary electrophoresis (CE) was developed for the analysis of two antipsychotic
drugs, perphenazine (PPH) and fluphenazine (FPH). The parameters related to CE separation and
ECL detection, including the detection potential, the buffer pH value and concentration, the
separation voltage, and Ru(bpy)(2+) concentration, were investigated in detail. Under optimum
conditions, PPH and FPH were well separated and detected within 11 min. The linear ranges
were 0.1-5 M for PPH, and 0.1-7.5 M for FPH, respectively. The limits of detection of PPH
and FPH were 5 and 10 nM (S/N=3). The relative standard deviations (n=3) of the ECL intensity
and the migration time were less than 2.5 and 0.65% in a day, and less than 3.4 and 1.7% in
different three days. The proposed method was successfully applied to determine PPH and FPH
in spiked urine samples with satisfactory results (Xu et al., 2014).
A thin-layer chromatography (TLC)-densitometry method has been developed to identify and
quantify haloperidol, amitriptyline, sulpiride, promazine, fluphenazine, doxepin, diazepam,
trifluoperazine, clonazepam, and chlorpromazine in selected psychotropic drugs. Separation was
performed on precoated silica gel 60 F254 TLC plates. Chromatograms were developed in
various mobile phases, and 8 of 30 tested phases were selected based on spot location and
developing time. The identification and quantification were carried out based on ultraviolet
densitometric measurements at chosen wavelengths. In addition to retention coefficients, the
absorption spectra recorded directly from chromatograms were also used in qualitative analysis.
Under established experimental conditions, high sensitivity of the method was achieved. The
limit of detection ranged from 0.009 to 0.260 microg, depending on the wavelength selected for
measuring. A satisfactory recovery, ranging from 92.99 to 104.70%, was achieved for individual
constituents (Malanka and Krzek, 2005).
A new spectrofluorometric method was developed for the determination of a ternary mixture of
dexamethasone, dexchlorpheniramine maleate, and fluphenazine hydrochloride in dosage forms
where the literature did not reveal any method for analysis of this mixture. The method was
based on the use of the first and second derivatives of the ratio of the emission spectra with a
zero-crossing technique. The ratio spectra were obtained by dividing the emission spectrum of
the mixture by that of one of the components. The concentrations of the other components were
then determined from their respective calibration graphs treated similarly. The method can
29
resolve the spectral overlapping of the three components and was applied successfully for the
determination of these drugs in synthetic mixtures and in commercial dosage forms (El-Yazbi et
al., 2006).
A simple, rapid, and sensitive spectrofluorometric method has been developed for the
determination of olanzapine (OLZ) and fluphenazine hydrochloride (FPZ HCl). The proposed
method is based on the quantitative quenching effect of the studied drugs on the native
fluorescence of eosin at pH 3.4 and 3.2 for OLZ and FPZ HCl, respectively. The fluorescence
was measured at 547 nm after excitation at 323 nm. The fluorescence-concentration plots were
rectilinear over the range of 0.05-1.0 and 0.10-1.0 g/mL, with lower detection limits of 1.8 10 -3
and 1.2 10-3 g/mL, for OLZ and FPZ HCl, respectively. The proposed method was successfully
applied to the analysis of commercial tablets and ampules containing the drugs, and the results
were in good agreement with those obtained with reference methods. The proposed method was
further applied to the determination of OLZ in spiked human plasma. The mean recovery was
98.62 +/- 0.24% (n = 4). The method was also used for stability studies of FPZ HCl upon
oxidation with hydrogen peroxide, and the kinetics of the reaction were studied. A proposal for
the reaction pathway was postulated (Belal et al., 2008).
The aim of the present study was to develop rapid disintegrating tablets of Flupentixol
dihydrochloride, a slightly bitter antipsychatric drug. An attempt has been made to prepare
bitterless rapid disintegrating tablet using Eudragit E100 as a taste masking agent. The tablet was
prepared with three super disintegrants e.g. sodium starch glycolate, cross carmellose sodium
and crospovidone, each one was added in three different concentration 2%, 3% and 4%; mass
extrusion was the technique used for the preparation of these tablets. The blend was examined
for angle of repose, bulk density, tapped density, compressibility index and Hausners ratio. The
compressed tablets were evaluated for hardness, drug content, friability, disintegration time invitro and in-vivo, wetting time and dissolution rate. The contents of the prepared tablets were
characterized by X-ray diffraction and Fourier transform infrared spectroscopy (FTIR). Different
nine formulas showed in-vitro disintegration times ranges from 11.8 sec to 61 sec , but it was 150
sec for F1 ( formula without any super disintegrant) .These results were nearly correlated with in
vivo disintegration times for the ten formulas. In vitro dissolution studies showed the release in
the following descending order of super disintegrants: Crospovidone>Croscarmellose sodium>
30
Sodium Starch Glycolate. Maximum in vitro dissolution rate was found to be with formulation
F10 which contains crospovidone (4%). Thus, F10 was considered the best among the other
formulations. The stability study was conducted as the International Conference on
Harmonization (ICH) guidelines and the formulations subjected again for changes in hardness,
friability, drug content, wetting time and disintegration time. Crospovidone at a concentration of
4% w/w is suitable for preparing rapid disintegrating tablet of Flupentixol dihydrocloride (Elbary
et al., 2011).
In the year of 1999 a study was performed to check the comparative effectiveness of
Fluphenazine decanoate. Dose reduction strategies for the maintenance treatment of
schizophrenia are designed to maintain the benefits of antipsychotic drug therapy while reducing
risks. Previous strategies with decanoate preparations have been based on the use of lower doses
per injection to achieve dose reduction; these strategies have achieved dose reduction but have
resulted in some increase in symptoms. The authors tested a new dose reduction approach:
increasing the interval between injections during intramuscular decanoate antipsychotic
treatment. The two dose regimens did not differ significantly in relapse, symptom, or side effect
measures. The every-6-weeks regimen was associated with a significant reduction in total
antipsychotic exposure. The use of injections every 6 weeks instead of every 2 weeks may
increase compliance and improve patients comfort as well as decrease cumulative antipsychotic
exposure, without increasing relapse rates or symptoms. (Carpenter et al., 1999)
In another study determination of Fluphenazine Dihydrochloride was done by using simple and
cost effective UV-spectroscopy method in pure form and in pharmaceutical formulations.
Methanol was selected as the solvent as the drug is highly soluble in it. The result was accurate
and precise and there was no interference of the excipients (Yunus et al., 2011).
2.3 Determination and analysis of Nortriptylineas a single drug or in combination with

other drugs
The objective of this research is to develop a simple, sensitive and validated kinetic
spectrophotometric method for the determination of nortriptyline hydrochloride in pure and
pharmaceutical formulations. The method is based on derivatization of drug with1-chloro-2,4dinitrobenzene (CDNB) in dimethyl sulfoxide (DMSO) medium at room temperature (30 10C).
31
The reaction was followed spectrophotometrically by measuring the increase in absorbance at

390 nm as a function of time. Under the optimized experimental conditions, Beers law obeyed
in the concentration range of 20-100 g/ml for both initial rate and fixed time methods. The
limits of quantitation are 2.975 and 3.680 g/ml for initial rate and fixed time methods,
respectively. The method has been successfully applied to the determination of nortriptyline in
pharmaceutical formulations. Statistical comparison of the results with the reference method
shows excellent agreement and indicates no significant difference in accuracy and precision
(Rahman et al., 2014).
A method is described for the determination of nortriptyline in sugar-coated tablets. Nortriptyline
is extracted into dilute aqueous hydrochloric acid containing triflupromazine hydrochloride as an
internal standard. The acidic extract is then chromatographed by a reversed-phase separation
using a basic solvent system in conjunction with a phenyl Corasil column. The main advantages
of the method are the simple extraction, the over-all speed of analysis and the degree of precision
obtained. The method has been used to monitor the stability of experimental formulations and
could readily be modified for the assay of single tablets (Salmon and Wood, 1976).
Amitrityline and its metabolite nortriptiline are tricyclic antidepressant drugs widely used for the
treatment of several psychiatric disorders. Several methods have been published for the
determination of these two antidepressant drugs in pharmaceuticals, biological materials and
environmental samples. In this review some of analytical techniques such as ultraviolet/visible
spectrophotometry, fluorimetry, capillary electrophoresis, and chromatographic methods
(gaschromatography and high-performance liquid chromatography) were discussed. Although
HPLC and capillary electrophoresis methods are extensively employed in spite of that UV/VIS
spectrophotometry are still popular because of the inherent simplicity, low cost, and reliability
for determination of drugs in pharmaceutical preparations (Khatoon et al., 2013).
A spectrophotometric procedure is described for determination of nortriptyline hydrochloride in
pure and dosage form as well as in the presence of its degradate. 3-Methyl-2-benzothiazolinone
hydrazone (MBTH) has been used as the chromogenic reagent, where aqueous solutions of the
drug and reagent are treated with cerium (IV) ammonium sulphate in an acidic medium.
Nortriptyline hydrochloride reacts to give a blue coloured product having two absorption
maxima at 619 and 655 nm. Various parameters affecting the reaction have been studied. Beer's
32
law is obeyed in the concentration range of 24-216 mug ml -1 of nortriptyline hydrochloride, with
mean percentage recoveries of 100.22 +- 0.870 and 100.66 +- 0.642% for both maxima, 619 and
655 nm, respectively. Results were statistically analyzed and compared with those obtained by
applying the British Pharmacopoeia (1993) method (El-Ragehya et al., 2001).
Two simple, fast, and sensitive extractive spectrophotometric methods for determination of
nortriptyline hydrochloride (NTPH) in pure and pharmaceutical formulations have been
developed. These methods are based on the formation of chloroform-soluble ion-association
complexes of NTPH and bromophenol blue (BPB) and bromopyrogallol red (BPR) in NaOAcHCl buffer of pH 3.29. Absorption maxima of both complexes were recorded at 410 nm and at
425 nm, respectively for BPB and BPR. Reaction conditions were optimized to obtain the
maximum color intensity. The systems obeyed Beers law in the analytes concentration ranges of
0.1-7.2 mg mL-1 and 0.5-23.4 mg mL-1 for BPB and BPR, respectively. The proposed methods
are simple, accurate, and suitable for analysis of pharmaceutical formulations (Kumar et al.,
2007).
Two simple, sensitive and rapid extractive spectrophotometric methods have been developed for
the assay of the antidepressant drug nortriptyline (NOR) hydrochloride in pure form and in
different dosage forms. The methods involve the formation of colored ion-pairs between the drug
and the complex of niobium(V)-thiocyanate (Nb-SCN) or iron(III)-thiocyanate (Fe-SCN)
followed by their extraction with butanol or a mixture of butanol and chloroform and quantitative
determination at 360 nm and 490 nm, using Nb-SCN and Fe-SCN, respectively. The
experimental conditions were optimized to obtain the maximum colour intensity. The methods
permit the determination of nortriptyline over a concentration range of 15-100 microg/ml and 524 microg/ml with the detection limit of 0.84 microg/ml and 0.32 microg/ml, using Nb-SCN and
Fe-SCN, respectively. The proposed methods are applicable for the assay of the investigated drug
in different dosage forms and the results are in good agreement with those obtained by the
official and HPLC methods. No interference was observed from common excipients present in
pharmaceutical formulations. The proposed procedures were applied to determine the amount of
nortriptyline hydrochloride as active ingredient in the presence of its degradation product,
dibenzosuberone. The extractive spectrophotometric methods can also be used to determine the
33
amount of nortriptyline hydrochloride in tablets after its solid phase extraction (SPE) (Misiuk
and Tykocka, 2007).
Two simple, rapid and sensitive extractive spectrophotometric methods have been developed for
the assay of nortriptyline hydrochloride (NTPH) in pure and pharmaceutical formulations. These
methods are based on the formation of chloroform soluble ion-association complexes of NTPH
with bromocresol green (BCG) and with methyl orange (MO) in KCl-HCl buffer of pH 2. The
colored species exhibited absorption maxima at 416 and 422 nm for BCG and MO with molar
absorptivity values of 2.88 104 and 2.29 104 L/mol cm, respectively. Reaction conditions
were optimized to obtain the maximum color intensity. Various analytical parameters have been
evaluated and the results have been validated by statistical data. The methods were successfully
applied to the analysis of NTPH in pharmaceutical formulations (Manjunatha et al., 2009).
Three simple and selective methods are proposed for the determination of nortriptyline
hydrochloride in bulk form and in tablets. The first two methods are based on the formation of
charge-transfer complexes between the drug base as a n-donor and quinhydrone or p-chloranil as
pi-acceptor. The products exhibit absorption maxima at 497 and 560 nm in acetonitrile for
quinhydrone and p-chloranil, respectively. The third method is based on the interaction of Nalkylvinylamine formed from the condensation of the free secondary amine group and
acetaldehyde with p-chloranil to give a vinylamino substituted quinone. The coloured product
exhibits an absorption maximum at 650 nm in dioxane. All variables were studied to optimize
reaction conditions. Beer's law was obeyed and the relative standard deviations were found to be
less than 1.5%. The methods have been applied to the analysis of nortriptyline hydrochloride in
the bulk drug and in tablets (Attia, 2000).
The effect of adding surface active agents to electrolytes containing nortriptyline hydrochloride
on the voltammetric response of a hanging mercury drop electrode (HMDE) was studied. The
current signal due to the reduction process was a function of the amount of nortriptyline
hydrochloride, pH of the medium, type of the surfactant, and accumulation time at the electrode
surface. Addition of Tween-20 to the nortriptyline hydrochloride containing electrolyte enhances
the reduction current signal. Voltammograms of the drug with Tween-20 in Britton Robinson
buffers of pH 2-11 exhibit a single well-defined reduction peak, which may be due to the
reduction of -C horizontal line C group. The reduction process was irreversible over the entire
34
pH range, and the mechanism of reduction was postulated on the basis of controlled potential
electrolysis and coulometry. Application of Tween-20 in the electrochemical determination of
nortriptyline hydrochloride using square-wave voltammetry at the HMDE enhanced the detection
limit of the analyte concentration from 8.24 ng/mL in the absence of surfactant to 0.92 ng/mL
when present (Jain et al., 2009).
The release of nortritptyline hydrochloride from oil-in-water (o/w) microemulsions (isopropyl
myristate as oil, propylene glycol as cosurfactant, polysorbate 80 as surfactant and phosphate
buffer, pH 7.4, as the continuous phase) containing increasing concentrations of polyethylene
glycol 400, used to facilitate the diffusion of a drug from the inner oily phase of the
microemulsion to the outer aqueous phase of such a dispersion system, was studied by
determining the permeability constants of the drug through hydrophilic and lipophilic
membranes separating the o/w microemulsions from the receiving aqueous phase (phosphate
buffer pH 7.4). The permeability of nortriptyline hydrochloride from microemulsions through the
lipophilic membrane increased as the concentration of polyethylene glycol 400 in the disperse
system increased. The apparent permeability constant for nortriptyline hydrochloride, from the
microemulsion without polyethylene glycol, was 1.36 x 10(-3) cm x h(-1), it increased up to 7.80
x 10(-3) cm x h(-1) in the presence of polyethylene glycol at a concentration of 50% (v/v) of the
initial volume of the aqueous phase (Moreno et al., 2000).
In this work a novel method for the determination of nortriptyline in flow-injection systems has
been developed. The proposed method was used for the fast determination of nortriptyline in its
pharmaceutical formulations. The developed technique is very simple, precise, accurate, time
saving, and economical, compared to all of the previously reported methods. The effects of
various parameters on the sensitivity of the method were investigated. The best performance
obtained at pH value of 2, scan rate value of 30 V/s, accumulation potential of 400 mV, and
accumulation time of 0.5 s. The proposed method has some advantages over other reported
methods such as, no need for the removal of oxygen from the test solution, a subnanomolar
detection limit, and finally the method is sufficiently fast for the determination of any such
compound, in a wide variety of chromatographic methods. The potential waveform, consisting of
the potential steps for cleaning, accumulation and potential ramp of analyte, was continuously
applied on an Au disk microelectrode (12.5 microm in radius). The detection limit of the method
35
was 2.0 x 10(-11) M. The relative standard deviation of the method at 1.2 x 10(-8) M was 2.1%
for eight runs (Norouzi et al., 2007).
36
Chapter Three
MATERIALS & METHODS
3.1 MATERIALS
37
3.1.1 Sample Collection

For the purpose of experimentation to observe the photolytic degradation of fluphenazine
hydrochloride and nortriptyline hydrochloride as well as to assess the packaging efficiency, 300
tablets of Norflu (Fluphenazine 0.5 mg &Nortriptyline 10 mg) were collected from the local
drug store in Dhaka as a sample. All the tablets were from the same batch (T1094007). Among
them 100 tablets were kept light protected for control tests and the remaining 200 tablets were
subjected to various lighting conditions over certain periods of time for conducting experiments
to determine their potency.
3.1.2 Samples
Table 3.1: Samples used in the experiment
Sample Name
Source (Supplier Name)
Batch No.
Norflu tablets
Acme pharmaceuticals LTD.
T1094007
3.1.3 Reagents
Table 3.2: Reagents used in the experiment including source
3.1.4
Reagents Name
Source (Supplier Name)
Concentrated Hydrochloric
Acid (35 % )
Distilled Water
MERK, Germany
Laboratory (East West University)
Equipment & Instruments

Table 3.3: Lists of equipment used for the experiment
Serial
No.
Equipments
Source
(Supplier
Name)
Origin
UVSpectrophotometer
Shimadzu UV1800
Japan
Distill Water Plant
SMIC
China
Electronic Balance
Precisa
XB120A
Switzerland
3.1.5 Images of Instruments

38
Some images of important instruments those were used in different tests during research work.
Figure 3.1: [Left to right] Shimadzu UV-1800 Double Beam Spectrophotometer and Electronic
Balance
Figure 4.2: Distilled Water Plant

3.1.6 Apparatus
Some apparatus are listed in the following table those were used throughout the experiments.
Table 3.4: List of Apparatus used throughout this project
Serial No.
1
2
3
4
5
6
7
9
10
11
13
14
Apparatus
Beakers
Thermometer
Test tubes
Volumetric Flasks (25ml,50 ml & 100 ml)
Electric Bulb (25 Watt&40watt)
Plastic Containers
Aluminum foil paper
Filter Papers
Mortar & Pestles
Spatula
Glass Rod
Pipette pumper
39
Serial No.
15
16
17
Apparatus
Pipette (5 ml & 10 ml)
Glass and Plastic Funnel
Lamp
3.2 METHOD
3.2.1. Preparation of the solvent (0.1N HCL)
1) Lab solvent (HCL) stock solution was collected and its strength was found to be 35%
2) Then the concentration of the lab solvent stock solution was determined in Normality
Determination of the Concentration of the Lab Solvent (HCL) in Normality (N):
100 ml of the lab solvent stock solution contains --- 35 gm of HCL
1 ml of the lab solvent stock solution contains ------ (35 / 100) gm of HCL
1000 ml of the lab solvent stock solution contains -- ((35 x 1000) / 100) gm of HCL
= 350 gm of HCL
So, we know that
36.5 gm of HCL present in 1000 ml
=1N
1 gm of HCL present in 1000 ml
= (1 / 36.5) N
350 gm of HCL present in 1000 ml
= ((1 x 350) / 36.5) N
= 9.589 N (~ 9.6 N)
3) After the determination of the concentration of the lab solvent stock solution in
Normality (N), the amount of lab solvent (9.7N HCL) stock solution required to make
250 ml of 0.1N HCL solvent was calculated as below.
Determination of the amount of 9.7N HCL required to make 250 ml of 0.1N HCL:
Using the V1S1 = V2S2,
where,
S1 = Conc. of lab solvent (HCL) stock solution = 9.6 N
S2 = Final concentration of the solvent (HCL) = 0.1 N
V1 = Volume of the lab solvent (HCL) stock solution = ?
V2 = Final volume of the solvent (HCL) = 250 ml
V1 = (V2S2) / S1
=> V1 = (250 ml x 0.1 N) / 9.6 N
=> V1 = 2.604 ml (~ 2.6 ml) of lab solvent (HCL) stock solution
Thus 2.6 ml of 9.6 N HCL is required to be dissolved in 250 ml of water to dilute its
concentration to 0.1 N HCL.
4) Then 2.6 ml of 9.6 N HCL was transferred from the lab solvent stock solution to a
250 ml volumetric flask which was then filled with water up to mark to make 250 ml
of 0.1 N HCL.
40
3.2.2 Determination of max& Preparation of the Standard Curve of Fluphenazine

hydrochloride and Nortriptyline hydrochloride
1) Standards of both Fluphenazine hydrochloride and Nortriptyline hydrochloride was
selected, Sanit of Square pharmaceuticals. The potency of both standard compounds
were 99.99%
2) The specific max for both Fluphenazine hydrochloride and Nortriptyline
hydrochloride, at which the absorbances would be measured, were determined from
the UV spectrometer by using the standards that were obtained from.
3) The specific max for Fluphenazine hydrochloride was determined to be 260nm and for
Nortriptyline hydrochloride, it was determined to be 239 nm.
4) Ten serial concentrations of the Standards of Fluphenazine hyrdrochloride and
Noetriptyline hydrochloride were prepared for the purpose of creating a standard
curve.
Preparation of the stock solution for both Fluphenazine hydrochloride and Nortriptyline
hydrochloride using the standard obtained from:
For Fluphenazine hydrochloride:
-
50 mg of the standard compound, that is Fluphenazine hydrochloride obtained

fromSanitwas weighed and dissolved in 25 ml of 0.1N HCL (which is the solvent) in a 25
ml volumetric flask for the 1st dilution.
Thus the concentration was calculated to be:
Concentration of 1st dilution = amount of substance added / volume
= (50 / 25) mg/ml
= 2 mg/ml
Then 0.5 ml of that 2 mg/ml Fluphenazine hydrochloride solution was taken and
dissolved in 50ml of 0.1N HCL
That 0.5 ml contained 1 mg of Fluphenazine hydrochloride. So the concentration finally

turned out to be:
Concentration of 2nd dilution = amount of substance added / volume
= (1 / 50) mg/ml
= 0.02 mg/ml
41
Then 5 ml of that 0.02 mg/ml Fluphenazine hydrochloride solution was taken and
dissolved in 50ml of 0.1N HCL
That 5 ml contained 0.1 mg of Fluphenazine hydrochloride. So the concentration finally turned

out to be:
Concentration of the stock solution = amount of substance added / volume
= (0.1 / 50) mg/ml
= 0.002 mg/ml
For Nortriptyline hydrochloride:
-
50 mg of the standard of Nortriptyline hydrochloride was weighed and dissolved in 25 ml

of 0.1N HCL in a 25 ml volumetric flask.
Thus the concentration of the 1st dilution was calculated to be:

Concentration of 1st dilution = amount of substance added / volume
= (50 / 25) mg/ml

= 2 mg/ml
Then 0.5 ml of that 2 mg/mlNortriptyline hydrochloride solution was taken and dissolved
in 50 ml of 0.1N HCL.
That 0.5 ml contained 1 mg of Melitracen hydrochloride. So the concentration final turned out to
be:
Concentration of the stock solution = amount of substance added / volume
= 1 / 50 = 0.02 mg/ml
Preparation of five serial concentrations of solution for both Fluphenazine hydrochloride and
Nortriptyline hydrochloride:
-
Both Fluphenazine hydrochloride and Nortriptyline hydrochloride each had

the concentration of their stock solution as 0.002 mg/ml and 0.02 mg/ml
respectively.
Six serial concentrations that were prepared for Fluphenazine hydrochloride

were as follows 0.0001 mg/ml, 0.0002 mg/ml, 0.0003 mg/ml, 0.0004 mg/ml
0.0005mg/ml& 0.0006 mg/ml for a final volume of 10 ml. While for
Nortriptyline hydrochloride the seven serial concentrations prepared were as
follows 0.001 mg/ml, 0.002 mg/ml, 0.003 mg/ml, 0.004 mg/ml 0.005 mg/ml ,
0.006 mg/ml & 0.007 mg/ml for a final volume of 10 ml.
42
Table 3.5: List of Concentrations used for preparation of Standard Curve

of Fluphenazine hydrochloride &Nortriptyline hydrochloride
Sample Name
Fluphenazine
Nortriptyline
Sample no.
1
2
3
4
5
6
1
2
3
4
5
6
7
Concentration (mg/ml)
0.0001
0.0002
0.0003
0.0004
0.0005
0.0006
0.001
0.002
0.003
0.004
0.005
0.006
0.007
The solution that were required from the stock solution to prepare the above
concentrations were calculated using S1V1=S2V2 formula, where S1= initial
strength or concentration, S2= final strength or concentration, V1= initial
volume and V2= final volume.
Thus the following concentrations were prepared as such for Fluphenazine
hydrochloride and Nortriptyline hydrochloride as per the calculations
provided below.
For Fluphenazine hydrochloride

V1= S2V2 / S1 = (0.0001 x 10) / 0.002 = 0.5 ml of stock solution required to make 0.001 mg/ml
concentration of the final solution of 10 ml (0.5 ml of stock solution + 9.5 ml of 0.1N HCL) of
Fluphenazine hydrochloride.
V1= S2V2 / S1 = (0.0002 x 10) / 0.002 = 1 ml of stock solution required to make 0.002 mg/ml
concentration of the final solution of 10 ml (1 ml of stock solution + 9 ml of 0.1N HCL) of
43
concentration of the final solution of 10 ml (1.5ml of stock solution + 8.5 ml of 0.1N HCL) of
V1= S2V2 / S1 = (0.0006x 10) / 0.002 = 3 ml of stock solution required to make 0.006 mg/ml
For Nortriptyline hydrochloride
Nortriptyline hydrochloride.
44
5) Then the Absorbance values were measured using a UV spectrophotometer against

those five serial concentrations each for Fluphenazine hydrochloride and
6) Two standard curves were plotted. One for Fluphenazine hydrochloride and the other
for Nortriptyline hydrochloride.
7) From those standard curve two straight line equations were obtained which were in
the form of y = mx+c, where the components of the equations are described as
provided below:
m = gradient value, y = absorbance values, x = concentrations and c = y-intercept.
3.2.3 Sampling, Analysis by UV-Spectrophotometry & Determination of Potency of the
pharmaceutical drugs (fluphenazine + nortriptyline) under various lighting condition
To determine the photo-stability of the drug (Fluphenazine hydrochloride and
Nortriptyline hydrochloride) in their packaging, the tablets were subjected to various
types of light exposure, which were as follows:
I. Direct Sunlight exposure
II. Dark condition
III.Electric Bulb exposure (25 watt& 40 watt)
1. Under Sunlight condition
1. 36 tablets were kept exposed to sunlight condition for 7 hours at a stretch.
Table 3.6: Direct Sunlight Exposed Sample List

Total Number of
Sample
36
Sample
collection
Interval
(hrs)
Temperature (0C)
1.5
37
34
4.5
32
30
45
2. After every 1.5 hours 9 tablets were collected and wrapped up with foil paper to
prevent any further exposure to the lighting condition and the temperature noted
using a thermometer.
3. The foil papers should be labeled to identify the intervals at which the drugs were
collected.
4. The tablets were then used for potency determination to see the effect of the
exposure of sunlight to the drug components, fluphenazine and nortriptyline.
5. For potency determination, laboratory analysis was done by using UV
spectroscopy technique:
a. First, three tablets from those sampled tablets were taken.
b. Then the total weight of those three tablets was noted using an analytical
balance and the average weight (which is equal to the weight for one tablet
containing both active ingredients and excipients) was calculated using the
formula given below:
c.
Then
Average wt. (in grams) =
Total wt. of the tablets

No. of tablets
the
three tablets were crushed by using mortar and pestle.

d. Next, approximately the weight of 1 tablet of crushed tablet powder was
taken and dissolved in 50 ml of the solvent (0.1N HCl) (leading to 50
times dilution).
e. Afterwards that 50 ml solution was filtered and 10 ml of that filtered
solution was taken from that 50ml of the solution of tablet powder and
solvent and was dissolved in 25ml of the solvent (leading to another 2.5
times dilution; total dilution factor 125 times).
f. Next, 5ml of the solution was taken from that 125 times diluted solution
and was dissolved in another 25ml of the solvent (0.1N HCL)(leading to 5
times dilution; total dilution factor = 50 x 2.5 x 5 = 625 times).
g. Then from there the solution was poured into a cuvette/container and was
inserted into the UV spectrophotometer to observe the absorbance value
for both Fluphenazine hydrochloride and Nortriptyline hydrochloride).
46
6. Then using the absorbance value obtained from UV spectrophotometer, the value
was plotted into the standard curve to obtain the total amount of the drug that is
present in one tablet
7. Steps 5 to 6 were repeated again for another sampling hour.
8. Under Dark Condition
1. 36 tablets were kept in dark condition for 7 hours at a stretch.
Table 3.7: Dark Condition Sample List
1)
Total Number of
Sample collection
Interval (hrs)
Sample
36
1.5
4.5
2)
2. After every 1.5 hours 9 tablets were collected and wrapped up with foil paper to
prevent any further exposure to the lighting condition and the temperature was noted
using a thermometer.
3. The foil papers should be labeled to identify the intervals at which the drugs were
collected.
4. The tablets were then used for potency determination to see the effect of the
exposure of sunlight to the drug components, fluphenazine and nortriptyline.
5. For potency determination, laboratory analysis was done by using UV
47

c.
Then

No. of tablets
the
three tablets were crushed by using mortar and pestle.

times dilution).
and was dissolved in another 25ml of the solvent (0.1N HCL)(leading to 5
6. Then using the absorbance value obtained from UV spectrophotometer, the value
was plotted into the standard curve to obtain the total amount of the drug that was
present in one tablet.
7. Steps 5 to 6 were repeated again for another sampling hour.
3. Under 25 W bulb lighting condition
1) 36 tablets were exposed to 25 W lighting conditions for 7 hours at a stretch.
Table 3.8: Electric (25 W) Bulb Exposed Sample List
48
Total Number of
Sample
36
Sample
collection
Interval
(hrs)
Temperature (0C)
1.5
27
27
4.5
28
28
2) After every 1.5 hours 9 tablets were collected and wrapped up with foil paper to
prevent any further exposure to the lighting condition and the temperature was
noted using a thermometer.
3) The foil papers should be labeled to identify the intervals at which the drugs were
collected.
4) The tablets were then used for potency determination to see the effect of the
exposure of 25 W bulbs lighting condition to drug ingredients: fluphenazine and
Nortriptyline.
5) For potency determination, laboratory analysis was done by using UV

No. of tablets
c. T
c. Then the three tablets were crushed by using mortar and pestle.
times dilution).
49

and was dissolved in another 25ml of the solvent (0.1N HCl) (leading to 5
6) Then using the absorbance value obtained from UV spectrophotometer, the value
7) Steps 5 to 6 were repeated again for another sampling hour.
4. Under 40 W bulb lighting condition
1) 36 tablets were exposed to 40 W lighting conditions for 7 hours at a stretch.
Table 3.9: Electric (40 W) Bulb Exposed Sample List

Total Number of
Sample
36
Sample
collection
Interval
(hrs)
Temperature (0C)
1.5
32
34
4.5
34
34
50
2) After every 1.5 hours 9 tablets were collected and wrapped up with foil paper to
prevent any further exposure to the lighting condition and the temperature was
noted using a thermometer.
3) The foil papers should be labeled to identify the intervals at which the drugs were
collected.
4) The tablets were then used for potency determination to see the effect of the
exposure of 25 W bulbs lighting condition to drug ingredients: fluphenazine and
nortriptyline.
5) For potency determination, laboratory analysis was done by using UV

No. of tablets
c. T
c. Then the three tablets were crushed by using mortar and pestle.
times dilution).
and was dissolved in another 25ml of the solvent (0.1N HCl) (leading to 5
51
6) Then using the absorbance value obtained from UV spectrophotometer, the value
7) Steps 5 to 6 were repeated again for another sampling hour.
52
Chapter Four
RESULT AND ANALYSIS
4.1 Standard curve preparation for Nortriptyline

The standard curve was made from Sanit, produced by Square Pharmaceuticals Ltd. For
different concentration of Nortriptyline hydrochloride we found different absorption. The results
are as follows:
Table 4.1: Concentration and Respective Absorbance for Standard Curve of Nortriptyline
Hydrochloride
Absorbance (at 239 nm)
0.001
0.218
0.002
0.277
0.003
0.332
53
0.004
0.362
0.005
0.404
0.006
0.466
0.007
0.534
By plotting the absorbance against the concentration of Nortriptyline hydrochloride a straight

line was found. From this an equation was derived where:
Y=49.92X+0.170 and R2=0.989
This equation was used to determine the concentration of Nortriptyline hydrochloride from
different samples absorbance
Figure 4.1: Plot showing straight line for Absorbance with respect to Concentration for
Nortriptyline
4.1.1 Result from sample that was exposed to sunlight
For our research purpose we have exposed tablets to the sunlight condition. We found 4 different
absorbance of Nortriptyline hydrochloride for four samples exposed to the sunlight and the
temperature was recorded respectively 37C, 34C, 32C and 30C each for 1.5 hour time
interval and it was observed that the concentration of Fluphenazine hydrochloride was declined
in each 1.5 hour time interval.
54
Table 4.1.1: Difference in Concentration and Absorbance in each 1.5 Hour time interval for
Nortriptyline hydrochloride
Time
Absorbance
Diluted Concentration
Original Amount
Interval
(at 239 nm)
from Samples in mg/ml
of Drug present
(625 times diluted)
(mg)
Potency (%)
0 hour
1.000
0.0157
9.81
98.13
1.5 hour
0.803
0.0126
7.875
78.75
3 hour
0.785
0.0123
7.687
76.88
4.5 hour
0.691
0.0104
6.50
65.00
6 hour
0.476
0.0061
3.812
38.12
Figure 4.1.1: Graph showing the difference in Concentration after each 1.5 hours time interval
for Nortriptyline hydrochloride
4.1.2 Result from sample that was kept in dark
For our research purpose we have kept the tablets in dark condition. We found 4 different
absorbance of Nortriptyline hydrochloride for four samples kept in dark condition covering the
strips with foil paper, each for 1.5 hour time interval and it was observed that the concentration
of Fluphenazine hydrochloride remains average in each 1.5 hour time interval.
Table 4.1.2: Difference in Concentration and Absorbance in each 1.5 hours time interval for
55
Time
Absorbance (at
Diluted
Original
Interval
239 nm)
Concentration from
Amount of
Samples in mg/ml
Drug present
(625 times diluted)
(mg)
Potency (%)
0 hour
0.954
0.0155
9.69
96.95
1.5 hour
0.899
0.0146
9.13
91.3
3 hour
0.834
0.0133
8.31
83.10
4.5 hour
0.774
0.012
7.5
75
6 hour
0.748
0.115
7.18
71.8
Figure 4.1.2: Graph showing the Concentration after each 1.5 hours time interval for
4.1.3 Result from Samples that were exposed to under Lamp (25 watt)
We found four different absorbance of Fluphenazine hydrochloride for four samples exposed to
the lamp (25 watt), each for 1.5 hour time interval and it was observed that the concentration of
Fluphenazine hydrochloride was declined in each 1.5 hour time interval.
56
Time
Absorbance (at
Diluted
Original
Interval
260nm)
Concentration from
Amount of
Samples in mg/ml
Drug present
(625 times diluted)
Potency (%)
(mg)
0 hour
0.872
0.0137
8.63
86.38
1.5 hour
0.812
0.0128
8.037
80.37
3 hour
0.684
0.0102
6.435
64.35
4.5 hour
0.676
0.0101
6.335
63.35
6 hour
0.552
0.0084
5.233
52.33
Nortriptyline hydrochloride was declined in each 1.5 hour time interval
57
Time
Absorbance
Original Amount of
Interval
(at 239nm)
Drug present (mg)
Potency (%)
(625 times diluted)

0 hour
0.850
0.0135
8.46
84.68
1.5 hour
0.829
0.0132
8.250
82.50
3 hour
0.826
0.0131
8.187
81.87
4.5 hour
0.808
0.0128
8.00
80.00
6 hour
0.789
0.0124
7.75
77.50
4.2 Standard curve preparation for Fluphenazine Hydrochloride
The standard curve was made from Sanit, which is produced by Square Pharmaceuticals Ltd.
For different concentration of Fluphenazine hydrochloride and we found different absorption.
The results are as follows:
Table 4.2: Concentration and Respective Absorbance for Standard Curve of Fluphenazine
Hydrochloride
58
Absorbance (at 260 nm)
0.0001
0.048
0.0002
0.079
0.0003
0.135
0.0004
0.172
0.0005
0.22
0.0006
0.279
By plotting the absorbance against the concentration of Fluphenazinehydrochloride a straight

line was found. From this an equation was derived where:
Y=461.6X-0.006 and R2=0.993
This equation was used to determine the concentration of Fluphenazine hydrochloridefrom
different samples absorbance.
Figure 4.2: Plot showing straight line for absorbance with respect to concentration for
Fluphenazine
4.2.1 Result from sample that was exposed to sunlight
59
For our research purpose we have exposed tablets to the sunlight condition. We found 4 different
absorbance of Fluphenazine hydrochloride for four samples exposed to the sunlight and the
temperature was recorded respectively 37C, 34C, 32C and 30C each for 1.5 hour time
interval and it was observed that the concentration of Fluphenazine hydrochloride was declined
in each 1.5 hour time interval.
Fluphenazine hydrochloride
Time
Absorbance (at
Original Amount
Potency (%)
Interval
260nm)
from Samples in
of Drug present
mg/ml(625 times
(mg)
0.471
94.41
0 hour
0.340
diluted)
0.00074
1.5 hour
0.260
0.00057
0.360
72.06
3 hour
0.251
0.00051
0.348
69.62
4.5 hour
0.214
0.00047
0.298
59.60
6 hour
0.086
0.00019
0.124
24.92
60
Figure 4.2.1Graph showing the difference in Concentration after each 1.5 hour time interval for
4.2.2 Result from sample that was kept in dark
For our research purpose we have kept the tablets in dark condition. We found 4 different
absorbance of Fluphenazine hydrochloride for four samples kept in dark condition covering the
strips with foil paper, each for 1.5 hour time interval and it was observed that the concentration
of Fluphenazine hydrochloride remains average in each 1.5 hour time interval.
Time
Absorbance (at
Original Amount
Interval
260nm)
of Drug present
(625 times diluted)
(mg)
Potency (%)
0 hour
0.265
0.00058
0.367
73.68
1.5 hour
0.256
0.00056
0.354
70.97
3 hour
0.253
0.00056
0.350
70.16
4.5 hour
0.249
0.00055
0.345
69.08
6 hour
0.233
0.00051
0.323
64.74
61
Figure 4.2.2: Graph showing the Concentration after each 1.5 hour time interval for
Time
Absorbance (at
Diluted
Original
Interval
260nm)
Concentration from
Amount of
Samples in mg/ml
Drug present
(625 times diluted)
(mg)
Potency (%)
0 hour
0.265
0.00058
0.367
73.68
1.5 hour
0.255
0.00056
0.353
70.70
3 hour
0.253
0.00056
0.350
70.16
4.5 hour
0.242
0.00053
0.335
67.18
6 hour
0.231
0.00051
0.321
64.20
62
Figure 4.2.3:Graph showing the difference in Concentration after each 1.5 hour time interval for
Time
Absorbance (at
Original
Interval
260nm)
Amount of
(625 times diluted)
Drug present
Potency (%)
(mg)
0 hour
0.267
0.00058
0.369
74.09
1.5 hour
0.247
0.00054
0.342
68.54
3 hour
0.236
0.00052
0.327
65.56
4.5 hour
0.224
0.00049
0.311
62.31
6 hour
0.195
0.00043
0.272
54.45
63
Figure 4.10: Graph showing the difference in Concentration after each 1.5 hour time interval for
Chapter Five
64
DICUSSION
In our experiment we found that the concentration of Fluphenazine hydrochloride and

Nortriptyline hydrochloride decreased gradually in every ovation of light exposure.
We found that the potency of the sample we used, which is Noflu , gradually decreased with
time when exposed to sunlight. At Zero hour the potency was about 100% but after 6 hours of
sunlight exposure the potencies of Nortriptyline and Fluphenazine were 38.12% and 24.92%
respectively. This means with sunlight exposure the concentration falls drastically.
However when we exposed our sample in dark condition for the same time interval, the potency
decline was not so drastic.
When we kept our sample tablet under the electrical bulb (25 watt & 40 watt) and tested them
after every one and half hour, we saw that the concentration of Fluphenazine hydrochloride and
Nortriptyline hydrochloride decreased gradually. When kept under 25 Watt light exposure the
degradation of Nortriptyline hydrochloride was faster compared to that of 40 Watt light exposure.
In the dark the degradation result was similar to that of 25 Watt light exposure. There was no
consistency in the results. So the reason for potency degradation might be for transparent blister
packaging and for some other reasons. Further research needs to be done in order to come to an
effective conclusion.
65
Chapter Six
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74

Determination of Packaging Efficiency of Norflu (Fluphenazine-Nortriptyline) in Case of Normal Packaging

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ABSTRACT

1.1 About antipsychotic medications

The experience of hearing voices (hallucinations).

1.1.2 Types of antipsychotics

fewer side-effects such as trembling or stiffening of muscles

Table 1: Food and Drug Administration-approved first-generation antipsychotics (Seida et

Age Group for Which

Adults and children (112 years)

Severe behavioral problems

Adults and children

Adults and children 12 years

Generalized nonpsychotic anxiety

Table 2: Food and Drug Administration-approved second-generation antipsychotics (Seida

Age Group for Which

Age Group for Which

Bipolar disorder (manic/mixed)

monotherapy or adjunctive to lithium or

Children (617 years)

Treatment resistant schizophrenia

younger patients with schizophrenia

Bipolar disorder (acute manic)

Adults and adolescents (1317

Major depressive disorder

Adults and adolescents (1317

Age Group for Which

Irritability associated with autism

Children (516 years)

Bipolar disorder (maintenance)

Acute agitation in patients with

1.1.3 Mechanism of action of antidepressants

1.1.4 Dosage of antipsychotic medications

1.1.5 Side-effects of antipsychotic medications (Mental Health Care, 2014)

Parkinson's disease - for example, tremor and muscle stiffness.

1.2 Antidepressant medications (Timms, 2012b, Sane Australia, 2014b)

1.2.1 Types of antidepressant medications (Mayo Clinic Staff, 2011)

2) MAOIs (Monoamine oxidase inhibitors):

3) SSRIs (Selective Serotonin Reuptake Inhibitors):

4) SNRIs (Serotonin and Noradrenaline Reuptake Inhibitors):

1.2.3 Dosage of antidepressant medications (National Health Service, 2013)

1.2.4 Common side effects of antidepressants (Allen, 2011)

1.3 Fluphenazine (College of Psychiatric and Neurologic Pharmacists, 2013)

Figure: Fluphenazine structure

Figure: Synthesis of Fluphenazine

1.3.2 Fluphenazine hydrochloride (U.S. National Library of Medicine, 2011)

Figure: Structure of Fluphenazine hydrochloride

FluphenazineHydrochloride is 510.44. Fluphenazine hydrochloride tablets are indicated in the

1.4 Nortriptyline (U.S. National Library of Medicine, 2014)

neurotransmitter. It is believed that by restoring the balance of these different neurotransmitters

Figure: Nortriptyline structure

1.4.1 Nortriptyline synthesis (Vardanyan and Hruby, 2006)

way utilizes the reaction of methaylamine with 5-(3-bromopropyliden)-10,11-dihyadro-5Hdibenmz[a,d]cycloheptene.

Figure: First method of nortriptyline synthesis

Figure: Second method of nortriptyline synthesis

Figure: Third method of nortriptyline synthesis

1.4.2 Nortriptyline hydrochloride (U.S. National Library of Medicine, 2014)

Figure: Structure of Nortriptyline hydrochloride

1.5 Fluphenazine-Nortriptyline combination

Table: Showing different Fluphenazine-Nortriptyline combination drugs sold by various

Generic Name Pharmaceuticals

1.5.1 Pharmacology (Square Pharmaceuticals, 2014)

1.5.2 Indications (Square Pharmaceuticals, 2014)

1.5.3 Dosage and administration (Square Pharmaceuticals, 2014)

1.5.4 Contraindication and precaution (Ineson, 1996)