Pharmaceutics – II (Dosage Form Science):

SUPPOSITORIES
INTRODUCTION
The word suppository is derived from Latin word ―suppositorium‖ which
means ―to place under‖.

Definition:
Suppositories are solid or semi-solid dosage forms intended for insertion into
the body cavities e.g. rectum, vaginal cavity, occasionally into the urethral tract where
these suppositories melt or soften or dissolve in the cavity fluid and exert a localized
or systemic effects.

OR

A suppository is a solid dosage form in which one or more APIs are dispersed
in a suitable base and molded or otherwise formed into a suitable shape for insertion
into rectum to provide local or systemic effects.

Explanation:

 Suppositories are commonly employed rectally and vaginally, occasionally

they’re used uretharlly and rarely they are also used nasally or orally.
 They have various shapes, sizes and weights.
 These are employed when a drug cannot tolerate orally or patient cannot
swallow a drug easily.
 The shape and size of suppository must be such that it is capable of being
easily inserted into the intended body cavity and once it is intended it must be
retained for an appropriate period of time.
 Suppository generally have been employed for three reasons to:
o Promote defecation
o Introduce drugs into body
o Treat anorectal diseases

THE THERAPEUTIC USES OF

SUPPOSITORIES
1. The drugs may be administered in the suppository dosage form for local or
systemic effect.
 2. Such health action depends on:
i. Nature of drug
ii. Concentration of drug
iii. Rate of drug absorption which depends upon the blood supply and
solubilities of the drugs
3. The lipid soluble or un-dissociated drugs are readily dissolved after release
from the base and fat.

Local Action:

1. The emollient (substances that soften the skin), the astringents (chemical
substances that constrict the body tissues to stop bleeding or to make skin less
oily – also called as protein precipitant), anti-bacterial agents, hormones,
steroids and local anesthetics are dispersed in the suppositories for the
treatment of local conditions of either vagina or urethra.
2. The rectal suppositories are primarily intended for the localized action and
these are most frequently used or employed to relieve the constipation, pain,
irritation, itching and inflammation associated with hemorrhoids (swollen or
painful condition in which bleeding can occur).
3. Anti-hemorrhoidal suppositories frequently contain a number of components
including:
i. Local anesthetics v. Vasoconstrictors
ii. Astringents vi. Analgesics
iii. Soothing agents vii. Emollients
iv. Protective
E.g. glycerin suppository as a laxative (increase bowel movement)
4. Vaginal suppositories are used for the local action e.g. antiseptics,
contraceptives (to stop child birth) etc.
5. Urethral suppositories may be used as anti-bacterial and as local anesthetics.

Systemic Action:
1. For systemic action, the mucous membrane of the rectum and vagina permit the
absorption of many soluble drugs.
2. A wide range of drugs are employed for systemic action e.g.
o Analgesics
o Anti-spasmodic (to treat spasm - Biscopan)
o Sedatives (induce sleep)
o Tranquilizers
o Anti-bacterial agents

Advantages of Suppositories over Oral Therapy:

 1. Some drugs are destroyed by the GIT enzymes (or by the pH of GIT). Such
drugs are administered in suppository form.
2. Drugs which cause gastric irritation may be given rectally in the form of
suppository.
3. To bypass the first pass action (drugs destroyed by portal circulation may
bypass the liver after rectal absorption) e.g.
a. Propranolol (Anti-hypersensitive)
b. Glycerol trinitrate (used in angina attack – placed under tongue or given
as suppository)
4. The route of administrations are also convenient for:
a. Adult patients
b. Unconscious persons
c. Mental retarded person
d. For infants who may unable to swallow the medicines
5. In vaginal cavity, for local antiseptics and anti-bacterial action.
6. This route has ability to administer somewhat larger doses of drugs than using
oral administration.
7. This route ensures a rapid drug effect systematically (as an alternate to
injections).
8. This route avoids bad taste or odour of drug.

Disadvantages of Suppository:
 The problem of patient acceptability.
 Suppositories are not suitable for patients suffering from diarrhea.
 In some cases the total amount of the drug must be given will be either too irritating
or in greater amount than reasonably can be placed into suppository.
 Incomplete absorption may be obtained because suppository usually promotes
evacuation of the bowel.
 A perceived lack of flexibility regarding dosage of commercially available
suppository resulting in underuse and a lack of availability.
 They’re expensive if made on demand.
 Different formulations of a drug with a narrow therapeutic margin, such as
aminophylline, cannot be interchanged without risk of toxicity.
 Defecation may interrupt the absorption process of the drug, if drug is irritating.
 There is possibility of degeneration of some drugs by the micro-flora present in the
rectum.

Examples of Drugs:
Following are the examples of drugs administered rectally in the form of
suppository for their systemic effects.
  Prochlorperazine (for nausea and vomiting)
 Chlorpromazine (as a tranquillizer)
 Oxymorphine HCl (narcotic analgesic)
 Indomethacin (NSAID analgesic and anti-pyretic)
 Ergotamine tartarate (relief of migraine)

Drugs Dispensing in Suppositories:

i. Hormones
ii. Steroids
iii. Emollients
iv. Astringents
v. Antibiotics
vi. Local anesthetics
vii. Local analgesics

FACTORS AFFECTING THE ACTION OF SUPPOSITORIES

First Step of Dissolution Depends Upon:

i. Melting point of base used

ii. Liquefaction of base used

Second Step of Diffusion Depends Upon:

i. Solubility of drug
ii. Particle size
iii. Spreading capacity
iv. Excipient viscosity at rectal temperature
v. Retention of active principles by excipients

Third Step of Absorption Depends upon:

i. pKa of drug
ii. pH induced to rectal fluid
iii. presence of buffers
iv. additive affects on membrane permeability
v. partition co-efficient of drug

Factor Affecting Drug Absorption Form Rectal Suppository:

1. Physiologic Factor:
  The human rectum is approximately 15-20 cm in the length, when empty of
fecal 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 include:
o Colonic Content:
 When systemic effect are desired from suppository greater absorption
may be expected from a rectum that is void than that with fecal matter.
An evacuation enema maybe administered before insertion of a
suppository.
 Diarrhea, colonic obstruction and tissue dehydration influence the rate
& degree of drug absorption from rectum.
o Circulation:
 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 hemorrhoid veins. The inferior is nearest to
the anus, the upper hemorrhoid vein —> portal circulation .thus it is
advisable to keep supp in the lower part of rectum. 50% -70% of drug
administered rectally, reported to go directly into general circulation.
o pH and lack of buffering capacity of the rectal fluid :
 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 be enhanced by change in pH of the rectal mucosa to one that
increase the proportion of unionized drugs.

2) Physiochemical Characteristics of the Drug:

A) Lipid water solubility of a drug (partition coefficient):

 The lipid water partition coefficient of a drug is important in selecting the

suppository base and in anticipating drug release from that base
 Lipophilic drug, in other word, distributed in a fatty suppository base has
fewer tendencies to escape to the surrounding queues fluids
 Thus 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
and oil-soluble drugs.

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
increase the proportion of unionized drugs

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.
 Scientists showed 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.

3) Physiochemical Characteristics of the Base and Adjuvant:

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.

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.

SUPPOSITORY BASES
Introduction:

 Base is an inert medium in which drug is incorporated to dissolve, suspend or

emulsify for a particular period of time.
 Suppository bases play an important role in the release of the medicaments
which they hold and therefore in the availability of the drug for absorption or
systemic effects for localized action.
 Bases alone used as emollient or lubricating effects or as vehicles in the
preparation of medicated suppositories.
Characteristics of an Ideal Suppository Base (water and fatty base):

 It should be good in appearance.

 It should melt at body temperature (37oC).
 It should be non-toxic and non-irritating.
 It should be compatible with a broad variety of drugs.
 It should shrink (congealing) sufficiently on cooling to release from the mould.
 It should be non-sensitizing.
 It should have melting and emulsifying property.
 It should be stable on storage.
 It can be manufactured by molding either by hand, machine or compression.
 It should be stable if heated above its melting point.
 It should keep its shape while handling.
 It should release the medicament easily.
 It should have good water number.
o It is the high percentage of water which can be imported.
o The amount of water in grams which can be incorporated in 100g of fat is
expresses by its value.
o The water no. can be increased by the addition of surface active agents or
other emulsifiers.

Additional Characteristics for Fatty Bases:

If the base is fatty it has following requirements.

1. Acid value is below 0.2.

 It is also called as neutralization value.
 It is the mass of KOH (Potassium hydroxide) in mg that is required to
neutralize one gram of chemical substance.
2. Saponification Value ranges from 200-245.
 It is the no. of mg of KOH required to neutralize the free acids and saponify
the esters contained in 1gm of a fat.
3. Iodine Value is less than 1.
 It is the no. of gm of iodine that reacts with 100g of fat or other unsaturated
material.

Classification of Suppository Bases:

Suppository bases are classified into two main categories according to their
physical characteristics and a third miscellaneous group.
 1. Fatty or oleaginous bases
a. Cocoa Butter (Theobroma Oil)
b. Hydrogenated Oil
2. The water soluble or water miscible bases
a. Glycerogelatin Base
b. Base of Polyethylene glycol
3. Miscellaneous bases
a. Generally a combination of hydrophilic and hydrophobic substances

FATTY OR OLEAGINOUS BASES

A. Cocoa Butter (Theobroma Oil)

 It is the number of this group of the substances.
 Cocoa butter NF is defined as, ―the fat obtained from the roasted seeds of
Theobroma cacao‖.

The Particular Characteristics of Cocoa Butter:

 Chemically it is triglyceride that is combination of glycerin with one or more

fatty acids.
 It is yellowish white solid, brittle fat which smells and taste like chocolate.
 Its melting point is between 300C to 350C.
 Its iodine value is ranges from 34 to 38.
 Its acid value is not higher than 4.
 Because cocoa butter is easily melt and rancidify it must be stored at cool and
dry place and must be protected from sunlight.
 It is an ideally suppository base melt just below body temperature and yet
maintains its solidity at usual room temperature.
 Cocoa butter exhibits marked polymorphism (the property of a substance
which exists in different crystalline forms).
 This phenomenon attributes to the high proportion of the unsaturated
triglycerides.
 Each of the different forms of cocoa butter has different melting points as well
as different drug release rates (Melting point increases hence release of drug
decreases).
 Knowledge of these polymorphic states is essential to know how uniform drug
release pattern can be obtained from the suppository bases consisting primarily
of cocoa butter.
Different Crystalline Forms of Cocoa Butter:
Cocoa butter exhibits in four states.

i. α-form:
The α-form melts at 240C and it is obtained by suddenly cooling the melted
cocoa butter to 00C.
ii. β-form:
It crystallizes out from the liquefied cocoa butter with stirring at 18-230C. Its
melting point ranges from 28 to 310C.
iii. β’-form:
β’-form changes slowly into the stable form which melts between 34 to 350C
and this change is accompanied by a volume contraction.
iv. γ-form:
It melts at 180C and it is obtained by pouring a cool cocoa butter before it
solidifies into a container which is cooled at deep freeze temperature.

Methods to Prevent the Unstable Crystalline Forms:

The formation of unstable crystalline forms can be avoided by different
methods:

1. If the mass is not completely melted, the remaining crystals prevent the
formation of unstable forms.
2. The small amount of stable crystals is added to the melted cocoa butter which
accelerates the change from unstable to stable form. This process is called as
seeding.
3. As a general rule, the minimum use of heating in the process to melt the fat is
recommended. Prolong heating must be avoided as much as possible e.g. cocoa
butter must be slowly and evenly melted preferably over water bath of the
warm water to avoid the formation of unstable crystalline forms.

Problems Associated with Volatile Drugs and the Cocoa Butter:

 Some drugs e.g. volatile oils, camphor, menthol, phenol or chloral hydrate,
lower the melting point of cocoa butter to considerable extent.
 In such case, the solidifying agents e.g. cetylester was about 20% or beeswax
about 4% may be melted with cocoa butter to compensate for the softening
effect of the added substances.
 The addition of hardening agent must not be so excessive that:
o It prevents the melting of the base after the suppositories have been inserted
into the body.
 o It interferes with the therapeutic agent so as to alter or modify the efficacy
of the product.

Disadvantages Cocoa Butter:

 Rancidity and slow deterioration during storage.

 Melt in warm weather.
 Liquefy when incorporated with certain drug such as: volatile oils, creosote,
phenol and chloral hydrate.
 Over heating lead to isomerizes to metastable form. So this will decrease
melting point.
 Low contractility during solidification, suppository will adhere to the mold and
will be necessitates uses of lubricant.
 Quality of cacao butter varies with origin and treatment.
 Water number is low (20-30), this could be improved by addition of 5-
10%tween61.
 Leakage from the body.

Advantages Cocoa Butter:

 Non reactive
 Melt at body temp
 Solidification point lies 12-13° C below melting point, during formulation the
mass can be stirring and maintain cacao butter liquid below its solidification
point.
 Emulsion can be added in Conc. 5-10 % to keep insoluble drug suspended.
 Increase conc. of water soluble drugs, lead to decrease melting point until
eutectic point is obtained
 Melted cocoa butter is viscous (semisolid) which help in corporation of drug.
The difference in melting point &solidification point is large to give chance for
incorporation with drugs.

B. Hydrogenated Oil (Cocoa Butter Substitutes)

Topical Treatment of Vegetable Oils to produce Suppository Bases:

 The fat type suppository bases are produce from a variety of material either
synthetic or natural in origin e.g. vegetable oils including:
o Coconut Oil
o Cotton Seed Oil
o Palmitic Oil
  These are modified by Esterification, hydrogenation or fractionation at
different melting range to obtain the desired product.

WATER SOLUBLE / MISCIBLE BASES:

 The main members of this group are:

o Glycerogelatin Bases
o Polyethylene glycol

A. Glycerogelatin Bases
 Glycerogelatin bases may be prepared by dissolving gelatin 20%, glycerin
(70%), and adding solution or suspension of medicament (10%).

Glycerogelatin Base in Vaginal Suppositories:

1. Glycerogelatin base is not frequently used in preparation of vaginal
suppositories where prolong localized action of medicinal agent is usually
desired.
2. It is slower to soften and mix with physiological fluids. It provides a more
prolonged release.
3. They have a tendency to absorb the moisture due to hygroscopic nature of
glycerin.
4. Therefore they must be protected from atmospheric moisture in order to
maintain their shape and consistency.
5. Due to hygroscopicity of the glycerin, these suppositories may have a
dehydrated effect and be irritating to tissue upon insertion.
6. The water present in formula for suppositories minimizes with water to reduce
the initial tendency of base to draw the water from mucus membrane which
irritate the tissue.

Glycerogelatin Base in Urethral Suppositories:

1. The urethral suppositories may be prepared from the Glycerogelatin base.
2. For urethral suppositories the gelatin constitutes about 60% of the weight of
formula, glycerin about 20% and the medicated aqueous portion 20%.
3. Urethral suppositories of glycerogelatin are more easily inserted then
suppositories with cocoa butter base, because of brittleness of cocoa butter and
its rapid softening at body temperature.

B. Polyethylene Glycol Bases (Carbowax)

  Polyethylene glycol is polymers of ethylene oxide and water prepare to various
chain length, molecular weights and physical states.
 These are available in a number of molecular weight ranges.
 The more commonly used polyethylene glycol bases are PEG 200, 400, 600,
800, 1500, 1540, 3350, 4000, 6000 and 8000.
 These numerical designations refer to the average molecular weight of the
polymers.
 PEG having average molecular weight of 200, 400 and 600 are clear colorless
liquids and those which have average molecular weight of greater than 1000
are wax-like solids with hardness increasing with an increase in molecular
weight.
 Various combinations of these PEG may be combined by fusion, using two or
more of various types to achieve a suppository base of desired consistency and
characteristics.
 PEG suppositories don’t melt at body temperature and dissolve slowly in body
fluids.
 It is possible to prepare suppositories from PEG mixture having melting point
higher than that of body temperature.

Advantages:
1. It permits the slow release of medicament from base.
2. Convenient storage of these suppositories without need of refrigerator and
without danger of softening in warm weather.
3. They’re chemically stable.
4. Inert, and non-irritating
5. It doesn’t allow bacterial growth.
6. Physical properties changes according to molecular weight.
7. It provides prolonged action.
8. It doesn’t stick to mold.
9. Suppositories are clean and smooth in appearance.

Disadvantages:
1. If PEG suppository doesn’t contain atleast 20% of water they can cause
irritation to mucous membrane after insertion. In such case they are dipped in
water just prior to use. This procedure prevents the moisture which is being
drawn from tissue after insertion and produces the ―stinging‖ sensation.

MISCELLANEOUS BASES:
 1. In the miscellaneous group of bases are included those which are mixtures of
the oleaginous and water soluble or water miscible materials.
2. These materials may be physical or chemical mixtures.
3. Some materials are preformed emulsions generally w/o type or they may be
dispersing in aqueous fluids.
4. One of these substances is polyoxyl 40 sterate.

Characteristics of Polyoxyl 40 Sterate:

a. It is a surface active agent that is employed in a no. of commercial
suppositories bases.
b. This substance is waxy white solid that is water soluble.
c. Its melting point is 39 – 400C.
d. Mixtures of many fatty bases including cocoa butter with emulsifying agent
capable of forming w/o emulsions.
e. These bases have ability to hold water or aqueous solutions and sometimes
refer to as hydrophilic suppositories bases.

METHODS OF PREPARATION OF SUPPOSITORIES

Suppositories are prepared by three methods:

A. Molding from a melt (fusion)

B. Compression (Cold Compression)
C. Hand Rolling and Shaping

Preparation of Suppositories by molding

(fusion):

 This method is most frequently employed both on a small scale and on an

industrial scale.

Bases Used:

 Cocoa butter
 Glycerinated gelatin
 Polyethylene glycol
 And most other bases are suitable for preparation by molding.

Suppository Molds:

 Molds in common use today are made from stainless steel, aluminum, brass, or
plastic.
 They’re reusable and disposable.
 Commercially available molds available for preparation of rectal, vaginal, and
urethral suppositories can produce individual or large numbers of suppositories
of various shapes and sizes.

Lubrication of the Mold:

 Mold is a hollow container used to give shape to molten or hot liquid material
when it cools and hardens.
 Depending on the formulation, suppository molds may require lubrication
before the melt is poured to facilitate clean and easy removal of the molded
suppositories.
 Lubrication is seldom necessary when the base is cocoa butter or polyethylene
glycol.
 Lubrication is usually necessary with glycerinated gelatin.
 A thin coating of mineral oil applied with the finger to the molding surfaces
usually suffices.
 Lubrication before the melt is poured to facilitate clean and easy removal of the
molded suppositories.

Calibration of the Mold:

 Each individual mold is capable of holding a specific volume of material in

each of its openings.
 Different bases prepared in the same mold will have different weight because
of the difference in the densities of the materials, similarly, any added
medicinal agent alters the density of the base, and the weight of the resulting
suppository differs from that of those prepared with base material alone.
 The pharmacist should calibrate each suppository mold for the usual base
(generally cocoa butter and a polyethylene glycol base) so as to prepare
medicated suppositories each having the proper quantity of medicaments.

Preparing and Pouring the Melt:

 Using the least possible heat over a water bath, the weighed suppository base
material is melted on porcelain casserole.
  Medicinal substances are incorporated into a portion of the melted base by
mixing on a glass or porcelain tile with a spatula.
 After incorporation, this material is stirred into the remaining base, which has
been allowed to cool almost to its congealing point.
- Any volatile materials or heat-labile substances should be incorporated at
this point with thorough stirring.
 The melt is poured carefully and continuously into each cavity of the mold,
which has been previously equilibrated to room temperature.
 If any un-dissolved or suspended materials in the mixture are denser than the
base, so that they have a tendency to settle, constant stirring, even during
pouring, is required.

Allowing the melt to cool and Congeal into Suppositories:

The mold is usually placed in the refrigerator, after hardening; the mold is
removed from the refrigerator and allowed to come to room temperature. Then the
sections of the mold are separated, and the suppositories are dislodged, with pressure
being exerted principally on their ends and only if needed on the tips.

Removing the formed suppositories from the mold:

 Generally, little or no pressure is required, and the suppositories simply fall out
of the mold when it is opened.

Advantages:

 It is a simple method.
 It gives suppositories that are more elegant than hand mould suppositories.
 Sedimentation of solids in base is prevented.
 It is suitable for heat labile medicaments.

Disadvantages:

 Air entrapment may take place.

 This air may cause weight variation.
 The drug or base may be oxidized in air.

Preparation of Suppositories by Cold-Compression (Fusion)

  Compression is especially suited for making suppositories that contain heat-
labile medicinal substances or a great deal of substances that are insoluble in
the base.
 In contrast to the molding method, compression permits no likelihood of
insoluble matter settling during manufacture.
 In preparation for compression into the molds, the base and the other
formulative ingredients are combined by thorough mixing.
 The friction of the process softening the base into a paste-like consistency.
 On a small scale, a mortar and pestle may be used. Heating the mortar in warm
water (then drying it) greatly facilitates the softening of the base and the
mixing.
 On a large scale, a similar process may be used, employing mechanical
kneading mixers and a warm mixing vessel.
 Suppositories may be prepared by forcing the mixed mass of the base and the
medicaments into special molds using suppository-making machines that apply
pressure to the mass out of a cylinder into the mold.

Advantages:

 This technique is time saving.

 It gives suppositories that are more elegant than hand mould suppositories.
 Suitable for heat labile medicinal substances.
 No mold preparation
 No heating is required.

Disadvantages:

 The disadvantage to compression is that the special suppository machine is

required and there is some limitation as to the shapes of suppositories that can
be made.
 Manipulation requires considerable skills.
 Appearance is not elegant.
 It is not commonly done.
 Hand Rolling Method

 This is the oldest and simplest method for the suppository preparation.
 It is a method of choice when only a few suppositories are to be prepared in a
cocoa butter base.
 A plastic like mass is prepared by ―triturating‖ grated cocoa butter and active
ingredients in a mortar.
 The mass is formed into a ball in the palm of hands, the rolled into a uniform
cylinder with a large spatula or small flat board on a pill tile.
 The cylinder is then cut into appropriate number of pieces which are rolled on
end to produce a conical shape.

Advantage:

 It has the advantage of avoiding the necessity of heating the coca butter.
 No equipment required
 No special calculations are to be done

Disadvantages:

 Difficult to manufacture
 Not pretty in appearance

Automatic Molding

 The molding operations (pouring, cooling and removal) can be performed by

machine.
 All filling, ejecting and mold-cleaning operations are fully automated.
 The output of a typical rotary machine ranges from 3500 to 6000 suppositories
an hour.
  Firstly, the prepared mass is filled into filling hopper where it is continuously
mixed and maintained at constant temperature.
 The suppository mould is lubricated by brushing or spraying.
 The cooling cycle is adjusted as required by individual suppository mass by
adjusting the speed of rotatory cooling turn table.
 After mass solidifies, the excess of material is scraped off and collected for
reuse.
 The solidified suppositories are moved to ejecting station, where the mould is
opened and suppositories are pushed out.

COMMERCIAL SUPPOSITORY PRODUCTION

 Automated filling of molds by volumetric dosing pumps

 Strips of perforated shells pass beneath dosing pumps & filled successively
 Passed through cooling chambers for solidification…..sealed and then
packaged
 Quality control procedures i.e. weight, volume, leakage are conducted

Injection Molding:
 Alternative to melt and pour molding
 Described by Snipes
 Use of injection molding technique developed for fabrication of plastics
 Excipients of choice are polyethylene glycol
 Povidone or silicon dioxide are added for viscosity or plasticity adjustment

CLASSIFICATION OF SUPPOSITORIES:

Suppositories are classified into following types:

1. Rectal suppositories
2. Vaginal suppositories or Pesseries
3. Urethral suppositories or Bougies
4. Nasal suppositories or Bouginaria
5. Ear suppositories
6. Oral suppositories (Not used anymore)

Rectal Suppositories:
1. These are conical or cylindrical in shape.
2. These have flat base and tapered at the other end for easy insertion into rectum.
 3. Its length is usually 32 mm and has a bullet shape e.g. Bisacodyl suppositories,
USP (10mg).
4. USP-NF states that adult rectal suppository should weight about 2 gram, when
cocoa butter is employed as the suppository base.
5. Rectal suppositories are used by infants or children are about half the weight
and size of the adult suppository and assume more pencil like shape.
6. Rectal suppositories are used for local, systemic or mechanical effect.
a. Local effect e.g. in hemorrhoids infection
b. Systemic effect e.g. infection away from rectum
c. Mechanical effect e.g. in evacuation of bowel in constipation

Some Official Rectal Suppositories

No. Drug Use Action
1 Aspirin Suppository Analgesic and Anti-pyretic Systemic
2 Biscodyl Suppository (Dulcolax) Laxative Local
3 Glycerine Suppository Laxative Local
Vaginal Suppositories or Pessaries:
1. The size of these suppositories is larger than rectal suppositories.
2. Officially, their weight is about 5g (3-6g).
3. They are globular, oval, and rod and cone shaped.
4. They are used for local actions.
5. When these suppositories are in tablet or capsule form they are called as tablet
inserts.
6. For their manufacture usually polyethylene glycol is used.
7. Parabens (e.g. Methyl parabens / propyl parabens) are used as preservative of
these suppositories.
8. For their use pH of vagina should be 4.5.
9. These suppositories are buffered to pH 4.5.
10. Pessaries are prepared either by molding in globular or oviform shape or by
compressing on a tablet into a conical shaped.

Official Vaginal Suppositories

No. Drug Use
1 Candidicin Anti-fungal
2 Diethyl stilbestrol Estrogen
3 Clindamycine Suppository Antibiotic
Urethral Suppositories (Bougies):
1. These are long, thin and pencil shaped.
2. These are rounded from both sides.
3. Their diameter is 5mm.
4. Their length for male is 25 mm and for female is 50 mm.
 5. Their weight for female is 2g and for male is 4g.
6. These are rarely prescribed.
7. For their formulation base is composed of glyceryl monosterate and
polyoxyethylene.
8. E.g. Furacin Urethral Inserts (Anti-septic)

Nasal Suppositories (Bouginaria):

1. These are pencil shaped similar to urethral suppositories.
2. These are shorter in length i.e. about 32 mm.
3. Base for their formulation is usually glycerogelatin base.

Oral Suppositories:
1. These are pencil shaped similar to urethral suppositories.
2. These are shorter in length i.e. about 32 mm.
3. Base for their formulation is usually cocoa butter.
4. E.g. Paracetamolo
 Paracetamolo 120 mg
 Composition: 1 suppository contains paracetamol 0.120g.
 Excipient: Semi-synthetic glyceride
 Pharmaceutical Form: Suppository
 Therapeutic Indication: Analgesic and Anti-pyretic
 Product: For Export Only
 Packaging: Box of 6 suppositories

Ear Inserts (Aurinaria):

1. These are meant for introduction in ear.
2. These are long, thin and cylindrical in shape.
3. These are prepared in urethral bougies mold and cut according to the size.
4. Their weight is about 1g.
5. Base used is Theobroma oil (cocoa butter).
6. These are rarely used.

SPECIFIC PROBLEMS IN FORMULATING SUPPOSITORIES:

1. Water in Suppositories:

Use of water as a solvent for drug should be avoided for the following.

Reasons:
  Water accelerates oxidation of fats.
 If water evaporates, the dissolved substance crystallizes out.
 Unless H2O is present at level than that requires for dissolving the drug, the
water has little value in facilitating drug absorption. Absorption from water
containing suppository enhance only if an oil in water emulsion exist with more
than 50% of the water in the external phase .
 Reaction between ingredients (in suppository) are more likely to occur in the
presence of water.
 The incorporation of water or other substances that might be contaminate with
bacteria or fungi necessitates the addition of bacteriostatic agents (as parabens)

2- Hygroscopicity:

 Glycerinated gelatin suppositories lost moisture by evaporation in dry climates

and absorbed moisture under conditions of high humidity
 PEG bases are also hygroscopic

3. Incompatibilities:

 PEG bases are incompatible with silver salt, tannic acid, aminopyrine , quinine
, icthammol, asprine , benzoc.aine & sulphonamides .
 Many chemicals have a tendency to crystallize out of PEG, e.g.: sodium
sarbital, salicylic acid & camphor.
 Higher concentration of salicylic acid softens PEG to an ointment-like
consistency, d- Aspirin complexes with PEG.
 Penicillin G, although stable in cocoa butter and other fatty bases, was found to
decompose in PEG bases .
 Fatty bases with significant hydroxyl values may react with acidic ingredients.

4- Viscosity:

 The viscosity of the melted suppository base is important in the manufacture of

the suppository and to its behavior in the rectum after melting.
 Melted cocoa butter have low viscosity than glycerinated gelatin and PEG type
base in low viscosity bases, extra
 Care must be exercised to avoid sedimentation of suspended particles.
 To overcome the problems caused by use of low viscosity bases:
o Use base with a narrower melting rang that is closer to body temperature.
o The inclusion of approximately 2% aluminum monostearate not only
increases the viscosity of the fat base but to maintain homogenous
suspension of insoluble material.
 o Cetyl, stearyl or myristyl alcohols or stearic acid are added to improve the
consistency of suppositories.

5- Brittleness:

 Suppositories made from cocoa butter are elastic and don't fracture readily.
 Synthetic fat base with high degree of hydrogenation and high stearate content
and higher solids content at room temperature are usually more brittle.
 To overcome
o The temperature difference between the melted base & the mold should be
minimal.
o Addition of small amount of Tween 80, castor oil, glycerin imparts
plasticity to a fat

6- Volume contraction:

 Occurs in many melted suppository base after cooling the mold, result in:
o Good mold release (contraction facilitate the removal of the suppository
from the mold , eliminating the need for mold release agents).
o Contraction hole formation at the open end of the mold, this will lowered
suppository . The contraction can be eliminated by pouring a mass slightly
above its congealing temperature into a mold warmed at about the same
temperature or the mold is overfilled so that the excess mass containing the
contraction hole can be scraped off.
 Lubricant or mold releasing agent:
o Cocoa butter adheres to suppository molds because of its low volume
contraction. A various mold lubricants or release agents must be used to
overcome this difficulty (mineral oil, aqueous solution of sodium lauryl
sulfate , alcohol , silicones , soap).
o The release of suppository from damaged mold was improved by coating
the cavities with polytetrofluoroethylene (Teflone).

7- Rancidity and Antioxidant:

Rancidity results from the autoxidation and subsequent decomposition of

unsaturated fats into low & medium molecular weight saturated & unsaturated
aldehydes , ketones and acids , which have strong unpleasant odor. Examples of
effective antioxidant are phenols such as ―hydroquinone or B-naphtholquinone.

QUALITY CONTROL OF SUPPOSITORIES:

1. Surface Appearance and Shape:

 To evaluate: absence of fissuring – absence of migration of active ingredient,
absence of pitting, absence of fat blooming (dullness of surface)

2. Melting Test Range:

 Macromelting range: measures the time it takes for the entire suppository to
melt when immersed in a constant temperature (370C) water bath.
 Micromelting range: is the melting range measured in capillary tubes for the fat
base only.
 The apparatus used for measuring the melting range of the entire suppository is
a USP tablet disintegration apparatus. The suppository is completely immersed
in the constant temperature water bath, and the time for the entire suppository
to melt or dispense in the surrounding water is measured. The in-vitro drug
release pattern is measured by using the same melting range apparatus.

3. Liquefaction or Softening Time Tests of Rectal Suppositories:

The "softening test" measures the liquefaction time of rectal suppositories are
an apparatus that simulate in-vitro conditions (at 37oC).

4. Breaking Test:

 It is designed as a method for measuring the fragility or brittleness of

suppositories.
 The apparatus consists of double-wall chamber in which the test suppository is
placed. Water at 37C is pumped through the double walls of the chamber, and
the suppository, contained in the drug inner chamber, supports a disk to which
a rod is attached. The outer end of the rod consists of another disc to which
weights are applied.

5. Mechanical Strength:

It is a force necessary to break a supp. And indicate whether supp is brittle or

elastic. (Not less than 1.8-2 Kg) by Erweka method.

6. Melting & Solidification:

Solidification can be determined by using evacuated flask into which the melt
is placed, the temp of cooling is noted to determine the solidification point.

7. Dissolution Testing:

The patterned is measured by using the same melting range apparatus. If the
volume of water surrounding the suppository is known, then by measuring aliquots of
the water for drug content at various intervals within the melting period. A (time
versus drug release) curve could be established and can be plotted.

DISPLACEMENT VALUES:

 The displacement value of a medicament is the no. of parts by weight of a

medicament that will displace one part of suppository base (normally
Theobroma oil).
 Displacement values for various medicaments are given in B.P.C. (British
Pharmaceutical Codex).
 It is the amount of drug that will displace one part of base.
OR
 It is the amount of the base which is displaced by certain amount of drug.

Mathematically,
𝑑
𝐷. 𝑉.
𝑎−𝑐
=
Where,

d = Amount of drug in suppositories

a – c = Amount of base e.g. Theobroma oil i.e. displaced by gram of medicine

 D.V. of a medicament is required when calculating the weight of suppository

base required preparing a medicated suppository.
 Because the density of the medicament may vary considerably from that of the
base, the weight of base required to make suppository will vary depending
upon the medicament used.

Problem # 1:

Calculate the quantities required to make 10 theobroma oil suppositories

(2g mould) each containing 400mg of zinc oxide (displacement value = 4.7).

Solution:

Total wt. of zinc oxide required = 400 mg × 10 = 4000 mg = 4

g

Wt. of base required for un-medicated suppositories = 2g × 10 = 20

g As the displacement value of ZnO = 4.7
And,

4.7 g of ZnO displace theobroma oil =1g

1 g of ZnO displace theobroma oil = 1/4.7

4 g of ZnO displace theobroma oil = 1/4.7 * 4 = 0.85

So,

Wt. of suppository base required to make medicated suppositories = 20 – 0.85

= 19.15 gm

Problem # 2:

Prepare 12 glycerogelatin suppositories containing 0.5% w/w cinchona

hydro-chloride. Use a 2g mould. (Glycerogelatin base has a density 1.2 times
greater than theobroma oil, therefore 1g suppository mould will produce a 1g
theobroma oil but 1.2g glycerogelatin suppository).

Solution:

Total wt. of suppository = 12 × 2 × 1.2 = 28.8g

Wt. of drug required = 28.8 × 0.5/100 = 0.144g

Wt. of base required = 28.8 – 0.144g = 28.66g

PACKAGING AND
STORAGE:

 Suppositories are often packaged in partitioned boxes that hold the

suppositories upright.
 Glycerine and glycerinated derivatives are often packed in screw-capped glass
containers.
 Many other suppositories are wrapped individually in tin, aluminum foil, paper,
plastic or PVC-polyethylene.
 Poorly packed suppositories may give rise to staining, breakage or deformation
by melting.
 Strip packaging is common place.
 Alternatively, suppositories may be molded directly into their packages and
then store below 300C to gain a specific shape.
 All suppositories particularly Theobroma oil suppositories and glycerogelatin
suppositories should be refrigerated.
  Polyethylene glycol suppositories are stored at usual room temperature without
requirement of refrigerator.

In-Packaging Molding:
A significant advance in suppository manufacturing was the development of
automated method for molding suppository, directly in their wrapping materials. This
is currently accomplished with either plastic or Al-foil.

Advantages of In-Packaging Molding:

A. High production rate
B. No generation of Scraping
C. No bulk handling
D. Maintenance of strict temperature control

_
Pharmaceutics – II (Dosage Form Science):

VAGINAL AND RECTAL SOLUTIONS

Vaginal Douches:

1. These powders are used to prepare solutions for vaginal douche, for irrigating
and cleansing of vagina.
2. These powders may be prepared and packed in bulk or as a unit packages.
3. Unit package is designed to contain the appropriate amount of powder to
prepare the specified volume of douche solution.
4. The bulk powders are used by teaspoon full (5ml) or tablespoon full (15 ml) in
preparation of desired solution.

Components of Douche Solution:

1. Boric acid (sodium borate)
2. Astringent e.g. Potassium or zinc sulphate
3. Anti-microbial agent e.g. iodine
4. Surfactant or detergents (sodium Lauryl sulphate)
5. Salts (Sod. Citrate or sodium chloride)
6. Quaternary ammonium compounds e.g. benzethonium chloride
7. Oxidizing agents e.g. sodium perborate
8. Aromatics, e.g. menthol, thymol, and phenol etc.

Use:
The douche powders are used for hygiene effect.

Rectal Douches (Enemas)

An enema is an introduction of fluid into the lower bowel through the rectum
for the purpose of cleansing or to introduce medication or nourishment

1. Retention enemas
a. Stimulant Enemas
b. Nutrient Enemas
c. Emollient Enemas
d. Sedative Enemas
e. Anesthetic Enemas
2. Evacuation enemas
 a. Simple Evacuant Enemas
b. Medicated Evacuant Enemas
c. Cold Evacuant Enemas
3. Medicated Evacuant Enemas:
a. Oil Enemas
b. Purgative Enemas
c. Astringent Enemas
d. Anthelmintic Enemas
e. Carminative Enemas

Purpose of Enemas:

 To stimulate defecation & to treat constipation ex: simple evacuant enema

 To soften hard faecal matter ex: oil enema
 To administer medication ex: sedative enema
 To protect and soothe the mucus membrane of intestine & to check diarrhoea
ex : emollient enema
 To destroy intestinal parasites ex : anthelminitic enema
 To relieve the gaseous distention ex : carminative enema
 To administer the fluid and nutrients ex: nutritive enema
 To relieve inflammation ex : astringent enema
 To induce peristalsis ex : purgative enema
 To stimulate a person in shock and collapse ex: stimulant enema
 To reduce the temperature ex : cold enema or ice enema
 To clean the bowels prior to x-ray studies, visualization of the bowel , surgery
on the bowel or delivery of a baby ex : saline enema
 To make diagnosis ex: barium enema
 To establish regular bowel functions during a bowel training programme
 To induce anesthesia ex : anesthetic enema

RETENTION ENEMAS:

1. A no. of solutions administered rectally for local effect e.g. hydrocortisone or

for systemic absorption e.g. aminophylline.
2. In case of aminophylline rectal administration minimizes the undesirable
gastrointestinal reaction associated with oral therapy.
3. Corticosteroids are administered as retention enemas for the treatment of
patients for ulcerative colitis.

Stimulant Enema:
  A stimulant enema is given in the treatment of shock and collapse
 It is also sometimes given in case of poisoning e.g. coffee enema is given in
case of opium poisoning
 Solutions:
a. Black coffee : 1 table spoon coffee powder to 300 ml of water
b. Brandy : 15 ml of brandy added to 120 to 180 ml of glucose saline
 Amount of solution: 180 to 240 ml
 Temp of solution: 108 to 110 degree Fahrenheit

Sedative enema:

 It is retention enema containing a sedative drug given to induce sleep

 Drugs used:
o Paraldehyde
o Chloral hydrate
o Potassium bromide
 Dose: As ordered by the doctor

Anesthetic Enema:

 It is a retention enema containing an anesthetic drug to produce anesthesia in

client
 Drugs used: Avertin
 Dose: 150 to 300 mg per kg of body weight

Emollient Enema:

 This is an introduction of bland solution into the rectum for the purpose of
checking diarrhea or soothing & relieving irritation on an inflamed mucus
membrane
 Solution used:
o Starch & opium : opium 1 to 2ml is added to 120 to 180 ml of starch
mucilage or rice water
o Starch mucilage alone
 Amount of solution: 120 to 180 ml
 Temp of solution: 100 to 105 degree Fahrenheit (37.8 to 40.5 degree
centigrade )

Nutrient Enema:

 It is a retention enema to supply food & fluids to the body.

 Selection of the fluids depends upon the ability of the colon to absorb it.
  Nutrient enema is particularly useful in conditions like haemophilia which
makes I.V. infusion difficult or undesirable
 Solutions :
o Normal saline
o Glucose 2 to 5%
o Peptonized milk 120 ml
 Amount of solution: 1100 to 1700 ml in 24 hour or 180 to 270 ml at 4 hourly
interval
 Temperature of solution: 100 degree Fahrenheit (37.8 degree Fahrenheit )

EVACUATION ENEMAS:
1. The rectal enemas are used to cleanse the bowel.
2. Many enemas are available in disposable plastic squeeze bottles containing
premeasured amount of enemas solution.
3. The active agents are solutions of:
a. Sodium phosphate
b. Sodium biphosphate
c. Glycerine
d. Light Mineral Oil

Simple Evacuant Enema:

 Purpose :
o To stimulate defecation & to treat constipation
o To relieve the gaseous distention by stimulating the peristalsis
o To relieve the retention of urine by reflex stimulation of the bladder
o To stimulate uterine contraction & to hasten the child birth
o To cleanse the bowel prior to x-ray studies, visualization of the bowels (ex:
sigmoidoscopy), surgery & retention enemas
 Solutions Used:
o Soap & water: soap jelly 50ml to 1 liter of water
o Normal saline: sodium chloride 1 teaspoon of half liter of water
o Tap water
 Amount of solutions to be used:
o Adults: 500 to 1000 ml ( 1 to 2 pint )
o Children's: 250 to 500 ml ( 0.5 to 1 pint )
o Infants: 250 ml or less
 Temp of solution:
o Adults : 105 to 110 degree Fahrenheit
 o Children : 100 degree Fahrenheit

Oil Enema:

 These are given to soften fecal matter in case of severe constipation.

 Before the 1st bowel movement after operation on the rectum or perineum.
 To avoid straining & injury to the sutures & wounds.
 It should be retained for half an hour to 1 hour to soften the faeces.
 It should then be followed by a soap & water enema to open the bowels.
 Solutions used:
o Olive oil
o Gingerly oil or sweet oil
o Castor oil & olive oil (1:2)
 Amount of solution to be used: 115 to 175 ml
 Temperature of the solutions: 100 degree Fahrenheit

Purgative Enema:

 These are given to cause the bowel to contrast actively & to evacuate its
contents.
 Its acts by their irritating effect on the mucus lining , stimulate peristalsis &
cause the evacuation of bowel.
 The stretching of the intestine due to this inflow of fluid causes the intestine to
contract & leads to the evacuation of bowel.
 Solutions used:
o Pure glycerin – 15 to 30 ml
o Glycerin & water – 1:2
o Glycerin & caster oil – 1:1
o Magnesium sulphate : 60 to 120 ml with sufficient amount of water to
dissolve it
o 1-2-3 enema : magnesium sulphate 30 ml, glycerin 60 ml, & water 90 ml
Amount & temp of solution is that of oil enema

Carminative Enema (Antispasmodic):

 These are given to relieve gaseous distention of the abdomen by causing

peristalsis & expulsion of flatus & faeces
 It is given as simple evacuant enema.
 Solution:
o Turpentine : 8 to 16 ml of turpentine mixed thoroughly with 600 to 1200 ml
of soap solution
 o Milk and molasses (granular sugar ) : 90 to 230 ml of molasses well mixed
with equal quantity of warm milk

Anthelmintic Enema:

 This is given to destroy & expel the worms from the intestines.
 Before the treatment is given the bowel should be cleansed by a soap water
enema so that the drug may come in direct contact with the worms & the lining
of the intestine.
 The treatment is given until the worms are destroyed.
 Solution :
o Infusion of quassia : 15gms of chips to 600 ml of water
o Hypertonic saline solution : sodium chloride 60 ml with 600 ml of water
 Amount of the solution: 250 ml

Astringent Enema:

 It contracts the tissues & the blood vessels, checks bleeding & inflammation,
lessens the amount of mucus discharge & gives a temporary relief in the
inflamed area.
 It is usually given in colitis & dysentery.
 They are usually given in the form of rectal or colonic irrigations.
 The solution is allowed to run in slowly & return quickly to avoid distension ,
pain & irritation of the inflamed wall.
 Solutions:
o Tannic acid : 2 gms to 600ml of water
o Alum : 30 gms to 600ml of water
o Silver nitrate 2% : (silver nitrate is dissolved in distilled water )
 Temperature of the solution: It is given as hot as the client can stand

Cold Enema (Ice Enema):

 This is given to decrease the body temperature in hyperpyrexia and heat stroke.
 It is given in the form of colonic irrigation.
 Complications :
o Hypothemia
o Abdominal cramps