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.”