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
• Chlorpromazine 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/Shelf Life
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.
Oral preparations of chlorpromazine hydrochloride should be stored in tightly closed
containers... 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.
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
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.
§ (Martindale, 1993).
§ 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)
§ 1 to 5 years 40 mg
§ More than 5 75 mg
Years

partition coefficient
Lipid suspensions containing from 0.1 to 0.2% by weight dimyristoylphosphatidylcholine
were mixed in a flow calorimeter with equal volumes of chlorpromazine hydrochloride at
concentrations ranging from 6×10−5 to 1.2×10−4 M. The vesicle 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

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.
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 (Martindale, 1989).
The sulfoxides of the phenothiazines have been
intensively studied and found to be significantly less
potent than the parent compound.
• 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.
Methods of Manufacturing
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. This material should be handled and stored per
label instructions to ensure product integrity.
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
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.