MAZAYA UNIVERSITY College

PHARMACY
5TH STAGE
DOSAGE FORM REPORT
FATIMA KAMEL KOMER
DESCRIPTION
Thorazine (chlorpromazine) is 10-(3-dimethylaminopropyl)-2-chlorphenothiazine, a
dimethylamine derivative of phenothiazine.is a phenothiazineanti-psychotic medication
used to treat psychotic disorders such as schizophrenia or manic-depression, and severe
behavioral problems in children. Thorazine is also used to treat nausea and vomiting,
anxiety before surgery, chronic hiccups, acute intermittent porphyria, and symptoms
of tetanus.

PHYSICO-CHEMICAL PROPERTIES
 Colour
White to creamy-white (Base and hydrochloride)
Both forms darken on prolonged exposure to light.
 State/Form
Powder or waxy solid (Base)
Crystalline powder (Hydrochloride)
 Description
Chlorpromazine base
Odourless or with an amine-like odour
 Melting point 56°C to 58°C.
 Boiling Point 200°C to 205 °C.
 Protein Binding
> 90% to plasma proteins, primarily albumin
 solubility
is practically insoluble in water, soluble 1 in 2 of alcohol, 1 in less than 1 of
chloroform, and 1 in 1 of ether. USP solubilities are 1 in 3 of alcohol, 1 in 2 of
chloroform, and 1 in 3 ether; freely soluble in dilute mineral acids; practically
insoluble in dilute alkali hydroxides. Chlorpromazine hydrochloride Soluble 1 in 0.4
of water, 1 in 13 of alcohol and of chloroform, and practically insoluble in ether. A
10% aqueous solution has a pH of 3.5 to 4.5.
 Stability
Chlorpromazine and its hydrochloride salt darken on prolonged exposure to light.
Commercially available preparations of chlorpromazine and its hydrochloride salt
should be protected from light.
 partition coefficient
Lipid suspensions containing from 0.1 to 0.2% by weight were mixed in a flow
dimyristoylphosphatidylcholine calorimeter with equal volumes of chlorpromazine
hydrochloride at concentrations ranging from 6×10−5 to 1.2×10−4 M. The vesicle
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 bilayer volume fraction of the suspension was determined by density measurements.
Linear relationships were obtained between heat production per ml suspension and
chlorpromazine concentration at each level of lipid volume. Using phase partitioning
as a model, the values of the partition coefficient and the enthalpy change were found
to be Kc′=1300 and ΔH=−30 kJ·mol−1 at 25°C
 Shelf Life 2 years

Excipients
 Tablets
 Lactose
 maize starch
 colloidal silicon dioxide
 magnesium stearate
 hypromellose
 polyethylene glycol 200
 titanium dioxide
 Ampoules
 Sodium sulfite anhydrous
 sodium metabisulfite
 sodium chloride
 sodium citrate
 water for injections

Brand names
 Ampliactil
 Cesalgin
 Largactil
 Promactil
 Thorazine
 Aminasine

Formulation
 Injection (Hydrochloride)
 Solution of 0.5% (25 mg) and 2.5% (50 mg)
 Tablets (Hydrochloride)
 25 mg, 100 mg
 Oral suspension (Embonate)
 Suppository (Base) 100 mg

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Therapeutic dosage

Adults
 Oral (Hydrochloride) 25 mg to 50 mg three times a day (initial dose). 75 mg at
night as a single dose. 25 to 100 mg three times daily (maintenance dose). 1 g or
more per day (certain psychotic patients)
 Parenteral
 Intramuscular 25 to 50 mg three to 4 times daily.
 Intravenous 25 mg to 50 mg (repeated as required).
 Rectal Up to 4 x 100 mg suppositories may be given in 24 hours
Note : Dosage of above forms varies according to the individual patient and
to the indication
Children
 Oral 0.5 mg/kg bodyweight every 4 to 6 hours.
 Parenteral
 Intramuscular 500 mcg/kg bodyweight every 6 to 8 hours.
 Rectal 25 mg suppositories available.
Note : For psychiatric indications in children over 5 years of age, one-third to
one-half the adult dose of the above dose forms may be given.
 Maximum daily doses for children (all dose forms)
 to 5 years 40 mg
 More than 5 Years 75 mg
Mode of action
 Toxicodynamics
Chlorpromazine has a wide range of activity arising from its depressant actions on the
central nervous system and its alpha-adrenergic blocking and weak antimuscarinic
activities.Chlorpromazine possesses sedative properties but patients usually develop
tolerance rapidly to the sedation. Its action on the autonomic system produces vasodilation,
hypotension, and tachycardia. Salivary and gastric secretions are reduced The sulfoxides
of the phenothiazines have been intensively studied and found to be significantly less
potent than the parent compound.

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  Pharmacodynamics
It is a dopamine inhibitor. In inhibits prolactin release inhibitory factor, thus stimulating
the release of prolactin. The turnover of dopamine in the brain is also increased. There is
some evidence that the antagonism of central dopaminergic function, especially at the
postulated D2-dopaminergic receptor, is related to therapeutic effect in psychotic
conditions.Chlorpromazine has anti-emetic, antipruritic, serotonin-blocking, and weak
antihistaminic properties, but slight ganglion-blocking activity. It inhibits the heat
regulating centre so that the patient tends to acquire the temperature of his surroundings
(poikilothermism). Chlorpromazine can relax skeletal muscle. It has membrane-stabilizing
and hence local anaesthetic properties.

KINETICS
 Absorption
Chlorpromazine is readily absorbed from the gastrointestinal tract but is subject to
considerable first-pass metabolism in the gut and the liver. Following oral administration,
peak plasma levels are reached in 1-4 hours; following intramuscular injection, peak
plasma levels usually occur in 15 - 30 minutes. Oral absorption is erratic and incomplete
with 10 - 80% of the oral dose reaching the systemic circulation. There is wide inter-subject
variation.
 Distribution
Chlorpromazine is widely distributed to the body tissue. It crosses the blood-brain barrier
and achieves higher concentrations in the brain than in the plasma. The average volume of
distribution of chlorpromazine is quite large, ranging from 10 - 35 L/Kg (mean 22 L/Kg). It
is highly protein-bound (90 - 99%). Chlorpromazine has been detected in urine for up to
one year after discontinuation of chronic administration.
 Metabolism
Chlorpromazine metabolism is complex. There is extensive first pass metabolism after oral
administration, accounting for a low oral bioavailability of unchanged drug, especially at
low oral doses. Over 150 metabolites have been postulated of which about half have been
detected in blood and urine. Major metabolic pathways are hepatic and include
demethylation, N-oxidation, sulphoxidation, deamination and conjugation. The metabolites
of clinical importance appear to be 7- hydroxychlorpromazine,3-hydroxychlorpromazine,
desmethylchlorpromazine and chlorpromazine N-oxide, all of which are biologically
active; and chlorpromazine sulphoxide, which is not biologically active. Chlorpromazine is
almost completely metabolised with less than 1% excreted in the urine as unchanged drug.
Serum levels of unchanged drug and clinical effect do not correlate well. A therapeutic
serum level is usually between 100-300ng/mL and toxic effects appear by 750ng/mL but
routine serum level monitoring is not necessary. Serum levels in chronic dosing may be
lower than those reached after acute dosing.
 Excretion
Chlorpromazine and its metabolites are removed from the body significantly in the urine, in
small amounts in faeces and in lesser amounts in sweat and hair. Average urinary excretion
in 24 hours ranges from 43 - 65% of the daily dose. There is a wide variation in the
elimination half lives proposed by various groups, and also wide inter-patient variation.
There may be several elimination phases consisting of an early phase of 2 - 3 hours, an
intermediate phase of 15 hours and a late phase of up to 60 days.
 Methods of Manufacturing

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 Heating 2-chlorophenothiazine and (3-chloropropyl) dimethylamine in the presence of
sodamide, followed by reaction with hydrogen chloride

Handling and Storage

Chlorpromazine hydrochloride oral solutions, tablets, and injection should be stored at a
temperature less than 40 °C, preferably between 15-30 °C; freezing of the oral solutions and
injection should be avoided. ... Chlorpromazine suppositories should be stored in well-closed
containers between 15-30 °C. ...Chlorpromazine hydrochloride oral concentrate solution should
be dispensed in amber glass bottles. Store in tight, light-resistant container. Slight yellowish
discoloration of the oral solutions or injection will not affect potency or efficacy, but they should
not be used if markedly discolored or if a precipitate is present. At the time of manufacture, air
in the containers of the commercially available chlorpromazine hydrochloride injection is
replaced with nitrogen to avoid oxidation.This material should be handled and stored per
label instructions to ensure product integrity.

Clinical Laboratory Methods

Gas-chromatographic analysis of chlorpromazine and some of its metabolites in human serum,
with use of a nitrogen detector.Mass fragmentography and gas-liquid chromatography can be
used to detect low levels of neuroleptics in man.High pressure liquid chromatography with an
electrochemical detector or ultraviolet detector can be used for determination of chlorpromazine
in plasma. Alternatively, chlorpromazine can be measured directly in plasma with a suitable
radioimmunoassay.

Detection in Body Fluids

method for the estimation of free and conjugated chlorpromazine in bio- logical fluids. This is
based on the fact that chlorpromazine causes a fairly sensitive reaction with sulphuric acid.
extracted with ether in an alkaline medium and then a salt is reformed which in the The
chlorpromazine base is presence of sulphuric acid gives a carmine red coloration. This
coloration is very stable and extremely sensitive, determination of quantities as small as 1:
800,000 being possible using Meunier's electro- photometer.

Case reports
Report of a 54-year-old woman on chlorpromazine who had a 15-year old history of pruritic
eruptions in light exposed areas.Recurrences had occurred once or twice a year.An eruption on
the hands occurred more frequently. Subsequent skin tests indicated that she had a combination
of 3 types of hypersensitivity to chlorpromazine, i.e. allergic contact dermatitis, photocontact
dermatitis and immediate allergic photosensitivity