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Mrs. Nisha Marcel
Assistant Professor
Department of Pharmaceutics
SJIPR
Mrs. Nisha Marcel Pharmaceutics II CBCS
11
1. Introduction
2. Suppository bases
3. Methods of formulation
4. QC test
5. Packaging, Storage, Stability
problems
Mrs. Nisha Marcel Pharmaceutics II CBCS 2
▪ Solid dosage forms of medicament for insertion into body cavities other than mouth.
▪ The medicament is incorporated into the suppository base and the product is
formulated such as way that it melt/dissolve at body temperature in the body cavity
fluids to release the medicament.
▪ A is a solid dosage form that is inserted into the rectum (rectal
suppository), and vagina (vaginal suppository) where it dissolves or melts and exerts
local or systemic effects. Suppositories are used to deliver medications that act
both systemically and locally.
Mrs. Nisha Marcel Pharmaceutics II CBCS 3
▪ Several different ingredients can be used to form the base of a suppository: cocoa
butter or a similar substitute, polyethylene glycol, hydrogels, and glycerinated
gelatine. The type of material used depends on the type of suppository, the type of
drug, and the conditions in which the suppository will be stored.
▪ The "torpedo" shape helps the device to travel internally, increasing its efficacy.
▪ Different shapes the suppositories manufactured:
Mrs. Nisha Marcel Pharmaceutics II CBCS 4
1. Medicinal substance enter the circulatory system (bypassing the liver)
2. High rate of absorption of medical substances
3. The degree and frequency of allergic reactions decreases
4. Less side effects
5. Painless and simple administration of the drug
6. Compactness of the dosage form
7. Gives localized and systemic action
8. Easy to use for paediatric and geriatric patients
9. Useful to promote evacuation of bowel
10. Unit dosage form of drug
Mrs. Nisha Marcel Pharmaceutics II CBCS 5
1. Irritant drugs cannot be administered
2. Causes embarrassment to patients
3. To be stored at low temperature
4. Cant easily be prepared
5. Cost-expensive
6. Some drug maybe be degraded by the microbial flora present in the rectum
7. Fluid content of the rectum is much less than that o the small intestine, this may
effect dissolution rate, etc.
Mrs. Nisha Marcel Pharmaceutics II CBCS 6
1. Should melt at body temperature
2. Should release medicament readily
3. Should be wetting & emulsifying properties
4. Should keep its shape
5. Should be non-toxic and non-irritant
6. Should be stable on storage i.e. does not change colour, odour or drug release
pattern
7. Should be compatible with different formulation method
8. Acid value below 0.2
9. Iodine value less than 7
10. Saponification value ranges from 200 to 245
Mrs. Nisha Marcel Pharmaceutics II CBCS 7
1. Rectal
2. Vaginal
3. Nasal Suppositories
4. Urethral
5. Earcones
Mrs. Nisha Marcel Pharmaceutics II CBCS
1.
2.
5.
4.
3.
8
1. Rectal Suppositories :
▪ It is inserted in the rectal.
▪ The weight of rectal suppository differs for children and adults.
▪ Usually in torpedo shape. The length is about 3cm.
2. Vaginal Suppositories :
▪ It is in oviform shape.
▪ About 3 – 5gm in weight.
▪ It contains the drugs which are used in the treatment of the infections of female
genitourinary tract and meant for contraception.
Mrs. Nisha Marcel Pharmaceutics II CBCS 9
3. Nasal Suppositories :
▪ These suppository are meant for introduction into nasal cavity.
▪ It is about 1gm in weight.
4. Urethral Suppositories :
▪ The weight of this suppository is about 2gm and 60-75mm long in Females.
▪ Those intended for males weigh 4gm each and are 100-150mm long.
▪ It is available in pencil shape.
5. Earcones Suppositories :
▪ It is also known as Aurinaries.
▪ These are meant for introduction into the ear.
▪ It is cylindrical in shape about 1gm in weight.
Mrs. Nisha Marcel Pharmaceutics II CBCS 10
1. Physiologic Factors
- Drugs absorbed by anorectal area and retain therapeutic action/values.
- Lower hemorrhoidal veins (50-70% drug absorption)
- Lymphatic circulation, pH.
2. Physiochemical characteristics of the drug
- Compatibility between drug and the excipients & suppository bases.
- Degree of ionization
3. Physiochemical characteristics of the base & adjuvants
- Properties of suppository bases affect drug absorption.
- Presence of adjuvant in base
4. Blood levels from different dosage forms
Mrs. Nisha Marcel Pharmaceutics II CBCS 11
▪ The human rectum is approximately 15-20 cm in the length,
when empty of faecal material.
▪ It contains 2 – 3 ml of inert mucous fluid
▪ In resting state, the rectum is non motile
▪ There is no villa or microvillus on rectal mucosa.
▪ Physiological factors:
o Colonic content
o Circulation
o pH and lack of buffering capacity of the rectal fluid.
Mrs. Nisha Marcel Pharmaceutics II CBCS 12
▪ When systemic effect are desired from suppository greater absorption may be
expected from a rectum that is void than that with faecal.
▪ An evacuation enema maybe administered before insertion of a suppository.
Diarrhoea, colonic obstruction and tissue dehydration influence the rate & degree of
drug absorption from rectum.
Mrs. Nisha Marcel Pharmaceutics II CBCS 13
▪ Drugs absorbed rectally partially by pass portal circulation, thereby enabling drug
destroyed in liver to exert systemic effect.
▪ Depending on the height at which absorption occurs at rectum, the drug passes into
inferior, middle or superior haemorrhoid veins.
▪ The inferior is nearest to the anus, the upper haemorrhoid vein nearer to portal
circulation, thus it is advisable to keep suppositories in the lower part of rectum.
▪ 50% - 70% of drug administered rectally, reported to go directly into general
circulation.
Mrs. Nisha Marcel Pharmaceutics II CBCS 14
▪ Rectal fluids are neutral (pH 7-8), have no effective buffer capacity.
▪ The barrier separating colon lumen from the blood is preferentially permeable to
the unionized forms of drugs, thus absorption of drug would ne enhanced by change
in pH of the rectal mucosa to one that increase the proportion of unionized drugs.
Mrs. Nisha Marcel Pharmaceutics II CBCS 15
A) Lipid water solubility of a drug (partition coefficient):
• the lipid water coefficient of a drug is important in selecting the suppository base and
in anticipating drug releaser from the base.
• Lipophilic drug, when distributed in a fatty suppositories base has fewer tendencies to
escape to the fluids.
• Water-soluble salt are preferred in fatty base suppository.
• Water – soluble base e.g. PEG which dissolve in the rectal fluids, release both
water – soluble & oil-soluble drugs.
Mrs. Nisha Marcel Pharmaceutics II CBCS 16
B) Degree of ionization:
▪ The barrier separating colon lumen from the blood is preferentially permeable to the
unionized forms of drugs, thus absorption of drug would be enhanced by increasing
the proportion of unionized drugs.
Mrs. Nisha Marcel Pharmaceutics II CBCS 17
C) Concentration of a drug in a base:
▪ The more drugs in a base, the more drug will be available for absorption.
▪ If the concentration of the drug in the intestinal lumen is above a particular amount,
the rate of absorption is not change by further increase in concentration of drug.
▪ In general, the rate limiting step in drug absorption from suppository is the
partitioning of the dissolved drug from the melted base and not the rate of solution of
drug in the body fluid.
▪ Studies show that the rate, at which the drug diffuses to the surface of the
suppository, particle size and presence of surface-active agents are factors that affect
drug release from suppositories.
Mrs. Nisha Marcel Pharmaceutics II CBCS 18
1) Nature of the base:
▪Suppository base capable of melting, softening or dissolving
to release the drug for absorption.
▪If the base irritating the colon, it will promote colonic
response, lead to increase bowl movement and decrease
absorption.
Mrs. Nisha Marcel Pharmaceutics II CBCS 19
2) Presence of adjuvant in base:
▪Adjuvant in a formula may affect drug absorption,
change the rheological properties of the base at
body temperature or affected the dissolution of the
drug.
Mrs. Nisha Marcel Pharmaceutics II CBCS 20
▪ Many studies have attempted to compare the oral dosage form with the rectal
administration.
▪ The results are inadequate, because of the different parameter used to make the
studies, the experiment conditions and choice of excipient.
Mrs. Nisha Marcel Pharmaceutics II CBCS 21
Mrs. Nisha Marcel Pharmaceutics II CBCS 22
1. It must retain the shape and size.
2. It should melt at body temperature.
3. It should be non-irritant.
4. It should shrink sufficiently to remove from mould.
5. It should not interfere in release or absorption of drug.
6. It should permit incorporation of drug.
7. It should be compatible with the drugs.
8. It should be physically stable on storage.
9. It should not be soften or harden on storage.
Mrs. Nisha Marcel Pharmaceutics II CBCS 23
Mrs. Nisha Marcel Pharmaceutics II CBCS 24
▪ A brief description of the composition of the base reveals the
source of the origin (natural/synthetic/modified)
▪ Physical or chemical incompatibilities with other constituents
may be predicted if the exact formula composition is known
including preservatives, antioxidants and emulsifiers.
Mrs. Nisha Marcel Pharmaceutics II CBCS 25
▪ Suppository bases don’t have a sharp melting point (complex mixture
of triglycerides), their melting characteristics are expressed as
ranges, indicating the temperature at which the fats start to melt and
the temperature at which completely melted.
▪ Melting range is usually determined by “Wiley melting point”,
“Capillary melting point”.
Mrs. Nisha Marcel Pharmaceutics II CBCS 26
▪ One can determine the solidification and melting ranges of fatty bases
as well as the moulding character, surface feel and hardness of the
bases.
▪ A base with sharp drop in solids over a short temperature span proves
brittle if molded too quickly.
▪ The solid content at room temperature could determine suppository
hardness. Since skin temperature is about 32°C, one can predict that
would be dry to touch from a solid content over 30% at that
temperature.
Mrs. Nisha Marcel Pharmaceutics II CBCS 27
▪ “It is the number of milligrams of KOH (Potassium Hydroxide) that
would neutralize the acetylate 1gm of fat”
▪ This is the measure of unesterified position of glycerides and reflects
the mono- and di-glyceride content of a fatty base.
Mrs. Nisha Marcel Pharmaceutics II CBCS 28
▪ This test allow to determine the time required for the
solidifying the base, when it is chilled in the mould.
▪ If the interval between the melting point and solidifying point is
10°C or more, time required for solidification may have to be
shortened for a more efficient manufacturing procedure by
refrigeration.
Mrs. Nisha Marcel Pharmaceutics II CBCS 29
▪ It is the number of grams of Iodine that reacts with 100gm of fat or other
unsaturated material.
▪ The possibility of decomposition by moisture, acids, oxygen (which leads to
rancidity of ats) increases with higher iodine value.
Mrs. Nisha Marcel Pharmaceutics II CBCS
▪ It is the amount of water in grams that can be incorporated in 100gm of fat.
▪ The “water number” can be increased by addition of surface-active agents.
30
▪ “The number of milligrams of KOH (Potassium Hydroxide) required to neutralize the
free fatty acids and saponify the ester contained in 1gm of a fat”
▪ From saponification value we can know the type of glyceride present (mono-, di- or
tri-) and also amount present.
Mrs. Nisha Marcel Pharmaceutics II CBCS
▪ It is the number of milligrams of KOH (Potassium Hydroxide) required neutralizing
the free fatty acids in 1gm substance (fat).
▪ Low acid value or absence of acid value is important for good suppository bases.
31
FATTY BASES
• Theobroma Oil
(melting tendency)
• Emulsified
Theobroma Oil
• Hydrogenated Oils
(resistant to
oxidation)
WATER SOLUBLE
& WATER
MISCIBLE BASES
• Glycero- gelatine
(Pessaries, Type A &
B)
• Soap glycerine
(hygroscopic)
• Polyethylene glycols
(macrogols)
EMULSIFYING
/SYNTHETIC
BASES
• Witepsol
• Massa Estarinum
• Massupol
Mrs. Nisha Marcel Pharmaceutics II CBCS 32
Mrs. Nisha Marcel Pharmaceutics II CBCS 33
Source:
• Theobroma is yellowish white solid fat obtained from the roasted seed of
Theobroma cocoa.
• It’s a mixture of glyceride of esters of stearic, oleic, palmitic & other fatty acids.
Properties:
• At room temperature it is a yellowish, white solid having a faint, agreeable
chocolate like odour.
• Chemically, it is a triglyceride (combination of glycerine and one or different fatty
acids) primarily of oleopalmitostearin and oleodistearine.
• It melts at 30 – 35°C, has a consistency of butter.
Mrs. Nisha Marcel Pharmaceutics II CBCS 34
▪ Advantages:
i. Melting just below the body temperature.
ii. Maintaining its solidity at usual room temperatures.
iii. Readily liquefy on heating and solidify on cooling
▪ Disadvantages:
i. Exhibits marked polymorphism
ii. Rancidity
iii. Stick to mould
iv. Leakage from body cavity
v. Immiscibility with body fluid.
vi. Chloral hydrate or lactic acid liquefy it.
Mrs. Nisha Marcel Pharmaceutics II CBCS 35
Mrs. Nisha Marcel Pharmaceutics II CBCS
▪ The use of 5% glyceride monostearate, 2-3% cetyl alcohol, 4% bees wax & 12%
spermaceti is recommended to prepare emulsified Theobroma oil.
▪ They are obtain by hydrogenation of vegetable oils such as arachis oil, cotton seed oil.
It is use as a substitute for Theobroma oil & has number of advantages.
▪ Advantages: Resistance to oxidation, no lubricant required, it gives colourless,
odourless suppositories
36
Mrs. Nisha Marcel Pharmaceutics II CBCS 37
Mrs. Nisha Marcel Pharmaceutics II CBCS 38
▪ It is a mix of glycerine & water which is made stiff by addition of gelatine particularly
used for making pessaries.
▪ The suppositories prepared from glycerogelatin base is translucent which tend to dissolve
or melt in the body cavity and release the medicament for better absorption.
▪ This base is well suited for suppositories containing boric acid, bromide, iodide, opium
etc.
2 types
Type A Type B
Pharmagel A Pharmagel B
Acidic in nature Alkaline in nature
Used for acidic drug Used for basic drug
with isoelectric point pH 7-9 with isoelectric pH 4.7-5
Mrs. Nisha Marcel Pharmaceutics II CBCS 39
Disadvantages
• Formulation time depends on contents and quality of gelatine used.
• Gelatine is incompatible with many drug (gallic acid, tannic acid).
• More chances of bacteria & mould growth.
• Suppositories prepared are hygroscopic in nature.
Mrs. Nisha Marcel Pharmaceutics II CBCS 40
▪ In glycrogelatin suppositories the gelatine is replaced with either curd soap or sodium
citrate which makes the base sufficiently hard to prepare good quality of suppositories.
Advantages
• Chemically stable
• Non- toxic, non- irritant
• Doesn’t allow bacterial growth.
Disadvantage
• Hygroscopic in nature
• Requires special storage condition
• Good solvent property results in drug retention
• High solubility leads to supersaturation.
Mrs. Nisha Marcel Pharmaceutics II CBCS 41
▪ Commonly known as carbowaxes, macrogols or polyglycols.
▪ The physical character of these carbowaxes varies according to the molecular
weight.
▪ Less than 1000 Liquid more than 1000 Wax like solids
Mrs. Nisha Marcel Pharmaceutics II CBCS 42
▪ Advantages:
1. They are chemically stable
2. Non-irritant
3. Do not allow bacterial or mould growth
4. Physiologically inert substances
▪ Disadvantages:
1. Hygroscopic hence require special storage condition
2. Incompatible with tannins, phenols etc
Mrs. Nisha Marcel Pharmaceutics II CBCS 43
Mrs. Nisha Marcel Pharmaceutics II CBCS 44
Mrs. Nisha Marcel Pharmaceutics II CBCS
▪ It consist of triglyceride or saturated vegetable oil. The suppository prepared
should not be rapidly cool & to prevent them from brittle and fracture
condition.
▪ Mix of mono & tri glycerides. Also known as Adeps Solitus. Available in various grades
commonly used grade is “B” used for dispensing.
45
▪ It consists of glycerides esters mainly of lauric acid to which small amount of
glyceryl monostearate is added to improve its water absorbing capacity.
▪ Advantages
• Solidify rapidly
• Non- irritant
• Not effected on heating
▪ Disadvantages
• Hygroscopic in nature
• Should not be cooled rapidly
• Not very viscous after melting
Mrs. Nisha Marcel Pharmaceutics II CBCS 46
▪ 4 methods to formulate suppositories:
1. Hand Moulding
2. Compression Moulding
3. Pour Moulding
4. Automatic Moulding Machine
Mrs. Nisha Marcel Pharmaceutics II CBCS 47
▪ Oldest and simplest method of preparing suppositories by hand.
▪ Procedure : 1. By rolling the well blended suppository base containing the active
ingredient into desires shape.
2. The base is 1st grated and kneaded with the active ingredient by use of a mortar
and pestle resulting in plastic like well blended mass.
3. The active ingredients are usually finely powdered or dissolved in water or
sometimes mixed with a small amount of wool fat to help in incorporation with the
suppository base.
4. The mass is then rolled into cylindrical rod of desired length & diameter. The rod is
cut into portions & than one end is pointed.
5. Starch or talcum powder under rolling surface is used to prevent the mass from
adhering.
Mrs. Nisha Marcel Pharmaceutics II CBCS 48
▪ Practical & economic method for preparation of small number of suppositories.
Mrs. Nisha Marcel Pharmaceutics II CBCS 49
▪ Uniform & pharmaceutically elegant suppositories can be made by compressing the
grated the cold mass into desired shape.
▪ A hand funnel wheel pushes the piston against the suppository mass contained in a
cylinder. So that the mass is inserted into moulds.
▪ This method is simple and results in more elegant appearance than done by hand
moulding.
▪ Avoids sedimentation possibilities of insoluble solids in the suppository base.
▪ But this method is too slow for production of larger number of suppositories.
▪ Disadvantage: 1. exclusive for moulding fat type bases suppository
2. Leads to air entrapment which makes weight control impossible.
Mrs. Nisha Marcel Pharmaceutics II CBCS 50
Mrs. Nisha Marcel Pharmaceutics II CBCS 51
▪ Commonly used for producing suppositories in both small & large scale.
▪ Involves first melting the suppository base, and then dispersing or dissolving the
drug in the melted base.
▪ The mixture is removed from the heat and poured into a suppository mould. When
the mixture has congealed, the suppositories are removed from the mould.
▪ Suppositories are generally made from solid ingredients and drugs which are
measured by weight. When they are mixed, melted, and poured into suppository
mould cavities, they occupy a volume – the volume of the mould cavity. Since the
components are measured by weight but compounded by volume, density
calculations and mould calibrations are required to provide accurate doses.
▪ When a drug is placed in a suppository base, it will displace an amount of base as a
function of its density. So the displacement value is calculated prior to addition of
drug.
Mrs. Nisha Marcel Pharmaceutics II CBCS 52
Mrs. Nisha Marcel Pharmaceutics II CBCS 53
▪ The moulding operation (pour, cooling & removal) along with filling, ejection can be
performed automatically.
▪ The output of a typical rotatory machine ranges from 35000 – 6000 suppositories /
hour.
Mrs. Nisha Marcel Pharmaceutics II CBCS 54
Mrs. Nisha Marcel Pharmaceutics II CBCS
▪ A : Rotary suppository
moulding machine.
▪ 1 : filling device / feeding
hopper
▪ 2 : rotating cooling turntable
▪ 3 :suppository ejection
station
▪ 4 : scrapping device
▪ 5 : refrigerant inlet and
outlet
55
Mrs. Nisha Marcel Pharmaceutics II CBCS 56
1. Suppositories for systemic effect
2. Suppositories for local effect
3. Water in suppository
4. Hygroscopicity
5. Incompatibilities
6. Viscosity
7. Brittleness
8. Density
9. Volume Contraction
Mrs. Nisha Marcel Pharmaceutics II CBCS 57
10. Lubricants or Mould release agents
11. Dosage replacement factor
12. Weight & volume control
13. Rancidity & antioxidant
2. Suppositories for local effect
▪ The base used for local action drugs
are virtually non-absorbable, slow in
melting, slow in drug release as
contrasted with suppository bases
intended for systemic drugs.
▪ The drug must be homogenously
distributed in the suppository base.
Mrs. Nisha Marcel Pharmaceutics II CBCS 58
1. Suppositories for systemic effect
▪ Availability and cost of the
suppository base must be considered.
▪ The drug should be homogenously
dispersed in the base.
▪ Solubility of API in water and other
ingredients should be known.
▪ To enhance the homogeneity of drug
in the desired base, either a suitable
solvent is used or the drug is finely
comminuted before incorporation.
3. Water in suppositories
▪ Use of water as a solvent for
incorporation of substances in the
suppository bases should be avoided
for the following reasons:
1. Water accelerates the oxidation of
fats.
2. If the water evaporates the
dissolved drug crystallizes out.
3. Reactions between ingredients in
the suppository are more likely to
occur in the presence of water.
Sometimes anhydrous chemicals are
used to avoid this possibilities.
4. The incorporation of water
increases the chances of bacterial
contamination thus a bacteriostatic
agent is added such as parabens.
4. Hygroscopicity
▪ Glycerinated gelatine suppositories
looses moisture by evaporation in dry
climates & absorb moisture under
conditions of high humidity.
▪ PEG bases are also hygroscopic. The
rate of moisture change in PEG bases
depends not only on humidity and
temperature but also on the chain
length of the molecule.
▪ As the molecular weight pf these
ethylene polymers increases the
hygroscopicity decreases.
Mrs. Nisha Marcel Pharmaceutics II CBCS 59
5. Incompatibilities
❑ PEG :
▪ Incompatible with silver salts, tannic
acid, aminopyrine, quinine.
▪ Many chemicals have tendency to
crystallize out of PEG e.g. sodium
barbital, salicylic acid, camphor.
▪ Higher concentration of salicylic acid
softens it to the ointment consistency
and aspirin forms a complex with it.
▪ Penicillin G is stable in other fatty
acids but decompose in PEG bases.
▪ Fatty bases with significant -OH
values react with API.
6. Viscosity
▪ Low viscosity : melted cocoa butter,
its substitutes.
▪ High viscosity : Glycerinated base,
PEG
▪ Low viscosity base leads to
sedimentation of suspended
practices. Poor techniques leads to
non-uniform suppository.
▪ Precautions:
✓Addition of 2% Al. monostearate
increases the aids in maintaining a
homogenous suspension of insoluble
materials.
✓Cetyl stearyl / myristyl ROH / stearic
acid are added to improve the
consistency of suppositories.
Mrs. Nisha Marcel Pharmaceutics II CBCS 60
7. Brittleness
▪ Cocoa butter suppositories are quite
elastic & do not fracture easily.
▪ Synthetic fat bases with higher solid
content at room temperature are
unusually more brittle.
▪ Fracturing of suppositories such as
base is often by rapid chilling in an
extremely cold mould.
▪ To overcome this the temperature
differential b/w melted base and
mould should be as small as possible.
▪ Addition of small amount of Tween
80/85, castor oil, glycerine impacts
the plasticity.
8. Density
▪ To calculate the amount of drug per
suppository the density of base must
be known.
▪ The volume of the mould cavity is
fixed therefore the weight of the
individual suppository depends on the
density of the mass.
▪ Knowledge of suppository weight can
be obtained from a given mould &
density of given base.
Mrs. Nisha Marcel Pharmaceutics II CBCS 61
9. Volume contraction
▪ Occurs in many melted suppository
bases after cooling in the mould.
▪ The results are manifested in 2
following ways:
1. Good mould release
2. Contraction hole formation at the
open end of the mould
10. Lubricants or Mould release
agents
▪ Cocoa butter adhere – low volume of
contraction – difficult to remove –
lubricants / release agents.
▪ Egs: mineral oil, aqueous solution of
sodium lauryl sulphate, various
silicones, alcohol & tincture of green
soap.
▪ Applied by wiping / brushing /
spraying.
Mrs. Nisha Marcel Pharmaceutics II CBCS 62
11. Dosage replacement factor
▪ The amount of base replaced by the
API.
▪ The replacement factor “f ”
f = 100 (E – G)
(G) (X)
▪ E – weight of the pure base
suppository
▪ G – weight of the suppository
▪ X% - API
12. Weight & volume control
▪ The amount of API in suppository
depends on:
1. Its concentration in the mass
2. The volume of mould cavity
3. Specific gravity of the base
4. Volume variation within the 2% of
desired value
5. Weight variations – inconsistencies
in the manufacturing process – e.g.:
incomplete closure of mould,
uneven scrapings or + 5%
Mrs. Nisha Marcel Pharmaceutics II CBCS 63
13. Rancidity & antioxidant
▪ Rancidity – autooxidation &
subsequent decomposition of
unsaturated fats into low & medium
molecular weight saturated /
unsaturated aldehydes, ketones &
acids – have unpleasant odour.
▪ Eg: effective antioxidants – phenols,
tocopherols, ascorbic acids, tannins
etc.
Mrs. Nisha Marcel Pharmaceutics II CBCS 64
1. Melting Range Test
2. Softening Time
3. Breaking Test
4. Dissolution / Disintegration Time
Mrs. Nisha Marcel Pharmaceutics II CBCS 65
▪ This test is also called the macromelting range test and is a
measure of the time it takes for the entire suppository to melt
when immersed in a constant-temperature (37 °C) water bath.
▪ In contrast, the macromelting range test is the melting range
measured in capillary tubes for the fat base only.
▪ The suppository melting apparatus consists of a graduated tube like
glass test chamber. The sample to be tested is placed in a spiral
shaped glass test basket inside the test chamber which itself is
surrounded by a water jacket heated by circulation thermostat.
The time for the entire suppository to melt or disperse in the
surrounding water is measured.
Mrs. Nisha Marcel Pharmaceutics II CBCS 66
▪ Apparatus consists of a U-tube partially submersed in a
constant-temperature water bath.
▪ A constriction on one side holds the suppository in place in the
tube.
▪ A glass rod is placed on top of the suppository, and the time for
the rod to pass through to the constriction is recorded as the
“softening time”.
Mrs. Nisha Marcel Pharmaceutics II CBCS 67
▪ Brittleness of suppositories is a problem for which various
solutions have already been described. The breaking test is
designed as a method for measuring the fragility or brittleness
of suppositories.
▪ The apparatus used for the test consists of a double-wall
chamber in which the test suppository is placed.
▪ Water at 37 °C is pumped through the double walls of the
chamber, & the suppository contained in the dry inner
chamber supports a disc to which a rod is attached.
▪ The test is conducted by placing 600gm on the platform. At
1mnt intervals, 200 gm weights are added & the weight at
which the suppository collapses is the breaking point or the
force that determines the fragility or brittleness
characteristics of the suppository.
Mrs. Nisha Marcel Pharmaceutics II CBCS 68
▪ Early testing was carried out by simple placement of beaker
containing a medium.
▪ In an effort to control the variation in mass/medium interface
various means have been employed including wire mesh basket or a
membrane to separate the sample chamber from the reservoir.
Mrs. Nisha Marcel Pharmaceutics II CBCS 69
▪ Packaged in such a way that each
suppository should be overwrapped or
they must be placed in a container in
such a manner that they do not touch
each other.
▪ Staining, breakage or deformation by
melting caused by jostling or adhesion
can result from poorly wrapped and
packaged suppositories.
▪ Suppositories in direct contact with
one another by fusion resulting from
the changes in ambient temperature.
▪ Suppositories usually are foiled in tin
or aluminium, paper and plastic strips
are also used.
▪ Overwrapping of suppositories are
done by modern packaging machines
(8000 suppositories per hour)
▪ In one type of machine, the chill-
hardened suppositories are placed in
notched turntable and then fed to the
packaging station, from a roll, cut to
size and finally rolled around each
suppository.
Mrs. Nisha Marcel Pharmaceutics II CBCS 70
▪ A significant advance in suppository
manufacturing was the development
of methods for molding suppositories
directly in their wrapping material.
▪ Currently accomplished with either
plastic or aluminium foil.
▪ Using these techniques one machine
can make 12000 to 20000
suppositories per hour.
▪ Advantages include: high production
▪ In both plastic & aluminium
approaches, the tops of molds are left
open for the entrance of filling
nozzles. After the mass has been
injected, usually by means of small,
variable-throw piston pumps, the tops
are sealed. The strips are then passed
in an upright position through a
cooling station.
▪ Additional advantage: suited for
suppositories intended for tropical
climates.
Mrs. Nisha Marcel Pharmaceutics II CBCS 71
▪ Suppository should be protected from heat by storing at low temperature.
▪ PEG suppositories & other suppositories enclosed in a solid shell are less prone to
distortion at temperatures slightly above body temperature.
▪ Glycerinated gelatine suppositories should be protected from heat, moisture & dry
air by packaging in well sealed containers & storing in cool place.
Mrs. Nisha Marcel Pharmaceutics II CBCS 72
▪ The suppository (API + Base) must be chemically and physically stable at refrigerator
temperatures as well as room temperature storage conditions for at least years.
▪ Storage stability studies are normally conducted at 4°C and at room temperature (25
+ 3°C)
▪ Cocoa butter suppository sometimes in storage “bloom” (formation of a white
powder deposit on the surface). Usually can be avoided if the suppositories are
wrapped in foil & stored at uniform cool or refrigerator temperatures.
▪ Fat base suppositories have been shown to harden for a period of time after
manufacture.
▪ The suppository overwrap foil also can cause problems in time. For example if
suppository contains an acid, the foil wrapping may be attacked and develop
pinholes.
Mrs. Nisha Marcel Pharmaceutics II CBCS 73
▪ Definition: Solid dosage forms of medicament for insertion into body cavities other than
mouth.
▪ The "torpedo" shape helps the device to travel internally, increasing its efficacy.
▪ Advantages: Medicinal substance enter the circulatory system (bypassing the liver), High rate
of absorption of medical substances.
▪ Disadvantages: Irritant drugs cannot be administered, Causes embarrassment to patients.
▪ Ideal properties: Should melt at body temperature, Should release medicament readily, Should
be wetting & emulsifying properties, Should keep its shape.
▪ Types: Rectal, Vaginal, Nasal, Urethral, Earcones Suppositories.
▪ Factors affecting the rectal drug absorption:
Physiologic Factors
Physiochemical characteristics of the drug
Physiochemical characteristics of the base & adjuvants
Blood levels from different dosage forms
Mrs. Nisha Marcel Pharmaceutics II CBCS 74
▪ Desired features:
1. It must retain the shape and size.
2. It should melt at body temperature.
3. It should be non-irritant.
4. It should shrink sufficiently to remove from mould.
▪ Specifications:
Mrs. Nisha Marcel Pharmaceutics II CBCS 75
FATTY BASES
• Theobroma Oil
(melting tendency)
• Emulsified
Theobroma Oil
• Hydrogenated Oils
(resistant to
oxidation)
WATER SOLUBLE
& WATER
MISCIBLE BASES
• Glycero- gelatine
(Pessaries, Type A &
B)
• Soap glycerine
(hygroscopic)
• Polyethylene glycols
(macrogols)
EMULSIFYING
/SYNTHETIC
BASES
• Witepsol
• Massa Estarinum
• Massupol
Mrs. Nisha Marcel Pharmaceutics II CBCS 76
▪ 4 methods to formulate suppositories:
✓Hand Moulding
✓Compression Moulding
✓Pour Moulding
✓Automatic Moulding Machine
Mrs. Nisha Marcel Pharmaceutics II CBCS 77
Formulation considerations
1. Hygroscopicity
2. Incompatibilities
3. Viscosity
4. Brittleness
5. Density
6. Volume contraction
10. Lubricants or mould release agents
11. Dosage replacement factor
12. Weight and volume control
13. Rancidity and antioxidants
Mrs. Nisha Marcel Pharmaceutics II CBCS 78
1. Packaging of molded suppositories
2. In-package of molded suppositories
3. Storage
4. Evaluation of Suppository
▪ Melting Range Test
▪ Softening Time
▪ Breaking Test
▪ Dissolution / Disintegration Time
Mrs. Nisha Marcel Pharmaceutics II CBCS 79
Lachman Lieberman's The Theory And
Practice Of Industrial Pharmacy
Mrs. Nisha Marcel Pharmaceutics II CBCS 80
Mrs. Nisha Marcel Pharmaceutics II CBCS
1
2
81
Mrs. Nisha Marcel Pharmaceutics II CBCS
3 4
82
Mrs. Nisha Marcel Pharmaceutics II CBCS
5
83
Mrs. Nisha Marcel Pharmaceutics II CBCS 84

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Suppository

  • 1. Mrs. Nisha Marcel Assistant Professor Department of Pharmaceutics SJIPR Mrs. Nisha Marcel Pharmaceutics II CBCS 11
  • 2. 1. Introduction 2. Suppository bases 3. Methods of formulation 4. QC test 5. Packaging, Storage, Stability problems Mrs. Nisha Marcel Pharmaceutics II CBCS 2
  • 3. ▪ Solid dosage forms of medicament for insertion into body cavities other than mouth. ▪ The medicament is incorporated into the suppository base and the product is formulated such as way that it melt/dissolve at body temperature in the body cavity fluids to release the medicament. ▪ A is a solid dosage form that is inserted into the rectum (rectal suppository), and vagina (vaginal suppository) where it dissolves or melts and exerts local or systemic effects. Suppositories are used to deliver medications that act both systemically and locally. Mrs. Nisha Marcel Pharmaceutics II CBCS 3
  • 4. ▪ Several different ingredients can be used to form the base of a suppository: cocoa butter or a similar substitute, polyethylene glycol, hydrogels, and glycerinated gelatine. The type of material used depends on the type of suppository, the type of drug, and the conditions in which the suppository will be stored. ▪ The "torpedo" shape helps the device to travel internally, increasing its efficacy. ▪ Different shapes the suppositories manufactured: Mrs. Nisha Marcel Pharmaceutics II CBCS 4
  • 5. 1. Medicinal substance enter the circulatory system (bypassing the liver) 2. High rate of absorption of medical substances 3. The degree and frequency of allergic reactions decreases 4. Less side effects 5. Painless and simple administration of the drug 6. Compactness of the dosage form 7. Gives localized and systemic action 8. Easy to use for paediatric and geriatric patients 9. Useful to promote evacuation of bowel 10. Unit dosage form of drug Mrs. Nisha Marcel Pharmaceutics II CBCS 5
  • 6. 1. Irritant drugs cannot be administered 2. Causes embarrassment to patients 3. To be stored at low temperature 4. Cant easily be prepared 5. Cost-expensive 6. Some drug maybe be degraded by the microbial flora present in the rectum 7. Fluid content of the rectum is much less than that o the small intestine, this may effect dissolution rate, etc. Mrs. Nisha Marcel Pharmaceutics II CBCS 6
  • 7. 1. Should melt at body temperature 2. Should release medicament readily 3. Should be wetting & emulsifying properties 4. Should keep its shape 5. Should be non-toxic and non-irritant 6. Should be stable on storage i.e. does not change colour, odour or drug release pattern 7. Should be compatible with different formulation method 8. Acid value below 0.2 9. Iodine value less than 7 10. Saponification value ranges from 200 to 245 Mrs. Nisha Marcel Pharmaceutics II CBCS 7
  • 8. 1. Rectal 2. Vaginal 3. Nasal Suppositories 4. Urethral 5. Earcones Mrs. Nisha Marcel Pharmaceutics II CBCS 1. 2. 5. 4. 3. 8
  • 9. 1. Rectal Suppositories : ▪ It is inserted in the rectal. ▪ The weight of rectal suppository differs for children and adults. ▪ Usually in torpedo shape. The length is about 3cm. 2. Vaginal Suppositories : ▪ It is in oviform shape. ▪ About 3 – 5gm in weight. ▪ It contains the drugs which are used in the treatment of the infections of female genitourinary tract and meant for contraception. Mrs. Nisha Marcel Pharmaceutics II CBCS 9
  • 10. 3. Nasal Suppositories : ▪ These suppository are meant for introduction into nasal cavity. ▪ It is about 1gm in weight. 4. Urethral Suppositories : ▪ The weight of this suppository is about 2gm and 60-75mm long in Females. ▪ Those intended for males weigh 4gm each and are 100-150mm long. ▪ It is available in pencil shape. 5. Earcones Suppositories : ▪ It is also known as Aurinaries. ▪ These are meant for introduction into the ear. ▪ It is cylindrical in shape about 1gm in weight. Mrs. Nisha Marcel Pharmaceutics II CBCS 10
  • 11. 1. Physiologic Factors - Drugs absorbed by anorectal area and retain therapeutic action/values. - Lower hemorrhoidal veins (50-70% drug absorption) - Lymphatic circulation, pH. 2. Physiochemical characteristics of the drug - Compatibility between drug and the excipients & suppository bases. - Degree of ionization 3. Physiochemical characteristics of the base & adjuvants - Properties of suppository bases affect drug absorption. - Presence of adjuvant in base 4. Blood levels from different dosage forms Mrs. Nisha Marcel Pharmaceutics II CBCS 11
  • 12. ▪ The human rectum is approximately 15-20 cm in the length, when empty of faecal material. ▪ It contains 2 – 3 ml of inert mucous fluid ▪ In resting state, the rectum is non motile ▪ There is no villa or microvillus on rectal mucosa. ▪ Physiological factors: o Colonic content o Circulation o pH and lack of buffering capacity of the rectal fluid. Mrs. Nisha Marcel Pharmaceutics II CBCS 12
  • 13. ▪ When systemic effect are desired from suppository greater absorption may be expected from a rectum that is void than that with faecal. ▪ An evacuation enema maybe administered before insertion of a suppository. Diarrhoea, colonic obstruction and tissue dehydration influence the rate & degree of drug absorption from rectum. Mrs. Nisha Marcel Pharmaceutics II CBCS 13
  • 14. ▪ Drugs absorbed rectally partially by pass portal circulation, thereby enabling drug destroyed in liver to exert systemic effect. ▪ Depending on the height at which absorption occurs at rectum, the drug passes into inferior, middle or superior haemorrhoid veins. ▪ The inferior is nearest to the anus, the upper haemorrhoid vein nearer to portal circulation, thus it is advisable to keep suppositories in the lower part of rectum. ▪ 50% - 70% of drug administered rectally, reported to go directly into general circulation. Mrs. Nisha Marcel Pharmaceutics II CBCS 14
  • 15. ▪ Rectal fluids are neutral (pH 7-8), have no effective buffer capacity. ▪ The barrier separating colon lumen from the blood is preferentially permeable to the unionized forms of drugs, thus absorption of drug would ne enhanced by change in pH of the rectal mucosa to one that increase the proportion of unionized drugs. Mrs. Nisha Marcel Pharmaceutics II CBCS 15
  • 16. A) Lipid water solubility of a drug (partition coefficient): • the lipid water coefficient of a drug is important in selecting the suppository base and in anticipating drug releaser from the base. • Lipophilic drug, when distributed in a fatty suppositories base has fewer tendencies to escape to the fluids. • Water-soluble salt are preferred in fatty base suppository. • Water – soluble base e.g. PEG which dissolve in the rectal fluids, release both water – soluble & oil-soluble drugs. Mrs. Nisha Marcel Pharmaceutics II CBCS 16
  • 17. B) Degree of ionization: ▪ The barrier separating colon lumen from the blood is preferentially permeable to the unionized forms of drugs, thus absorption of drug would be enhanced by increasing the proportion of unionized drugs. Mrs. Nisha Marcel Pharmaceutics II CBCS 17
  • 18. C) Concentration of a drug in a base: ▪ The more drugs in a base, the more drug will be available for absorption. ▪ If the concentration of the drug in the intestinal lumen is above a particular amount, the rate of absorption is not change by further increase in concentration of drug. ▪ In general, the rate limiting step in drug absorption from suppository is the partitioning of the dissolved drug from the melted base and not the rate of solution of drug in the body fluid. ▪ Studies show that the rate, at which the drug diffuses to the surface of the suppository, particle size and presence of surface-active agents are factors that affect drug release from suppositories. Mrs. Nisha Marcel Pharmaceutics II CBCS 18
  • 19. 1) Nature of the base: ▪Suppository base capable of melting, softening or dissolving to release the drug for absorption. ▪If the base irritating the colon, it will promote colonic response, lead to increase bowl movement and decrease absorption. Mrs. Nisha Marcel Pharmaceutics II CBCS 19
  • 20. 2) Presence of adjuvant in base: ▪Adjuvant in a formula may affect drug absorption, change the rheological properties of the base at body temperature or affected the dissolution of the drug. Mrs. Nisha Marcel Pharmaceutics II CBCS 20
  • 21. ▪ Many studies have attempted to compare the oral dosage form with the rectal administration. ▪ The results are inadequate, because of the different parameter used to make the studies, the experiment conditions and choice of excipient. Mrs. Nisha Marcel Pharmaceutics II CBCS 21
  • 22. Mrs. Nisha Marcel Pharmaceutics II CBCS 22
  • 23. 1. It must retain the shape and size. 2. It should melt at body temperature. 3. It should be non-irritant. 4. It should shrink sufficiently to remove from mould. 5. It should not interfere in release or absorption of drug. 6. It should permit incorporation of drug. 7. It should be compatible with the drugs. 8. It should be physically stable on storage. 9. It should not be soften or harden on storage. Mrs. Nisha Marcel Pharmaceutics II CBCS 23
  • 24. Mrs. Nisha Marcel Pharmaceutics II CBCS 24
  • 25. ▪ A brief description of the composition of the base reveals the source of the origin (natural/synthetic/modified) ▪ Physical or chemical incompatibilities with other constituents may be predicted if the exact formula composition is known including preservatives, antioxidants and emulsifiers. Mrs. Nisha Marcel Pharmaceutics II CBCS 25
  • 26. ▪ Suppository bases don’t have a sharp melting point (complex mixture of triglycerides), their melting characteristics are expressed as ranges, indicating the temperature at which the fats start to melt and the temperature at which completely melted. ▪ Melting range is usually determined by “Wiley melting point”, “Capillary melting point”. Mrs. Nisha Marcel Pharmaceutics II CBCS 26
  • 27. ▪ One can determine the solidification and melting ranges of fatty bases as well as the moulding character, surface feel and hardness of the bases. ▪ A base with sharp drop in solids over a short temperature span proves brittle if molded too quickly. ▪ The solid content at room temperature could determine suppository hardness. Since skin temperature is about 32°C, one can predict that would be dry to touch from a solid content over 30% at that temperature. Mrs. Nisha Marcel Pharmaceutics II CBCS 27
  • 28. ▪ “It is the number of milligrams of KOH (Potassium Hydroxide) that would neutralize the acetylate 1gm of fat” ▪ This is the measure of unesterified position of glycerides and reflects the mono- and di-glyceride content of a fatty base. Mrs. Nisha Marcel Pharmaceutics II CBCS 28
  • 29. ▪ This test allow to determine the time required for the solidifying the base, when it is chilled in the mould. ▪ If the interval between the melting point and solidifying point is 10°C or more, time required for solidification may have to be shortened for a more efficient manufacturing procedure by refrigeration. Mrs. Nisha Marcel Pharmaceutics II CBCS 29
  • 30. ▪ It is the number of grams of Iodine that reacts with 100gm of fat or other unsaturated material. ▪ The possibility of decomposition by moisture, acids, oxygen (which leads to rancidity of ats) increases with higher iodine value. Mrs. Nisha Marcel Pharmaceutics II CBCS ▪ It is the amount of water in grams that can be incorporated in 100gm of fat. ▪ The “water number” can be increased by addition of surface-active agents. 30
  • 31. ▪ “The number of milligrams of KOH (Potassium Hydroxide) required to neutralize the free fatty acids and saponify the ester contained in 1gm of a fat” ▪ From saponification value we can know the type of glyceride present (mono-, di- or tri-) and also amount present. Mrs. Nisha Marcel Pharmaceutics II CBCS ▪ It is the number of milligrams of KOH (Potassium Hydroxide) required neutralizing the free fatty acids in 1gm substance (fat). ▪ Low acid value or absence of acid value is important for good suppository bases. 31
  • 32. FATTY BASES • Theobroma Oil (melting tendency) • Emulsified Theobroma Oil • Hydrogenated Oils (resistant to oxidation) WATER SOLUBLE & WATER MISCIBLE BASES • Glycero- gelatine (Pessaries, Type A & B) • Soap glycerine (hygroscopic) • Polyethylene glycols (macrogols) EMULSIFYING /SYNTHETIC BASES • Witepsol • Massa Estarinum • Massupol Mrs. Nisha Marcel Pharmaceutics II CBCS 32
  • 33. Mrs. Nisha Marcel Pharmaceutics II CBCS 33
  • 34. Source: • Theobroma is yellowish white solid fat obtained from the roasted seed of Theobroma cocoa. • It’s a mixture of glyceride of esters of stearic, oleic, palmitic & other fatty acids. Properties: • At room temperature it is a yellowish, white solid having a faint, agreeable chocolate like odour. • Chemically, it is a triglyceride (combination of glycerine and one or different fatty acids) primarily of oleopalmitostearin and oleodistearine. • It melts at 30 – 35°C, has a consistency of butter. Mrs. Nisha Marcel Pharmaceutics II CBCS 34
  • 35. ▪ Advantages: i. Melting just below the body temperature. ii. Maintaining its solidity at usual room temperatures. iii. Readily liquefy on heating and solidify on cooling ▪ Disadvantages: i. Exhibits marked polymorphism ii. Rancidity iii. Stick to mould iv. Leakage from body cavity v. Immiscibility with body fluid. vi. Chloral hydrate or lactic acid liquefy it. Mrs. Nisha Marcel Pharmaceutics II CBCS 35
  • 36. Mrs. Nisha Marcel Pharmaceutics II CBCS ▪ The use of 5% glyceride monostearate, 2-3% cetyl alcohol, 4% bees wax & 12% spermaceti is recommended to prepare emulsified Theobroma oil. ▪ They are obtain by hydrogenation of vegetable oils such as arachis oil, cotton seed oil. It is use as a substitute for Theobroma oil & has number of advantages. ▪ Advantages: Resistance to oxidation, no lubricant required, it gives colourless, odourless suppositories 36
  • 37. Mrs. Nisha Marcel Pharmaceutics II CBCS 37
  • 38. Mrs. Nisha Marcel Pharmaceutics II CBCS 38
  • 39. ▪ It is a mix of glycerine & water which is made stiff by addition of gelatine particularly used for making pessaries. ▪ The suppositories prepared from glycerogelatin base is translucent which tend to dissolve or melt in the body cavity and release the medicament for better absorption. ▪ This base is well suited for suppositories containing boric acid, bromide, iodide, opium etc. 2 types Type A Type B Pharmagel A Pharmagel B Acidic in nature Alkaline in nature Used for acidic drug Used for basic drug with isoelectric point pH 7-9 with isoelectric pH 4.7-5 Mrs. Nisha Marcel Pharmaceutics II CBCS 39
  • 40. Disadvantages • Formulation time depends on contents and quality of gelatine used. • Gelatine is incompatible with many drug (gallic acid, tannic acid). • More chances of bacteria & mould growth. • Suppositories prepared are hygroscopic in nature. Mrs. Nisha Marcel Pharmaceutics II CBCS 40
  • 41. ▪ In glycrogelatin suppositories the gelatine is replaced with either curd soap or sodium citrate which makes the base sufficiently hard to prepare good quality of suppositories. Advantages • Chemically stable • Non- toxic, non- irritant • Doesn’t allow bacterial growth. Disadvantage • Hygroscopic in nature • Requires special storage condition • Good solvent property results in drug retention • High solubility leads to supersaturation. Mrs. Nisha Marcel Pharmaceutics II CBCS 41
  • 42. ▪ Commonly known as carbowaxes, macrogols or polyglycols. ▪ The physical character of these carbowaxes varies according to the molecular weight. ▪ Less than 1000 Liquid more than 1000 Wax like solids Mrs. Nisha Marcel Pharmaceutics II CBCS 42
  • 43. ▪ Advantages: 1. They are chemically stable 2. Non-irritant 3. Do not allow bacterial or mould growth 4. Physiologically inert substances ▪ Disadvantages: 1. Hygroscopic hence require special storage condition 2. Incompatible with tannins, phenols etc Mrs. Nisha Marcel Pharmaceutics II CBCS 43
  • 44. Mrs. Nisha Marcel Pharmaceutics II CBCS 44
  • 45. Mrs. Nisha Marcel Pharmaceutics II CBCS ▪ It consist of triglyceride or saturated vegetable oil. The suppository prepared should not be rapidly cool & to prevent them from brittle and fracture condition. ▪ Mix of mono & tri glycerides. Also known as Adeps Solitus. Available in various grades commonly used grade is “B” used for dispensing. 45
  • 46. ▪ It consists of glycerides esters mainly of lauric acid to which small amount of glyceryl monostearate is added to improve its water absorbing capacity. ▪ Advantages • Solidify rapidly • Non- irritant • Not effected on heating ▪ Disadvantages • Hygroscopic in nature • Should not be cooled rapidly • Not very viscous after melting Mrs. Nisha Marcel Pharmaceutics II CBCS 46
  • 47. ▪ 4 methods to formulate suppositories: 1. Hand Moulding 2. Compression Moulding 3. Pour Moulding 4. Automatic Moulding Machine Mrs. Nisha Marcel Pharmaceutics II CBCS 47
  • 48. ▪ Oldest and simplest method of preparing suppositories by hand. ▪ Procedure : 1. By rolling the well blended suppository base containing the active ingredient into desires shape. 2. The base is 1st grated and kneaded with the active ingredient by use of a mortar and pestle resulting in plastic like well blended mass. 3. The active ingredients are usually finely powdered or dissolved in water or sometimes mixed with a small amount of wool fat to help in incorporation with the suppository base. 4. The mass is then rolled into cylindrical rod of desired length & diameter. The rod is cut into portions & than one end is pointed. 5. Starch or talcum powder under rolling surface is used to prevent the mass from adhering. Mrs. Nisha Marcel Pharmaceutics II CBCS 48
  • 49. ▪ Practical & economic method for preparation of small number of suppositories. Mrs. Nisha Marcel Pharmaceutics II CBCS 49
  • 50. ▪ Uniform & pharmaceutically elegant suppositories can be made by compressing the grated the cold mass into desired shape. ▪ A hand funnel wheel pushes the piston against the suppository mass contained in a cylinder. So that the mass is inserted into moulds. ▪ This method is simple and results in more elegant appearance than done by hand moulding. ▪ Avoids sedimentation possibilities of insoluble solids in the suppository base. ▪ But this method is too slow for production of larger number of suppositories. ▪ Disadvantage: 1. exclusive for moulding fat type bases suppository 2. Leads to air entrapment which makes weight control impossible. Mrs. Nisha Marcel Pharmaceutics II CBCS 50
  • 51. Mrs. Nisha Marcel Pharmaceutics II CBCS 51
  • 52. ▪ Commonly used for producing suppositories in both small & large scale. ▪ Involves first melting the suppository base, and then dispersing or dissolving the drug in the melted base. ▪ The mixture is removed from the heat and poured into a suppository mould. When the mixture has congealed, the suppositories are removed from the mould. ▪ Suppositories are generally made from solid ingredients and drugs which are measured by weight. When they are mixed, melted, and poured into suppository mould cavities, they occupy a volume – the volume of the mould cavity. Since the components are measured by weight but compounded by volume, density calculations and mould calibrations are required to provide accurate doses. ▪ When a drug is placed in a suppository base, it will displace an amount of base as a function of its density. So the displacement value is calculated prior to addition of drug. Mrs. Nisha Marcel Pharmaceutics II CBCS 52
  • 53. Mrs. Nisha Marcel Pharmaceutics II CBCS 53
  • 54. ▪ The moulding operation (pour, cooling & removal) along with filling, ejection can be performed automatically. ▪ The output of a typical rotatory machine ranges from 35000 – 6000 suppositories / hour. Mrs. Nisha Marcel Pharmaceutics II CBCS 54
  • 55. Mrs. Nisha Marcel Pharmaceutics II CBCS ▪ A : Rotary suppository moulding machine. ▪ 1 : filling device / feeding hopper ▪ 2 : rotating cooling turntable ▪ 3 :suppository ejection station ▪ 4 : scrapping device ▪ 5 : refrigerant inlet and outlet 55
  • 56. Mrs. Nisha Marcel Pharmaceutics II CBCS 56
  • 57. 1. Suppositories for systemic effect 2. Suppositories for local effect 3. Water in suppository 4. Hygroscopicity 5. Incompatibilities 6. Viscosity 7. Brittleness 8. Density 9. Volume Contraction Mrs. Nisha Marcel Pharmaceutics II CBCS 57 10. Lubricants or Mould release agents 11. Dosage replacement factor 12. Weight & volume control 13. Rancidity & antioxidant
  • 58. 2. Suppositories for local effect ▪ The base used for local action drugs are virtually non-absorbable, slow in melting, slow in drug release as contrasted with suppository bases intended for systemic drugs. ▪ The drug must be homogenously distributed in the suppository base. Mrs. Nisha Marcel Pharmaceutics II CBCS 58 1. Suppositories for systemic effect ▪ Availability and cost of the suppository base must be considered. ▪ The drug should be homogenously dispersed in the base. ▪ Solubility of API in water and other ingredients should be known. ▪ To enhance the homogeneity of drug in the desired base, either a suitable solvent is used or the drug is finely comminuted before incorporation.
  • 59. 3. Water in suppositories ▪ Use of water as a solvent for incorporation of substances in the suppository bases should be avoided for the following reasons: 1. Water accelerates the oxidation of fats. 2. If the water evaporates the dissolved drug crystallizes out. 3. Reactions between ingredients in the suppository are more likely to occur in the presence of water. Sometimes anhydrous chemicals are used to avoid this possibilities. 4. The incorporation of water increases the chances of bacterial contamination thus a bacteriostatic agent is added such as parabens. 4. Hygroscopicity ▪ Glycerinated gelatine suppositories looses moisture by evaporation in dry climates & absorb moisture under conditions of high humidity. ▪ PEG bases are also hygroscopic. The rate of moisture change in PEG bases depends not only on humidity and temperature but also on the chain length of the molecule. ▪ As the molecular weight pf these ethylene polymers increases the hygroscopicity decreases. Mrs. Nisha Marcel Pharmaceutics II CBCS 59
  • 60. 5. Incompatibilities ❑ PEG : ▪ Incompatible with silver salts, tannic acid, aminopyrine, quinine. ▪ Many chemicals have tendency to crystallize out of PEG e.g. sodium barbital, salicylic acid, camphor. ▪ Higher concentration of salicylic acid softens it to the ointment consistency and aspirin forms a complex with it. ▪ Penicillin G is stable in other fatty acids but decompose in PEG bases. ▪ Fatty bases with significant -OH values react with API. 6. Viscosity ▪ Low viscosity : melted cocoa butter, its substitutes. ▪ High viscosity : Glycerinated base, PEG ▪ Low viscosity base leads to sedimentation of suspended practices. Poor techniques leads to non-uniform suppository. ▪ Precautions: ✓Addition of 2% Al. monostearate increases the aids in maintaining a homogenous suspension of insoluble materials. ✓Cetyl stearyl / myristyl ROH / stearic acid are added to improve the consistency of suppositories. Mrs. Nisha Marcel Pharmaceutics II CBCS 60
  • 61. 7. Brittleness ▪ Cocoa butter suppositories are quite elastic & do not fracture easily. ▪ Synthetic fat bases with higher solid content at room temperature are unusually more brittle. ▪ Fracturing of suppositories such as base is often by rapid chilling in an extremely cold mould. ▪ To overcome this the temperature differential b/w melted base and mould should be as small as possible. ▪ Addition of small amount of Tween 80/85, castor oil, glycerine impacts the plasticity. 8. Density ▪ To calculate the amount of drug per suppository the density of base must be known. ▪ The volume of the mould cavity is fixed therefore the weight of the individual suppository depends on the density of the mass. ▪ Knowledge of suppository weight can be obtained from a given mould & density of given base. Mrs. Nisha Marcel Pharmaceutics II CBCS 61
  • 62. 9. Volume contraction ▪ Occurs in many melted suppository bases after cooling in the mould. ▪ The results are manifested in 2 following ways: 1. Good mould release 2. Contraction hole formation at the open end of the mould 10. Lubricants or Mould release agents ▪ Cocoa butter adhere – low volume of contraction – difficult to remove – lubricants / release agents. ▪ Egs: mineral oil, aqueous solution of sodium lauryl sulphate, various silicones, alcohol & tincture of green soap. ▪ Applied by wiping / brushing / spraying. Mrs. Nisha Marcel Pharmaceutics II CBCS 62
  • 63. 11. Dosage replacement factor ▪ The amount of base replaced by the API. ▪ The replacement factor “f ” f = 100 (E – G) (G) (X) ▪ E – weight of the pure base suppository ▪ G – weight of the suppository ▪ X% - API 12. Weight & volume control ▪ The amount of API in suppository depends on: 1. Its concentration in the mass 2. The volume of mould cavity 3. Specific gravity of the base 4. Volume variation within the 2% of desired value 5. Weight variations – inconsistencies in the manufacturing process – e.g.: incomplete closure of mould, uneven scrapings or + 5% Mrs. Nisha Marcel Pharmaceutics II CBCS 63
  • 64. 13. Rancidity & antioxidant ▪ Rancidity – autooxidation & subsequent decomposition of unsaturated fats into low & medium molecular weight saturated / unsaturated aldehydes, ketones & acids – have unpleasant odour. ▪ Eg: effective antioxidants – phenols, tocopherols, ascorbic acids, tannins etc. Mrs. Nisha Marcel Pharmaceutics II CBCS 64
  • 65. 1. Melting Range Test 2. Softening Time 3. Breaking Test 4. Dissolution / Disintegration Time Mrs. Nisha Marcel Pharmaceutics II CBCS 65
  • 66. ▪ This test is also called the macromelting range test and is a measure of the time it takes for the entire suppository to melt when immersed in a constant-temperature (37 °C) water bath. ▪ In contrast, the macromelting range test is the melting range measured in capillary tubes for the fat base only. ▪ The suppository melting apparatus consists of a graduated tube like glass test chamber. The sample to be tested is placed in a spiral shaped glass test basket inside the test chamber which itself is surrounded by a water jacket heated by circulation thermostat. The time for the entire suppository to melt or disperse in the surrounding water is measured. Mrs. Nisha Marcel Pharmaceutics II CBCS 66
  • 67. ▪ Apparatus consists of a U-tube partially submersed in a constant-temperature water bath. ▪ A constriction on one side holds the suppository in place in the tube. ▪ A glass rod is placed on top of the suppository, and the time for the rod to pass through to the constriction is recorded as the “softening time”. Mrs. Nisha Marcel Pharmaceutics II CBCS 67
  • 68. ▪ Brittleness of suppositories is a problem for which various solutions have already been described. The breaking test is designed as a method for measuring the fragility or brittleness of suppositories. ▪ The apparatus used for the test consists of a double-wall chamber in which the test suppository is placed. ▪ Water at 37 °C is pumped through the double walls of the chamber, & the suppository contained in the dry inner chamber supports a disc to which a rod is attached. ▪ The test is conducted by placing 600gm on the platform. At 1mnt intervals, 200 gm weights are added & the weight at which the suppository collapses is the breaking point or the force that determines the fragility or brittleness characteristics of the suppository. Mrs. Nisha Marcel Pharmaceutics II CBCS 68
  • 69. ▪ Early testing was carried out by simple placement of beaker containing a medium. ▪ In an effort to control the variation in mass/medium interface various means have been employed including wire mesh basket or a membrane to separate the sample chamber from the reservoir. Mrs. Nisha Marcel Pharmaceutics II CBCS 69
  • 70. ▪ Packaged in such a way that each suppository should be overwrapped or they must be placed in a container in such a manner that they do not touch each other. ▪ Staining, breakage or deformation by melting caused by jostling or adhesion can result from poorly wrapped and packaged suppositories. ▪ Suppositories in direct contact with one another by fusion resulting from the changes in ambient temperature. ▪ Suppositories usually are foiled in tin or aluminium, paper and plastic strips are also used. ▪ Overwrapping of suppositories are done by modern packaging machines (8000 suppositories per hour) ▪ In one type of machine, the chill- hardened suppositories are placed in notched turntable and then fed to the packaging station, from a roll, cut to size and finally rolled around each suppository. Mrs. Nisha Marcel Pharmaceutics II CBCS 70
  • 71. ▪ A significant advance in suppository manufacturing was the development of methods for molding suppositories directly in their wrapping material. ▪ Currently accomplished with either plastic or aluminium foil. ▪ Using these techniques one machine can make 12000 to 20000 suppositories per hour. ▪ Advantages include: high production ▪ In both plastic & aluminium approaches, the tops of molds are left open for the entrance of filling nozzles. After the mass has been injected, usually by means of small, variable-throw piston pumps, the tops are sealed. The strips are then passed in an upright position through a cooling station. ▪ Additional advantage: suited for suppositories intended for tropical climates. Mrs. Nisha Marcel Pharmaceutics II CBCS 71
  • 72. ▪ Suppository should be protected from heat by storing at low temperature. ▪ PEG suppositories & other suppositories enclosed in a solid shell are less prone to distortion at temperatures slightly above body temperature. ▪ Glycerinated gelatine suppositories should be protected from heat, moisture & dry air by packaging in well sealed containers & storing in cool place. Mrs. Nisha Marcel Pharmaceutics II CBCS 72
  • 73. ▪ The suppository (API + Base) must be chemically and physically stable at refrigerator temperatures as well as room temperature storage conditions for at least years. ▪ Storage stability studies are normally conducted at 4°C and at room temperature (25 + 3°C) ▪ Cocoa butter suppository sometimes in storage “bloom” (formation of a white powder deposit on the surface). Usually can be avoided if the suppositories are wrapped in foil & stored at uniform cool or refrigerator temperatures. ▪ Fat base suppositories have been shown to harden for a period of time after manufacture. ▪ The suppository overwrap foil also can cause problems in time. For example if suppository contains an acid, the foil wrapping may be attacked and develop pinholes. Mrs. Nisha Marcel Pharmaceutics II CBCS 73
  • 74. ▪ Definition: Solid dosage forms of medicament for insertion into body cavities other than mouth. ▪ The "torpedo" shape helps the device to travel internally, increasing its efficacy. ▪ Advantages: Medicinal substance enter the circulatory system (bypassing the liver), High rate of absorption of medical substances. ▪ Disadvantages: Irritant drugs cannot be administered, Causes embarrassment to patients. ▪ Ideal properties: Should melt at body temperature, Should release medicament readily, Should be wetting & emulsifying properties, Should keep its shape. ▪ Types: Rectal, Vaginal, Nasal, Urethral, Earcones Suppositories. ▪ Factors affecting the rectal drug absorption: Physiologic Factors Physiochemical characteristics of the drug Physiochemical characteristics of the base & adjuvants Blood levels from different dosage forms Mrs. Nisha Marcel Pharmaceutics II CBCS 74
  • 75. ▪ Desired features: 1. It must retain the shape and size. 2. It should melt at body temperature. 3. It should be non-irritant. 4. It should shrink sufficiently to remove from mould. ▪ Specifications: Mrs. Nisha Marcel Pharmaceutics II CBCS 75
  • 76. FATTY BASES • Theobroma Oil (melting tendency) • Emulsified Theobroma Oil • Hydrogenated Oils (resistant to oxidation) WATER SOLUBLE & WATER MISCIBLE BASES • Glycero- gelatine (Pessaries, Type A & B) • Soap glycerine (hygroscopic) • Polyethylene glycols (macrogols) EMULSIFYING /SYNTHETIC BASES • Witepsol • Massa Estarinum • Massupol Mrs. Nisha Marcel Pharmaceutics II CBCS 76
  • 77. ▪ 4 methods to formulate suppositories: ✓Hand Moulding ✓Compression Moulding ✓Pour Moulding ✓Automatic Moulding Machine Mrs. Nisha Marcel Pharmaceutics II CBCS 77
  • 78. Formulation considerations 1. Hygroscopicity 2. Incompatibilities 3. Viscosity 4. Brittleness 5. Density 6. Volume contraction 10. Lubricants or mould release agents 11. Dosage replacement factor 12. Weight and volume control 13. Rancidity and antioxidants Mrs. Nisha Marcel Pharmaceutics II CBCS 78
  • 79. 1. Packaging of molded suppositories 2. In-package of molded suppositories 3. Storage 4. Evaluation of Suppository ▪ Melting Range Test ▪ Softening Time ▪ Breaking Test ▪ Dissolution / Disintegration Time Mrs. Nisha Marcel Pharmaceutics II CBCS 79
  • 80. Lachman Lieberman's The Theory And Practice Of Industrial Pharmacy Mrs. Nisha Marcel Pharmaceutics II CBCS 80
  • 81. Mrs. Nisha Marcel Pharmaceutics II CBCS 1 2 81
  • 82. Mrs. Nisha Marcel Pharmaceutics II CBCS 3 4 82
  • 83. Mrs. Nisha Marcel Pharmaceutics II CBCS 5 83
  • 84. Mrs. Nisha Marcel Pharmaceutics II CBCS 84