SEMISOLID
Questions:
1.
What are the ideal
characteristics required for suppository bases? Write about two bases. [4]
(1999, 2001)
2.
Dispense 12 nos. of
suppositories of boric acid (D=1.6) each weighing 4 grams and containing 300mg
of Boric acid. [5] (1998)
3.
What is displacement value and
how do you calculate it? [2] (1999)
4.
Describe the procedure for the
preparation of cocoa butter suppositories containing zinc oxide as medicament.
[5] (1998)
TYPES
OF SUPPOSITORIES
1. Rectal suppositories: These are meant for introduction into the
rectum for local and systemic effect.
2.
Pessaries: These are
meant for introduction into vagina for local action. These are larger than
rectal suppositories (3 – 6 gm).
3.
Urethral bougies: These are meant
for introduction into urethra.
Weight: 2 – 4 gm Length:
2 – 5 inches.
4. Nasal bougies: These are meant for introduction
into nasal cavities.
Weight: 1gm Length:
9 – 10 cm
Properties of ideal suppository base
1.
It should melt at body
temperature or dissolve or disperse in body fluid.
2.
Release medicaments easily.
3.
Shape should remain intact
while handling.
4.
Non-toxic and non-irritant to
mucous membrane.
5.
Stable on storage.
6.
Compatible with any added
ingredients.
7.
Easily moulded and should not
adhere to the mould.
Classification of suppository bases
1.
Fatty bases – they melt at body
temperature.
2.
Water-soluble or water miscible base –
they dissolve or disperse in rectal secretions.
3.
Emulsifying bases – they emulsifies
small amount of aqueous solution of drug.
FATTY BASES
Example: Theobroma oil
(Cocoa butter), Synthetic fats.
Theobroma oil (Cocoa butter)
·
It is a yellowish-white solid
having chocolate flavor.
·
It is a mixture of glyceryl
esters of stearic, palmitic, oleic and other fatty acids.
Advantages:
(a)
A melting point range of 30 to
36 0C; hence it is solid at normal room temperatures but melts in
the body.
(b)
Ready liquefaction on warming
and rapid setting on cooling.
(c)
Miscibility with many
ingredients.
(d)
Blandness i.e. does not produce
irritation.
Disadvantages:
(a) Polymorphism
Cocoa butter has
three polymorphs a-crystals (unstable, m.p. 200C),
b-crystals (stable, m.p. 360C) and g-crystals (unstable, 150C).
When melted and
cooled it solidifies in different crystalline forms, depending on the
temperature of melting, rate of cooling and size of the mass. If melted below
360C and slowly cooled it forms stable b-crystals with normal melting point, but if over-heated it may
produce, on cooling, unstable g-crystals,
which melt at about 150C, or a-crystals, melting at about 200C. These unstable forms
eventually return to the stable condition but this may take several days and
meanwhile, the suppositories may not set at room temperature or, if set by
cooling, may remelt in the warmth of the patient’s home.
This lowering of
the solidification point can also lead to sedimentation of suspended solids.
Consequently, great care must be taken to avoid over-heating the base when
making theobroma oil suppositories.
(b) Adherence
to mould
Because
theobroma oil does not contract enough on cooling to loosen the suppositories
in the mould, sticking may occur, particularly if the mould is worn. This is
prevented by lubricating the mould before use.
(c) Softening
point too low for hot climates
To raise the
softening point, whit beeswax may be added to theobroma oil suppositories
intended for use in tropical and subtropical countries.
(d) Melting
point reduced by soluble ingredients
Substances, such
as chloral hydrate, that dissolve in theobroma oil, may lower its melting point
to such an extent that the suppositories are too soft for use. To restore the
melting point, a controlled amount of white beeswax may be added.
(e) Slow
deterioration during storage
This is due to
oxidation of the unsaturated glycerides.
(f) Poor
water absorbing capacity
This fault can be
improved by the addition of emulsifying agents.
(g) Leakage
from the body
Sometimes melted
base escapes from the rectum or vagina. This is most troublesome with pessaries
because of their larger size, and therefore, these are rarely made with
theobroma oil.
(h) Relatively
high cost
Synthetic fats
As a substitute
of theobroma oil a number of
hydrogenated oils, e.g. hydrogenated edible oil, arachis oil, coconut oil, palm
kernel oil, stearic and a mixture of oleic and stearic acids are recommended.
[N.B. Synthetic
suppositories bases are by hydrogenation and subsequent heat treatment of
vegetable oils such as palm oil and arachis oil. The oils are generally esters
of unsaturated fatty acids. Hydrogenation saturates the unsaturated fatty acids
and heat treatment splits some of the triglycerides into fatty acids and
partial esters (mono- and di-glycerides). ]
Advantages of these synthetic fats over theobroma oil:
1.
Their solidifying points are
unaffected by overheating.
2.
They have good resistance to
oxidation because their unsaturated fatty acids have been reduced.
3.
Their emulsifying and water
absorbing capacities are good. [They usually contain a proportion of partial
glycerides some of which, e.g. glyceryl monostearate, are w/o emulsifying
agents and, therefore, their emulsifying and water absorbing capacity are good.
4.
No mould lubricant is required because they
contract significantly on cooling.
5.
They produce colorless,
odourless and elegant suppositories.
Disadvantages:
1.
They should not be cooled in
refrigerator because they become brittle if cooled quickly. Certain additives
e.g. 0.05 % polysorbate80, help to correct this fault.
2.
They are more fluid than
theobroma oil when melted and at this stage sedimentation rate is greater. Thickeners such as
magnesium stearate , bentonite and colloidal silicon dioxide, may be added to
reduce this.
WATER SOLUBLE
AND WATER MISCIBLE BASES
Glycero-Gelatin base
·
This is a mixture of glycerol
and water made into a stiff jelly by adding gelatin.
·
It is used for the preparation
of jellies, suppositories and pessaries. The stiffness of the mass depends upon
the proportion of gelatin used which is adjusted according to its use.
·
The base being hydrophilic in
nature, slowly dissolves in the aqueous secretions and provide a slow
continuous release of medicament. Glycerogelatin base is well suited for
suppositories containing belladonna extract, boric acid, chloral hydrate,
bromides, iodides, iodoform, opium, etc.
·
Depending upon the
compatibility of the drugs used a suitable type of gelatin is selected for the
purpose. Two types of gelatins are used as suppository base
(i) Type-A
or Pharmagel-A which is made by acid hydrolysis (has isoelectric point between
7 to 9 and on the acid side of the range behaves as a cationic agent, being
most effective at pH 7 to 8. ) is used for acidic drugs.
(ii) Type-B
or Pharmagel-B which is prepared by alkaline hydrolysis (having an
isoelectric point between
4.7 to 5 and on the alkaline side of the range behaves as an anionic agent,
being most effective at pH 7 to
8 ) is used for alkaline drugs
Disadvantages:
Glycerogelain
base suppositories are less commonly used than the fatty base suppositories
because:
(i)
Glycerol has laxative action.
(ii)
They are more difficult to
prepare and handle.
(iii) Their solution time depends on the content and quality of the
gelatin and the age of the base.
(iv) They are hygroscope, hence must be carefully stored.
(v)
Gelatin is incompatible with
drugs those precipitate with the protein e.g. tannic acid, ferric chloride,
gallic acid, etc.
Soap-Glycerin Suppositories
·
In this case gelatin and curd
soap or sodium stearate which makes the glycerin sufficiently hard for
suppositories and a large quantity of glycerin upto 95% of the mass can be
incorporated.
·
Further the soap helps in the
evacuation of glycerin.
·
The soap glycerin suppositories
have the disadvantage that they are very hygroscopic, therefore they must be
protected from atmosphere and wrapped in waxed paper or tin foil.
Polyethylene glycol bases / Macrogol bases
(Carbowaxes)
Depending on
their molecular weight they are available in different physical forms.
Examples of
Macrogol bases:
I
|
II
|
III
|
IV
|
||
Macrogol 400
Macrogol 1000
Macrogol 1540
Macrogol 4000
Macrogol 6000
Water
|
-
-
-
33
47
20
|
-
-
33
-
47
20
|
20
-
33
-
47
-
|
-
75
-
25
-
-
|
By choosing a
suitable combination a suppository base with the desired characteristics can be
prepared.
Advantages:
1.
The mixtures generally have a
melting point above 420C, hence, does not require cool storage and
they are satisfactory for use in hot climate.
2.
Because of the high melting
point they do not melt in the body cavity, rather they gradually dissolve and
disperse, releasing the drug slowly.
3.
They do not stick to the wall
of the mould since they contract significantly on cooling.
EMULSIFYING
BASES
These are synthetic
bases and a number of proprietary bases of very good quality are available, few
of which are described below:
Witepsol
They consist of
triglycerides of saturated vegetable acids (chain length C12 to C18) with
varying proportions of partial esters.
Massa Esterium
This is another
range of bases, consisting of a mixture of di-, tri- and mono- glycerides of
saturated fatty acids with chain lengths of C11 to C17.
Massuppol
It consists of
glyceryl esters mainly of lauric acid, to which a small amount of glyceryl
monostearate has been added to improve its water absorbing capacity.
Advantages of these bases over cocoa butter:
1.
Over heating does not alter the
physical characteristics.
2.
They do not stick to the mould.
They do not require previous lubrication of the mould
3.
They solidify rapidly.
4.
They are less liable to get
rancid.
5.
They can absorb fairly large
amount of aqueous liquids.
Preparation of Suppositories
Moulds
The
suppository and pessary moulds are made of metals and have four, six or twelve
cavities. By removing a screw, they can be opened longitudinally for
lubrication, extraction of the suppositories and cleaning.
[N.B. The interior of the mould should
never be scrapped or rubbed with abrasive. For cleaning they are immersed in
hot water containing detergent, wiped gently with soft cloth and rinsed
thoroughly.]
Capacity
of moulds
The
nominal capacities of the common moulds are 1g, 2g, 4g and 8g.
Calibration
The
nominal capacity of a mould varies with the base selected. Each mould should be
calibrated before use by preparing a set of suppositories or pessaries using
the base alone, weighing the products and taking the mean weight as the true capacity. This procedure is
repeated for each base.
Displacement value
The
volume of a suppository from a particular mould is uniform but its weight will
differ with the density of the base.
Definition
It
is the quantity of the drug that displaces one part of the base. e.g. Zinc
oxide, D = 5.
Calculation of displacement value
Formula for calculation of the amount of base required in each mould
Lubrication of mould
If
the cavities are imperfect, i.e. poorly polished or scratched, it may be
difficult to remove the suppositories without damaging their surfaces. So
lubrication of the moulds is necessary.
In case of greasy or oily base water
soluble lubricants are required.
e.g. For cocoa butter the following
lubricant solution formula may be used:
Soft
soap 10g
Glycerol 10ml
Alcohol(90%) 50ml
For water soluble /miscible bases oily lubricant
may be used. e.g. For glycero-gelatin base liquid paraffin or arachis oil may
be used as lubricant.
Preparation method
(i)
Cold Hand Shaping
1.
Drug is triturated in a mortar
into fine powder.
2.
Cocoa butter is grated into
small particles.
3.
Drug is mixed with small
portion of cocoa butter in a mortar.
4.
One drop fixed vegetable oil is
added to give plasticity to the mass.
5.
Remainder of the cocoa butter
is added by geometric dilution (i.e. by adding the same amount of base as is
already in the mortar), triturated wit pressure. Heat generated by trituration
results in a plastic mass, which is cohesive and ready to roll.
6.
The mass is scrapped from the
mortar with a spatula and rolled into a ball.
7.
An ointment tile is taken,
dusted lightly with starch powder, ball is placed on it, rolled with a flat
faced spatula to form a cylinder. The cylinder is cut into desired number of
pieces with a sharp blade.
8.
One end of a suppository is
held firmly with a finger and the other end is tapered with the spatula to give
the shape of suppository.
(ii)
Cold compression
In
this case an instrument known as compression mould is used.
1.
Drug is powdered and mixed with
grated cocoa butter.
2.
The mixture is filled into a
chilled cylinder. The mixture is pressed within the cylinder by a piston until
a pressure is felt.
3.
Then the suppositories are
expelled from the cylinder.
(iii)
Fusion
This
is the main method of preparing suppositories.
1.
Drug is powdered in a mortar.
2.
Carefully grated cocoa butter
is taken into a beaker and heated in a water bath. When 2/3rd
portion is melted the beaker is taken out of the heat source. The rest of the
mass is melted by stirring with a glass rod. [If cocoa butter is heated to
clear liquid then unstable a, and g - crystals will form and the suppositories will remain in melted
state at room temperature.]
3.
Drug is added into the beaker
and stirred thoroughly to mix with the “creamy” base.
4.
The “creamy” melted base is
then poured into previously lubricated mould.
5.
The mould is allowed to
congeal, then placed in the refrigerator for 30 minutes to harden (forms stable
b-crystal after 24 hours of refrigeration).
6.
Mould is taken out from the
refrigerator and surface is trimmed off. The mould is opened and the
suppositories are expelled out of the mould by gentle pressure with the finger.
Packaging and Dispensing
·
The suppositories are wrapped
in aluminium foils. The aluminium foil is cut into the shape of a trapezium and
the suppository is rolled in it. The two ends are folded.
·
Several such suppositories are
best dispensed in sectioned-suppository boxes, ointment jars etc.
·
Upon dispensing the
prescription, the pharmacist should advise the patient about the proper use of
these suppositories.
·
The label should read: ‘Unwrap and insert through rectum.’
·
The patient is advised to ‘Keep the suppositories in a refrigerator’
to avoid melting in warm room temperature.
Ques:
Dispense 12 nos. of suppositories of boric acid (D=1.6) each weighing 4 grams
and containing 300mg of Boric acid. [5] (1998)
Calculation:
For boric acid suppositories cocoa butter
can be used as base.
Since there will be some loss so two extra
suppositories were prepared
Working
Formula:
Ingredients
|
For
1 supp.
|
Conversion
factor
|
For
14 supp.
|
Boric acid
Cocoa butter
|
0.3g
3.8125g
|
14
|
4.2g
53.8g
|
Preparation
The suppositories were prepared by fusion
method.
1.
Since cocoa butter is an oily
material so the moulds were lubricated by using the following lubricating
solution of Soft soap 10g, Glycerol 10ml, Alcohol(90%) 50ml.
2.
Drug is powdered in a mortar.
3.
Carefully grated cocoa butter
is taken into a beaker and heated in a water bath. When 2/3rd
portion is melted the beaker is taken out of the heat source. The rest of the
mass is melted by stirring with a glass rod.
4.
Drug is added into the beaker
and stirred thoroughly to mix with the “creamy” base. The “creamy” melted base
is then poured into previously lubricated mould.
5.
The mould is allowed to
congeal, then placed in the refrigerator for 30 minutes to harden.
6.
Mould is taken out from the
refrigerator and surface is trimmed off.
Mould is taken out from the
refrigerator and surface is trimmed off.
Packaging and Dispensing : Aluminium foil was cut
into the shape of a trapezium and the suppository was rolled in it. The two
ends were folded. The suppositories were wrapped in aluminium foils. Twelve suppositories
were packed in an ointment jar.
Advice to the patient: Upon
dispensing the prescription, the pharmacist should advise the patient about the
proper use of these suppositories.
INHALATIONS
Definition:
These are liquid preparations containing
volatile substances. They are used to relieve congestion and inflammation of
the respiratory tract.
Mode
of use:
Method-I: The liquid is taken in a handkerchief and inhaled. They include
components those are volatile at room temperature.
Method-II: The liquid preparation is added to hot, but not boiling water
(about 650C) and the vapor is inhaled for about 10 minutes. This
type of inhalations includes simple solution of medicaments, dissolved in
alcohol or aqueous dispersions, containing light magnesium carbonate to adsorb
the volatile ingredients.
Ingredients:
Oils like eucalyptus oil, pine oil etc.
Solids like menthol, thymol, etc.
Example: of a prescription Rx
Eucalyptus
oil 10 ml
Menthol 3 gm
Water
upto 100ml
Preparation
(i)
Menthol is finely powdered in a
glass mortar.
(ii)
The oil is added and stirred
until menthol is dissolved.
(iii)
Light magnesium carbonate
powder (1 gm MgCO3 for 2 ml oil and 1 gm MgCO3 for 2 gm
menthol) is added in small amounts and mixed well in the mortar.
(iv)
Water is added to the mixture
to produce a pourable cream.
(v)
The cream is transferred to a
tared bottle. Mortar is rinsed and the rinsing is added to the bottle.
Packaging:
Narrow mouthed, screw-capped, and colorless
fluted bottle is used.
Special
instructions on label:
1.
‘Not to be taken’.
2.
‘Add one teaspoonful to a pint
of hot, not boiling water and inhale the vapor.
[N.B. Us of boiling water would vaporize
the ingredients too quickly and cause discomfort to the patient.]
SPRAY
Definition:
Sprays are
preparations of drugs in aqueous, alcoholic or glycerin-containing media. They
are applied to the nasal mucosae, throat or deep in the lungs with an atomizer
or nebuliser.
Use:
·
Nasal sprays are used to reduce
congestion in the nose and to treat infections in the nasal tract.
·
Throat spray are used for
conditions such as laryngitis, pharyngitis and tosilitis.
·
Sprays for action in the lungs,
e.g. Adrenaline and Atropine Spray, Compound B.P.C. produces bronchial relaxant
action to relieve asthma and hay fever.
Container:
Small, narrow mouthed, screw-capped,
colored, fluted bottles are used. Atomizers or nebulizers are used to reduce
the liquid into fine droplets. There are three types of atomizer/nebulizers:
1.
Squeeze bottle type: The
solution is squeezed through a nozzle to produce the droplets. Droplet size
large.
2.
Atomizer: The solution is
sprayed from a scent spray type of device. Droplets are large.
3.
Nebulizer: The larger droplets
are removed (by baffles) and a very fine mist is produced.
When the aim
is to retain the solution in the nasal tract the droplets may be larger but
when the aim is to carry the droplets of liquids deep into the lungs then the
droplets must be finer so a nebulizer is generally used.
N.B. When the
droplets are carried to the lungs the solutions usually evaporates and becomes
smaller. Those smaller droplets may be readily exhaled. To reduce the rate of
evaporation a high vapor pressure liwuid like propylene glycol or glycerol is
added to the solution.
Label: “Not to be taken.”
Advice to the patient: The pharmacist should demonstrate the
patient about the proper use of atomizer / nebulizer.
THROAT PAINTs
Questions:
1. Write short note on throat paint. [3]
(2000)
Definition
Throat paints are viscous liquids for
application in the throat mucosae with a soft brush.
Throat paints are viscous due to a high
contact of glycerin, which being sticky, adhere to the affected site and
prolong the action of the medicaments.
Examples:
1.
Compound Iodine Paint (Mandl’s
Paint) – used for pharyngitis or tonsilitis
2.
Crystal Violet Paint – used for
thrush.
3.
Phenol glycerin (diluted with
equal volume of glycerin to reduce its causticity) produces analgesic effect in
tonsilitis and ulcerative stomatitis.
4.
Tannic acid Glycerin, has
astringent action, relieves from sore throat.
e.g. Mandl’s Throat Paint
Formula: Potassium iodide 25g
Iodine 12.5g
Alcohol
90%v/v 40ml
Water 25ml
Peppermint
oil 4ml
Glycerol
upto 1000ml
Method of preparation
(i)
Potassium iodide is dissolved
in water.
(ii)
Iodine is added in the
concentrated potassium iodide solutions to form KI3 (or higher
iodides).
(iii) Peppermint oil is dissolved in alcohol 90%v/v and the alcoholic
solution is added to the iodine solution.
(iv) Volume is made up with glycerin.
Container
·
A wide mouthed, fluted, light
resistant (required for peppermint oil), screw-capped, glass-jar is used.
·
A wax card liner is used for
screw caps (because iodine attacks other materials).
Label
Advice
to the patient:
Pharmacist should demonstrate the use of
throat brush to the patient.
EYE DROPS
Questions:
1.
How are the eye drops made?
What are the precautions to be taken in their preparation?[4] [2001]
2.
Write a short note on
preparation of eye drops. [5] (1998)
Definition
Eye drops are aqueous or oily solutions or
suspensions for instilling into the conjunctival sac with a dropper.
Uses:
Local anaesthetic – Xylocaine 4% eye drop
Anti-inflammatory –Diclofenac sodium eye drop
Anti-septics – Povidone iodine eye drop
Diagnostic agents – Rose Bengal dye
Miotics –
Pilocarpine eye drop
Mydriatics –
Atropine sulphate, Homatropine, Cyclpentolate sodium eye drop.
Artificial tear
Formulation
of eye drops.
1. Sterility
A
wide variety of microorganisms may cause eye infections.
Bacteria: Staphylococcus aureus, Proteus vulgaris, Bacillus subtilis, Pseudomonas
aeruginosa
Fungi: Aspergilus fumigatus
Virus: Certain
adenovirus
The Most dangerous organism is Pseudomonas aeruginosa, and it can grow
even in simple salt solutions or in store distilled or deionized water used for
preparation of eye drops.
Though intact
cornea is not susceptible to infections but conjunctivas may get infected.
In case of
accidental damage to cornea or after a surgical procedure the cornea may get
badly ulcerated. So all eye drops should be sterile.
2. Foreign Particles
The inflamed eye is very
sensitive to particulate matter that cause discomfort. Larger particles may
produce abrasion on cornea and infection may occur. So eye drops should be
clarified to remove fibres and other solid contaminants.
In
case of suspension type eye drops 90% of the particle should be below 5mm and none of the particle should be larger than 50mm.
e.g.
Hydrocortisonme acetate eye drop, Hydrocortisone and Neomycin eye drop.
3. Tonicity
Lachrymal
fluid is isotonic with 0.9%w/v sodium chloride solution. Eye drops having
tonicity equivalent to sodium chloride solutions ranging in concentration from
0.5 to 2%w/v are generally well tolerated. Beyond this range the eye-drops may
produce irritation or pain.
4. pH of eye drops
Tear has pH of 7.4 and their
buffering power (due to carbonic acid, weak organic acids and proteins) is
enough to neutralize quickly the pH of unbuffered solutions over a wide range
(pH 3.5 to 10.5) provided he volume is small (i.e. 1 to 2 drops only). So
highly concentrated solutions of very acidic drugs and strongly buffered
solutions will produce irritation.
5. Physicochemical nature of drug or
preservative
The chemical or physical nature
of a medicament or preservative may produce pain.
e.g. Local
anaesthetic amethocaine produces pain due to surface activity and by
denarutation of protein.
6. Viscosity
Sometimes, thickening agents are
added to eye-drops to prolong the contact with eye.
Methlcellulose,
hydroxypropylmethylcellulose (HPMC, Hypermellose) are generally used as
thickening agents in 0.5 to 1%w/v.
PREPARATION OF EYE DROPS
Preparation of solution type eye-drops
involves four steps:
1.
Preparation of a bactericidal
and fungicidal vehicle
2.
Solution of the medicament(s)
and adjuncts
3.
Clarification
4.
Sterilization
1. Preparation
of bactericidal and fungicidal vehicle
Aqueous
eye-drops must be prepared in a bactericidal and fungicidal vehicle. In case of
multiple-dos containers there is possibility of contamination during removal of
each dose (i.e. drop).
Examples of preservatives used in
eye-drops:
(i) Phenylmercuric
nitrate 0.002%w/v
Phenylmercuric acetate 0.002% w/v
(ii)
Benzalkonium chloride 0.01%w/v
(iii)
Chlorhexidine acetate 0.01%w/v
(iv) Other - Chlorocresol 0.05%w/v
Chlorobutol 0.5%w/v
Thiomersal 0.01%w/v
The rubber closures of the vials are
pre-treated with preservative. Preservatives are dissolved in purified water to
make a solution.
3.
Dissolution of medicaments and adjuncts
Medicaments and adjuncts are
weighed and dissolved in the vehicle, if required heated or cooled or by
changing of pH.
4. Clarification
The solution is filtered to remove
any particles. Membrane filter (Millipore AA) with a mean pore size of 0.8mm may be used to remove any particle.
5. Sterilization
Three methods of sterilization of eye-drops
are recommended
(i) Heating in an autoclave
If the product
is thermostable then eye-drops, packed in the final container can be sterilized
in an autoclave at 15psi pressure, 1210C temperature for 15minutes.
(ii) Maintaining at 98 to 1000C
for 30 minutes
Medicaments
those are not stable at autoclaving temperature (i.e. 1210C) but can
be withstand a temperature of 1000C, can be sterilized by boiling
the container (of eye-drop) in a water-bath at 98 to 1000C for 30
minutes.
(iii) Filtration
This method is
used in case of thermolabile drugs.
Instruments
used: Membrane filter of nominal pore
size 0.22 ± 0.02 mm (e.g. Millipore GS) in a membrane holder.
The filtration
apparatus, the filter membrane, receiver and the final container, closures are
sterilized. The clarified solution is then passed through the membrane filter
under pressure, collected in the receiver and transferred in the final
containers and sealed. All these processes of filtering and transferring are
done aseptically.
Precautions to be taken during preparation
1.
Some preservatives (like PMN or
PMA) interact with plastic containers, rubber closures hence appropriate
packaging materials should be used. If the vehicle is stored then it should be
sterilized before storage and should be used within one week.
2.
If the medicament is oxidized
then it should be prepared in N2 or inert gas atmosphere.
3.
The filter membrane for
clarification should not shed fibers or particles. Hence the filter-medium
should be washed with purified water (previously passed through membrane
filter) thoroughly.
4.
The membrane filters should
maintain their integrity.
5.
Finally sterility tests should
be carried out in each batch of eye-drops.
Container
For multiple-application containers:
(i) Traditional
eye-dropper containers
(ii) Plastic
container
(iii) Injection
vials with separate dropper.
Label
The aims of labeling eye-drops are
1. To
prevent use of a contaminated product.
(a)
Eye-drops for home use: Warning: Avoid
contamination during use.
(b)
For hospital out-patient
department: “Sterile until opened”
Warning:
Use an unopened container for each patient who has
undergone
surgery, otherwise discard remainder at the end of a day.
(c) Eye-drops for hospital in-patients : “Sterile until opened”
Warning:
Use a separate container for each eye of each patient and
discard
remainder one week after first opening.
(d) Eye-drops for operating theatre:
“Sterile until opened”
Warning:
Use an unopened container for each patient.
2. To prevent damage to the
eyes
Eye-drops for hospital
use should have label mentioning the name of preservative used.
3. To prevent use of an
incorrect preparations or strength
Eye drops for hospital use must be
labeled with name of the preparation and the concentration of active
ingredients.
4. Other information
(i) Date of
sterilization e.g. Sterilized 05.03.2003
(ii) FOR EXTERNAL USE ONLY
EMULSIONS
Questions
1.
Classify emulsifying agents and
discuss them. [8] (2001, 1998)
2.
Describe the wet gum method and
dry gum method of preparation of arachis oil emulsion [4], (1999)
3.
Differentiate between emulsion
and suspensions. Give a brief note on emulgents with suitable examples. [8]
(1998)
Definition
An emulsion is a thermodynamically unstable dispersed system
consisting of at least two immiscible liquid phase, one of which is dispersed
as globules in the other liquid phase. The liquid that forms globules is called
the internal phase or dispersed phase and the liquid in which
the droplets are dispersed is called continuous
phase or external phase.
The system is
stabilized by the presence of an emulsifying
agent or emulgents or emulsifiers.
Emulsified systems range from lotions of
relatively low viscosity to ointments and creams, which are semisolid in
nature.
Types of emulsions
(I) Ordinary emulsion systems / Primary
emulsion systems / Simple emulsion systems
(i)
o/w type - oil
dispersed in water
oil
® dispersed phase water ®
continuous phase
(ii)
w/o type - water
dispersed in oil
water ®
dispersed phase oil ® continuous phase
(II) Special emulsion systems
(i)
Multiple emulsions ® w/o/w - type and o/w/o - type
(ii)
Micro emulsion
Determination of types of emulsions
Several
methods are commonly used to determine the type of emulsion. The types of
emulsion determined by one method should always be confirmed by means of second
method.
(1)
Dye solubility test
A small amount of a water soluble dye (e.g.
methylene blue or brilliant blue) may be dusted on the surface of the emulsion.
If
water is the external phase (i.e. o/w type) then the dye will be dissolved
uniformly throughout the media.
If
the emulsion is of the w/o -type then particles of dye will lie in clumps on
the surface.
(2)
Dilution test
This
method involves dilution of the emulsion with water. If the emulsion mixes
freely with the water, it is of o/w -type. Generally, addition of disperse
phase will crack an emulsion.
(3)
Conductivity test
This
test employs a pair of electrodes connected to an external electric source and
immersed in the emulsion. If the external phase is water, a current will pass
through the emulsion and can be made to deflect a volt-meter needle or cause a
light in the circuit to glow. if the oil is the continuous phase then the
emulsion will fail to carry the current.
Methods
for determination of emulsion type:
Test
|
Observation
|
Comments
|
1. Dilution test
2. Dye test
3. Conductivity test
4. Fluorescence test
5. CoCl2 / filter paper test
|
Emulsion can be diluted only with
external phase.
Water-soluble solid dye tints only o/w
emulsion and reverse. Microscopic observation usually is helpful.
Electric current is conducted by o/w
emulsions, owing to the presence of ionic species in water.
Since oils fluoresce under UV-light, o/w
emulsions exhibit dot pattern, w/o emulsions fluoresce throughout.
Filter paper impregnated with CoCl2
and dried (blue) changes to pink when (o/w) emulsion is added.
|
Useful for liquid emulsions only.
May fail if ionic emulsifiers are
present.
Fails in nonionic o/w emulsions.
Not always applicable
May fail if emulsion is unstable or
breaks in presence of electrolyte.
|
Additives used in emulsion
dosage forms
A. Oil phase
The choice of
lipid phase depends on the ultimate use of the product.
(i)
If the oily phase is the
active-ingredient itself (e.g. liquid paraffin emulsion) the formulator has
nothing to chose from.
(ii)
The drug in a pharmaceutical
preparation should not be too soluble in lipid phase then it will reduce the
rate of transfer of the drug molecule to other phases.
(iii) Emulsions prepared for topical purpose (e.g. cosmetics and
pharmaceutical emulsions) should possess a good “feel”. Emulsions normally
leave a residue of the oily components on the skin after the water has
evaporated. Therefore, the tactile characteristics of the combined oil phase
are of great importance in determining consumer acceptance of an emulsion
TABLE
1: Ingredients for oil-phase of emulsions
Class
|
Identity
|
Consistency
|
Hydrocarbon
Hydrocarbon
Hydrocarbon
Hydrocarbon
Ester
Ester
Ester
Ester
Alcohols
Fatty acids
Ethers
Silicones
Mixed
Mixed
|
Mineral oils
Petrolatum
Polyethylene
waxes
Microcrystalline
waxes
Vegetable oils
Animal fats
Lanolin
Synthetic
(e.g. isopropyl myristate)
Long chain
(natural & synthetic)
Long chain
(natural & synthetic)
Polyoxypropylenes
Substituted
silicones
Plant waxes
(e.g. Candellia)
Animal waxes
(e.g. Beeswax)
|
Fluids of
varying viscosity
Semisolid
Solids
Solids
Fluids of
varying viscosity
Fluids or
solids
Semisolid
Fluids
Fluids or
solids
Fluids or
solids
Fluids of
varying viscosity
Fluids of
varying viscosity
Solid
Solid
|
B. Emulsifying agent: The emulsifying agents stabilize an
emulsion by various mechanisms. They are also known as emulgents or
emulsifiers.
Classification of emulsifiers:
Type
|
Examples
|
Mode of action
|
|
Hydrophilic colloids
|
Vegetable source
Gum acacia
Tragacanth
Starch
Animal source
Wool fat
Egg yolk
Gelatin
Synthetic
Methyl
cellulose, Hydroxyethyl cellulose,
|
(i)
They do not reduce the
surface tension but forms a rigid film on the oil droplets and form a stable
o/w emulsion - thus inhibits coalescence of
droplets.
(ii)
As an auxiliary emulsifier
they increase the viscosity of the continuous phase so that movement of
dispersed phase is reduced.
|
 |
Finely divided solid particles
|
Colloidal clays:
bentonite (aluminium silicate)
veegum (magnesium aluminium silicate).
|
(i)
They tend to absorb at the
oil-water-interface and form thick impenetrable films.
(ii)
Sometimes increases the
viscosity of water (as continuous phase).
|
 |
Synthetic Surface Active Agents
|
Anionic
Potassium stearate
Sodium lauryl sulphate
Cationic
Cetyl trimethyl ammonium bromide (or cetrimide)
Ampholytic
N-dodecyl
alanine
Non-ionic
Sorbitan
mono-oleate
(TWEEN)
Polyoxyethylene sorbitan mono-oleate
(Polysorbate)
|
(i)
They form a flexible film on
the oil-water interface.
(ii)
They lower interfacial
tension markedly and this contributes to the stability of emulsion.
In case of ionic surfactants surface
charge is developed, increasing the zeta-potential, which will cause
repulsion between two adjacent globules.
|
 |
C. Preservatives
Sources of contamination:
(i)
Contaminated raw materials
(ii)
Poor sanitation during
preparation
(iii) Contamination by the end users
Substrates of contamination:
(i)
Mainly the water phase is a
good medium for microbial growth.
(ii)
Some ingredients, such as
carbohydrates, pectin, proteins, sterols, and phosphates readily supports the
growth of a variety of microorganisms.
Preservatives commonly used:
Chlorocresol, chlorobutanol,
mercurials [e.g. phenyl mercuric nitrate (PMN), phenyl mercuric acetate (PMA),
esters of parahydroxy benzoate (methyl, propyl, butyl, benzyl paraben), sodium
benzoate, sorbic acid etc.
Since microorganisms can reside
in the water or the lipid phase or both, the preservative should be available
at an effective level in both phases. So it is advisable to add oil soluble and
water soluble preservative simultaneously.
A good example
is methyl and propyl paraben. In this case methyl paraben is soluble in water
while propyl and higher esters are almost water-insoluble.
D. Antioxidants
The inclusion of an antioxidant
in an emulsion formulation may be necessary to protect, not only an active
ingredient but also formulation components (e.g. unsaturated lipids) which are
oxygen labile.
Oxidation occurs
spontaneously under mild conditions generally involved some free radical
reactions.
Kinetic
measurements of fat oxidation in o/w emulsions indicate that the rate of
oxidation is dependent on
(i)
the rate of oxygen diffusion in
the system,
(ii)
oxygen pressure (i.e. oxygen
content)
(iii) trace element of metal such as Cu, Mn, or Fe or their ions may
catalyze the oxidative reactions. Thus the use of chelating agents, in a
formulation may markedly improve product stability.
(iv) Some oxidative degradation is pH dependent. So the pH stability
profile of the drug and of protective formulation should be established during
product development.
List of selected antioxidants for emulsion system:
1. Chelating agents e.g. Citric acid, EDTA (Ethylene diamine tetraacetic
acid), Phenyl alanine
Phosphoric acid (H3PO4)’ Tartaric acid
2. Preferentially oxidized compounds (Reducing
agents)
e.g.
Ascorbic acid, Sodium sulphite (Na2SO3), Sodium bisulfite
(NaHSO3)
Sodium metabisulfite (Na2S2O5)
3. Chain terminators
Water soluble compounds e.g. Cystine hydrochloride, Thioglycerol,
Thioglycollic acid, Thiosorbitol
Lipid soluble compounds e.g.
Alkyl gallates (octyl, propyl, dodecyl), Butylated hydroxy toluene (BHT)
Butylated hydroxy anisole (BHA), a-tocopherol (Vit-E)
Hydroquinone
Preparation of Emulsions
Emulsions can be prepared by the following
methods:
1.
Dry gum method
2.
Wet gum method
3.
Bottle method
Generally all the emulsions for oral
purpose are prepared with gum acacia. To prepare a thick acacia emulsions,
using mortar and pestle, a thick primary emulsion must be made first. The
quantities for primaru emulsions have been obtained by experience and are given
in table 2.
TABLE 2. Quantities for primary emulsions
prepared by gum acacia
Type of Oil
|
Examples
|
Quantities
for primary emulsion (parts)
|
||
Oil
|
Water
|
Gum
|
||
Fixed
|
Almont oil
Arachis oil
Castor oil
Cod-liver oil
|
4
|
2
|
1
|
Mineral
|
Liquid paraffin
|
3
|
2
|
1
|
Volatile oil
|
Turpentine oil
Cinnamon oil
Peppermint oil
|
2
|
2
|
1
|
Oleo-resin
|
Male Fern Extract
|
1
|
2
|
1
|
1. Dry
gum method
·
The oil is measured with dry, clean measuring cylinder and taken in a
mortar .
·
The required quantity of gum
acacia powder is taken in the mortar and triturated with the oil until it is
dispersed.
·
Water required to prepare the
primary emulsion is added at once into the oil and triturated vigorously with
the pestle until a clicking (or characteristic cracking) sound appears. This
thick, white or nearly white cream is called primary emulsion.
·
More water is added to this
primary emulsion to produce the required volume.
·
If any soluble ingredients are
to be added it is added in the second part of the water.
2. Wet gum method
·
The calculated quantity of gum
is triturated with water (quantity required for primary emulsion) in a mortar
with a pestle to form a mucilage.
·
Given amount of oil is
incorporated in the mucilage in small portions with rapid trituration until a
clicking sound is produced and the product becomes white or nearly white. Thus
a primary emulsion is formed.
·
More water is added to produce
the volume.
3. Bottle method
This method is
used for the preparation of emulsions of volatile and other non-viscous oils.
N.B. Because of
low viscosity the volatile oils require greater amount of gums.
The emulsion may
be prepared both by dry gum and wet gum method.
·
By dry gum method the oil and
gum are taken in a stoppered bottle and shaken vigorously, then water (required
to form primary emulsion) is taken and shake vigorously to form the primary
emulsion. Water is added to produce the volume.
·
By wet gum method gum and water
(required for primary emulsion) are taken in stoppered bottle and shaken produce
a mucilage. Oil is added and shaken vigorously to form the primary emulsion and
then required amount of water is added to produce the volume.
Problems of emulsion systems
The physical
stability of an emulsion system is evidenced by (i) creaming, (ii) flocculation
and / or (iii)coalescence.
Creaming
Creaming is the
upward or downward movement of dispersed droplets related to the continuous
phase due to the difference of density between two phases.
Creaming is undesirable in a pharmaceutical product where
homogeneity is essential for the administration of correct and uniform dose. It
may still be acceptable if it can be redispersed by a moderate shaking.
However, in case of cosmetic products creaming is usually unacceptable because
it makes the product inelegant.
Creaming or
sedimentation brings the particle closer together and may facilitate a serious
problem of coalescence.
The rate at
which a spherical droplet or particle sediments in a liquid is governed by
Stoke’s equation.
d2(r1 - r2)g where v = velocity of creaming
v = d
= diameter of globule
18h r1 , r2 = densities of dispersed phase and
continuous phase respectively
h = viscosity of the continuous medium
A consideration
of this equation shows that the rate of creaming will be decreased by:
(i)
reduction of droplet size
(ii)
a decrease in the density
difference between the two phases
(iii) increase in the viscosity of the continuous phase
Flocculation
 |
Flocculation is reversible aggregation of droplets of the internal
phase in the form of three-dimensional
clusters.
In the floccules
the droplets remain aggregated but intact. The droplets can remain intact when
the mechanical or electrical barrier is sufficient to prevent droplet
coalescence.
e.g. if an insufficient
amount of emulsifier is present, emulsion droplets aggregate and coalesce.
Coalescence
 |
Coalescence is a growth process during which the emulsified
particles join to form larger particles.
Any evidence for
the formation of larger droplets by merger of smaller droplets suggests that
the emulsion will eventually separate completely. Coalescence ultimately leads
to phase separation – this phenomenon is known as “cracking of emulsion”.
Remedy:
Addition of a
strong protective coating on the oil droplets either by a hydrocolloid or fine
particulate emulsifier.
Other problems
Any agent that will destroy the
interfacial film will crack the emulsion. Some factors are:
(i)
the addition of a chemical that
is incompatible with the emulsifying agent. Examples include surfactants of
opposite ionic charges, addition of large ions of opposite charge, addition of
electrolytes such as Ca and Mg salts to emulsions stabilized with anionic
surfactants.
(ii)
Bacterial growth: Protein materials and
non-ionic surfactants are excellent media for bacterial growth.
(iii) Temperature change: Protein emulsifying agent may be denatured and the solubility
characteristics of non-ionic emulsifying agents change with a rise in
temperature. Heating above 700C destroys almost all emulsions.
Freezing will crack an emulsion; this may be due to the ice-crystals disrupting
the interfacial film around the droplet.
Difference between emulsion and suspension
Emulsions
|
Suspensions
|
1.
They contain two immiscible
liquids, one of which is dispensed as minute globules into the other.
2.
Emulsifying agents are
required to make a stable emulsion.
3.
Emulsions are mainly of two
types: o/w and w/o.
4.
During storage, freezing
should be avoided as it may lead to cracking of emulsion.
|
1.
They contain finely divided
solid particles dispersed in a liquid or semisolid vehicle.
2.
Suspending agents are
required to make a stable suspension.
3.
Suspensions are mainly of two
types:
(i)
Flocculated and (ii) De-flocculated.
4.
During storage, freezing
should be avoided as it may lead to aggregation of suspended particles.
|
Container: Wide mouthed, screw capped, colourless, plain bottles are used.
Label
Instruction: “Shake the bottle before use.” “Do not keep in refrigerator.”
