Tablets Part 1 - Merged

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Pharmaceutical Technology

Tablets
Learning objectives:

At the end of this chapter the students will be able to:

1. Define and Differentiate between various types of tablet dosage forms.

2. Compare and contrast advantages and disadvantages of various types of


tablet dosage forms.

3. List categories of inert ingredients, with examples, which are employed in


the manufacture of compressed tablets
4. Describe tablet coating types and coating process. (functional vs. plain)

5. State quality standards and USP compendial requirements for tablets


Tablets:-
• According to the European Pharmacopeia, tablets are defined as unit
solid dosage forms each containing one or more active ingredient and
obtained by compressing (or molding) uniform volumes of particles
with the aid of suitable pharmaceutical excipients.
• Tablets are used mainly for systemic drug delivery but can also be
used for local drug action
• For systemic drug delivery, the drug must be released from the tablet
then dissolved to be absorbed through the GIT barriers to reach the
systemic circulation by which it reaches its site of action
• It can be used for local drug delivery in mouth or GIT, or can be used
to alter the pH of the stomach in case of hyperacidity (antacids)
Tablets are popular dosage forms for several
reasons (advantages)
• The oral route represents a convenient and safe way of drug
administration
• Compared to liquid dosage forms, tablets have general advantages in
terms of the chemical and microbiological stability of the dosage
form
• The manufacturing procedure enables accurate dosing of drug
• Tablets are convenient to handle and can be prepared in a versatile
way with respect to their use and the delivery of the drug (diverse
uses).
• Tablets can be produced with robust and quality-controlled
production procedures that ensure the product produced meets its
predetermined specifications.
• Tablets may be formulated to release the therapeutic agent
at a particular site within the GIT to reduce side effect,
promote absorption at that site and provide a local effect
(e.g. ulcerative colitis). This is not achieved by liquid
preparations
• Tablets may be formulated to contain more than one
therapeutic agent (even if there is an incompatibility
between each active ingredient). By formulation as two
layered tablet each layer contains only one drug.
The main disadvantages of tablets

• The problem of poor bioavailability of drugs due to


unfavorable drug properties, eg. poor solubility, poor
absorption properties, poor wettability and instability in the
gastrointestinal tract. Besides, some drugs may cause local
irritant effects or cause harm to the GIT mucosa
• Biopharmaceutical Classes?????
• The manufacture of tablets requires a series of unit
operations and therefore there is an increased level of
product loss at each stage in the manufacturing process.
• The compression properties of certain therapeutic agents
like paracetamol are poor (high dose drugs) and may
present problems in their subsequent formulation and
manufacture as tablets

• The administration of tablets to certain groups, e.g.


children and the elderly, may be problematic due to
difficulties in swallowing

• Drugs of bitter taste/bad odor/oxygen or moisture


sensitivity require the tablet to be coated
Bio-Pharmaceutical Classes
Requirements of an ideal tablet formulation
1- It must be strong and hard enough to withstand handling
2- The drug must be bioavailable which must be confirmed by
disintegration, dissolution and bioavailability studies
3- Must be of uniform weight and drug content (two quality control
tests are carried out to ensure those uniformities; uniformity of weight
and uniformity of content)
4- Must be elegant in shape
5- Must maintain its content of active constituents during storage
6- Freedom from defects such as cracks, contamination and
discoloration
7- Must be of suitable size for ease of administration
DIFFERENT TYPES OF TABLETS
• Immediate release tablets (conventional) such as orally
disintegrating, chewable, effervescent, sublingual and buccal
tablets. They are characterized by rapid release of the drug
after administration or the tablet is dissolved and
administered as a solution.
• Modified release tablets include
1. Extended: such as sustained release tablets where the
drug is released from the matrix for an extended period
time nearly at constant rate (1st order

2. Delayed release tablets Where the drug is liberated from the


tablet after passing certain time after administration After this period has
elapsed, the release is normally rapid not extended.
• Example of this type is an enteric coated tablet.
• In case of local treatment in the lower part of intestine or in the colon,
a delayed release approach can be combined with a modified drug
release to achieve better treatment.
• 3. Oral disintegrating tablet (ODT)
Types of Tablets:
1. Oral Compressed Tablets
 Also called “Peroral tablets”; tablets intended to be swallowed
with water

 Either uncoated, sugar-coated, or film coated

 May be intended for local effect in the GIT or for systemic effect
after absorption of active constituent

 May be intended for immediate (conventional), delayed (e.g.


enteric), or extended release (controlled release) of the drug

Scored or grooved surface


2. Medicated lozenges
 Compressed tablets (troche) intended to be sucked slowly to
release drug in buccal cavity (could be prepared by molding)

 Mostly contain bactericides or local anesthetics for local action


in mouth/throat, may contains vit c for systemic action.

 Must be palatable, so contain flavored sugar

Disc shape
3. Effervescent Tablets
 Compressed tablets disintegrate in water by liberation
of CO2 from acid-base reaction (disintegrants addition?).

e.g. Citric and tartaric acid and bicarbonates

 Ingredients must be anhydrous to prevent acid-base


reaction during storage, Must be manufactured, packed
and stored in dry conditions

 Drug: vitamins, analgesics, proton pump inhibitors


4. Sublingual and Buccal Tablets
 Tablets intended to be placed under the tongue or on the side of
cheek

Properties: small, flat, soft (not highly compressed), and flavored.

 Used for drugs such as glyceryl trinitrate (angina) and certain


steroids that are absorbed more rapidly from the sublingual mucosa
than stomach where they may become inactivated by enzymatic
action or by gastric acidity or first pass effect

Buccal tablet erodes slowly


5. Chewable Tablets
 Tablets intended to be chewed in mouth and dissolved in the mouth
 Disintegrate by the action of the teeth (disintegrant??).
 Sweet and flavored (e.g. using mannitol (gives cooling sensation) as
excipient)
Creamy base
 Adv:
Used by children and patients with swallowing difficulty
Convenient (no need for water to swallow)
e.g. Antacids and Vitamins
6. Solution Tablets
They should be freely soluble in water and
produce a clear solution.
 Drug(s), and excipients must be water-soluble
and the tablets should not be over-compressed,
otherwise dissolution will be retarded.
 Solution tablets are a convenient mean of
preparing antiseptic solutions, douches and gargles.
7. Hypodermic Tablets
In this type of tablets, all drugs, and excipients must be of the
highest purity, freely soluble in water to be used for preparation
of solution to be injected and the tablets must not be over
compressed.
Tablets to be dissolved in only 1-2 ml of sterile water for
injection
Manufactured under aseptic conditions.
Machine parts coming into contact with the granules of this
tablet should be also sterilized before use
8- Multiple compressed tablets
• These are compressed tablets made by more than
compression cycle. (layered or tablet inside tablet)
• This process is best when separation of active ingredients is
needed for (chemical and physical) stability issues
• Or, if the mixing process is inadequate to guarantee
uniform distribution of two or more active ingredients
• Staged drug release
• The unique appearance of the layered tablets
• https://www.youtube.com/watch?v=i5ZUS8WkUWY
9- Instantly disintegrating or dissolving tablets
Instant-release tablets (rapidly dissolving tablets or RDTs)
are characterized by disintegrating or dissolving in the mouth
within one minute, some within 10 seconds.
Oro-dispersable tablets vs. conventional
Method of preparation: (Lyophilization or freeze drying
[porous hygroscopic plug], Soft direct compression by adding
super-disintegrants and small quantity of effervescent
materials that are very water soluble)
Drug solubility?
Used by children and the elderly or patients with swallowing
difficulty
Bubble packaging, peel the back of the package for tablet
removal.
10- Vaginal tablets
Called vaginal inserts are uncoated, bullet shaped or ovoid
tablets to produce local effect.
Prepared by compression
Applied by applicator.
Used to treat bacterial or fugal infections
Pharmaceutical Technology

Powders and Granules


Learning objectives:

At the end of this chapter the students will be able to:

1. Differentiate between a powder and a granule and between different


types of granules .

2. Explain how the powders and granules sizes are classified

3. Describe the advantages and disadvantage of powders and granules


dosage vs. other drug delivery. And the advantages of granules drug
delivery system vs. powders drug delivery.
4. Classify the powders or granules according to its route of administration:

5. Mention the mixing (blending) methods of Powders

6. Differentiate between the fusion method and wet method for the
preparation of effervescent granulated salts

7. Determine the packaging material and storage conditions that are


suitable for different types of powders and granules
Powders and Granules as solid dosage forms:-
• Powders and granules are dispensed in many routes of administration
like oral, inhalation, parenteral for reconstitution and topical route.
Powders Granules
Definition A formulation in which a solid drug powder A formulation in which drug powder particles
has normally been mixed with other have been aggregated to form larger free
powdered excipients to produce a final flowing particles (agglomerates) to withstand
product. For internal or external use handling.
Pharmaceutical Mixing or blending process Mixing and granulation processes
operation (s) used in
its manufacture
Its use Can be Can be
1. Finished 1. Finished
2. Intermediate product used during 2. Intermediate product used during
tablet and capsule manufacture tablet and capsule manufacture
Size of granules Size classification of powders
Size 4-12 mesh
2-4 mm/final product
Size 12-20 mesh
0.85-2 mm/intermediate
250 µM – 2.36 mm

250-850 µM

80-425 µM1

150-250 µM

Sieve size 80 (180 µM)

https://www.youtube.com/watch?v=UKKDXbZNR0U
Particle size can influence a variety of important factors,
including the following:

Dissolution rate
Suspendability of particles
Uniform distribution of the drug substance in a powder mixture
or solid dosage form
The advantages of powder dosage form:
1- Solid dosage forms are more chemically stable than liquid
ones. The shelf life of powders for antibiotic syrups is 2-3 years,
but once they are reconstituted with water it is only 1-2 weeks.
2- Powders and granules are a convenient form in which to
dispense drugs with a high dose.
For example, the dose of Compound Magnesium Trisilicate Oral
(antacid) Powder is 1-5 g and, although it is feasible to
manufacture tablets to supply this dose, it is often more
acceptable to the patients to disperse a powder in water and
swallow it.
3- Orally administered powders and granules of soluble
medicaments have a faster dissolution rate than tablets
or capsules, as these must first disintegrate before the
drug dissolves.
Drug release from such powdered or granulated
preparations will therefore generally be faster than
from the corresponding tablet or capsule.
4- Easy to swallow
The disadvantages of this type of dosage form:
A- The bitter taste of some drugs is a well-known
formulation problem

• Several formulation strategies to mask the bitter taste of


these drugs include the sugar coating process by sweeteners
like sugars and the formulation into an effervescent drug
product.
• The evolution of CO2 during effervescence reaction causes
numbness of taste buds in the tongue leading to masking the
bitter taste of drugs.
B- Powders and granules are not suitable for the drugs
which are inactivated in, or cause damage to the stomach.
Like NSAIDs
These drugs, like erythromycin, must be formulated as
enteric-coated granules or tablets instead of powders
or normal granules.

C- Bulk powders or bulk granules are not suitable for


the administration of potent drugs with a low dose like
digoxin. ?????
• Powders and granules are subject to such variables as variation
in spoon fill (e.g. ‘level’ and ‘heaped’ spoonful) and variations
in the bulk density of different batches of a powder.
• Divided dosage form preparations Vs the bulk preparations and
tablets or capsules are the best dosage forms of these drugs.
But tablets and capsules are used commonly for this purpose.
(The divided dosage form means that powder is divided to
provide individual doses)
D- It is less convenient for patients to carry a large container
containing several doses compared to a small container or strips
containing unit doses (tablets and Caps).
Advantages and Disadvantages of granules
Advantages Disadvantages
• Granules are more flowable
compared to powder. • The masking of bitter tastes may be
• Segregation of the constituents a problem with this type of
of the powder mixture could be preparation.
avoided by granulation. • Granules are not a good method
• Granules are more stable of administering potent drug
against humidity and with low dose.
atmosphere. • Instability in presence of
• Granules are more easily wetted moisture.
by liquids than light and fluffy • Problems in packaging and storage.
powders.
Why we prepare granules when we
have powders?
• To avoid powder segregation.
• To enhance the flow of powder.
• Granules have higher porosity than powders.
• To improve the compressibility of powders.
• Materials, which are slightly hygroscope, may
adhere & form a cake if stored as a powder.
Classification of powders or granules according to
its route of administration:
• Powders can be classified according to its route of administration
into:
1- Oral powders
2- Inhalation powders
3- Nasal powders
4- Topical powders
5- Dusting powders
6- Ear powders
7- Oral powders or granules for solution or suspension
8- Oral powders or granules for syrup
9- Powders for injection
1- Oral Powders

• Oral powders are formulations composed of solid, loose,


dry particles of varying degrees of fine particle size.
• They contain one or more active substances with or
without excipients and if necessary, approved coloring
matter and flavoring.

• They are generally administered in or with water or another


suitable liquid, or they may also be swallowed directly.
2- Inhalation Powders (DPIs)

• The powders for inhalation are considered the most effective


methods of delivering active ingredients to the lung for the
treatment of asthma and chronic obstructive pulmonary disease.

• It needs an inhalation device used by the patient at the time of


administration where the drug is inhaled as a cloud of fine
particles.
• The drug may be preloaded in the inhalation device or filled into
hard gelatin capsules or foil blisters which are loaded into an
inhalation device prior to use.
Types of DPIs
(Dry powder inhalers)

A B D F
C E

A, Aerolizer; B, Diskus; C, Flexhaler; D, Handihaler; E, Neohaler; F, Twisthaler and G,


17Turbohaler Dr. Hesham M. Tawfeek 3/30/2021
Type of DPIs

18 Dr. Hesham M. Tawfeek 3/30/2021


• The suitable particle size to achieve the best delivery to
the lung is preferably less than 5µm (micronized).
• The high-energy powders produced by micronization
have poor flow properties because of their static,
cohesive and adhesive nature.
• To improve the flow properties, poor flowing drug
particles are generally mixed with larger ‘carrier’ particles
(median size usually 30-150 µm) of an inert excipient,
usually lactose (a lactose monohydrate), which is known
to dissolve in lung fluids.
• The drug has a particle size of 5 µm and the carrier of 30-
150 µm are mixed to produce an ordered mix in which
the small drug particles attach to the surface of the larger
carrier particles.
• This process enhance the liberation of drug from the
inhalation device and also ensures that the content
uniformity of capsule. As well as a good dispersion into
the lung
3- Nasal Powders
• Nasal powders have medicinal effects intended for
inhalation into the nasal cavity by means of a suitable
device.
• Some potent drugs are presented in this way because they
are rapidly absorbed when administered as a fine powder
via the nose (since the nose provides direct access to the
blood)
• Also, the drug is mixed with an inert excipient such as
lactose that aid in liberation and dispersion of the drug at
the administration site.
4- Topical powders
• They are used for cutaneous application.
• They are solid, loose, dry particles of varying degrees of
fineness that contain one or more active pharmaceutical
ingredients, with or without excipients, and if necessary,
appropriate coloring matter.
5- Dusting Powder
• Dusting powders are powders for cutaneous
application which have a suitable fineness.
• Dusting powders are normally dispensed in glass or
metal containers with a perforated lid. So, the
powder must flow well from such container to
ensure that it can be dusted over the affected area.
• The active ingredients must therefore be diluted
with materials having reasonably good flow
properties such as purified talc or maize starch.
Canesten Powder (clotrimazole) is used as an
antifungal agent.
• They may be used for lubricant purposes such as Talc
Dusting Powder.
• The talc or kaolin excipient (mineral) must be free from
pathogenic micro-organisms through their sterilization
before their incorporation with the starch, or alternative
terminal sterilization must be used.
• This is done because talc and kaolin may be
contaminated at source with spores of organisms causing
tetanus and gangrene.
6- Powders or granules for solution or suspension
• Powders or granules for oral solutions or suspensions generally
conform to the definitions in the normal pharmacopeial standards for
oral powders or granules.
• After dissolution or suspension formation after reconstitution, the
resulting product should comply with the general requirements for
oral solutions or oral suspensions.
• The aim of this strategy is to enhance the stability of the developed
product.
• The excipients used are coloring matter, flavoring agents and
excipients that facilitate dispersion and dissolution and to prevent
caking.
• Amoxicillin for oral Suspension and Erythromycin Ethylsuccinate for
oral Suspension.
7- Powders or granules for syrup

• The aim of this formulation strategy is to enhance stability of


the developed product.
• The reconstituted powders or granules for syrup are
characterized by a sweet taste and a viscous consistency like
ordinary syrups.
• The necessary ingredients for syrup formulation including
flavoring agents like sucrose or other polyols are formulated
and stored in the dry powdered or granulated state and then
reconstituted (usually by the addition of water) at the time of
dispensing.
8- Powders for injection
• The stability of parenteral formulation is the cornerstone in its
product development.
• Some drugs which are unstable in aqueous solutions must be
formulated immediately prior to its use.
• The ingredients are presented as sterile powders in ampoules or vials
and sufficient diluent like sterile water for injection is added from a
second container to produce the required drug concentration and the
injection is used immediately.
• The formulation of powder for injection must contain isotonic agent that
ensures the reconstituted powder is isotonic with the biological fluids.
Tonicity????
• Isotonic solution: the solutions on either
side of a cell membrane are isotonic if the
concentration of solutes outside the cell is
equal to the concentration of solutes inside
the cell.
Mixing (blending) of Powders
1- Spatulation:
Small amounts of powders are blended by movement of a
spatula through the powders on a sheet of paper or tile.
Efficient for eutectic mixtures
This method is not suitable for a large quantities of powders
containing one or more potent substances because
homogenous blending may not occur.
Not efficient for aggregates (no size reduction).
2- Trituration
• It is used both to comminute and to mix powders. If
comminution is desired a porcelain mortar with rough inner
surface is preferred to a glass mortar.
• A glass mortar may be preferred for chemicals that may stain a
porcelain mortar
• Pulverization Vs Lavigation
3- Sifting:-
During sifting powders are mixed by passing them through
sifters. This process results in a light, fluffy product
4- Geometric dilution
• It is employed when a potent substances are to be mixed with a
large amount of a diluent.
• The potent drug is placed upon an approximately equal volume of the
diluent in a mortar and the substances are thoroughly mixed by
trituration.
• A second portion of diluent equal in volume to the powder mixture in
the mortar is added and trituration is repeated
• The process is continued, adding diluent equal in volume to the
mixture in the mortar at each step until all the diluent is incorporated
5- Tumbling
• It is process of mixing powders in large containers rotated
by a motorized process.
• These blenders are widely employed in industry
Shelf life and storage of internal
powders
(1) Shelf life of internal powders is 2-4 weeks.
(2)Proprietary powders often have a longer
shelf life because of protective packaging.
(3)Storage for these powders should be
moisture proof and airtight.
Shelf life and storage of external powders
• Shelf life of external powders is 4 weeks.
• Dry powders should remain stable for long
period of time if packaged and protected
from atmosphere.
• Store in a cool and dry place.
Containers for internal powders
• Extemporaneously prepared individualy
wrapped powders are often dispensed in a
paperboard box.
• It is preferable to use a screw-top glass or
plastic container which provides an air tight
seal and protection against moisture.
• Bulk powders are packed in an airtight glass
or plastic jar.
Containers for internal powders
Containers for external powders
• Powders for external use may be packed in
glass,metal or plastic containers with a sifter-
type cap. Some are also available
commercially in pressurized
containers,containing other excipients such
as propellant.
Containers for external powders
Labels and advice for internal powders
• Powders are usually mixed with water or
another suitable liquid before taking,depending
upon their solubility.
• Powders for babies can be placed directly into mouth
followed by a drink to wash down the powder.
• Bulk powders should be shaken and measured
carefully before dissolving in a little water and
taking.
Labels and advice for internal powders:
Labels and advice for external powders
• For external use only.
• Store in cool ,dry place.
Labels and advice for external powders:
Classification of Granules

Granules are classified into following categories:


1)Effervescent granules.
2)Coated granules.
3)Gastro-resistant granules.
4)Modified release granules.
Effervescent granules
• Effervescent granules are uncoated granules generally
containing acid substances and carbonates or
hydrogen carbonates which react rapidly in the
presence of water to release carbon dioxide.
• They are intended to be dissolved or dispersed in
water before administration.
• Effervescent granules should be stored in an
airtight container to be kept away from humidity
The Effervescent Reaction

• The effervescence is the evolution of gas bubbles from a


liquid, as the result of a chemical reaction.
• The most common reaction for pharmaceutical purpose is
the acid-base reaction between sodium carbonate and citric
acid:
granules Effervescent
• This reaction starts in presence of water, even with a very
small amount as catalyzing agent.

• Because water is one of the reaction products, it will


accelerate the rate of reaction, leading to difficulty in
stopping the reaction.

• The whole manufacturing and storage of effervescent


products has to take into consideration minimizing the
contact with water.
Formulation

• Acid materials as acid source such as citric acid,


tartaric acid, and ascorbic acid. Tartaric acid and citric
acid are more frequently used as source of hydrogen
(acidic protons) to promote the reaction (2:1).
• Solid carbonates salts are the most popular source for
effervescence; bicarbonate forms are more reactive
than carbonates.
• Examples like sodium bicarbonate, sodium carbonate,
potassium carbonate and potassium bicarbonate.
• Binders which are very finely distributed on the powder bed. The
most popular binder for effervescent tablets is polyvinylpyrrolidone
(PVP) types K25 and K30 which are preferred for their water
solubility, low viscosity and dissolution rate due to its important role
for the final purpose of effervescent tablets.
• Additives including sweeteners, coloring agents and flavors.
• Lubricants can be used in case of effervescent tablets. They must be
water soluble such as sodium benzoate, sodium acetate, L-leucine
and PEG 6000.
• Magnesium stearate, the most effective lubricant in tablet
manufacture, must be used only in combination with sodium lauryl
sulfate, a surface active agent that helps in its dispersion (because
magnesium stearate is hydrophobic)
Preparation:-
• Effervescent granules are prepared by two general
methods:-

• The dry or fusion method


• The wet method
The Fusion Method???
• In the fusion method, the one molecule of water present
in each molecule of citric acid acts as the binding agent
for the powder mixture.
1- Before the mixing of powders, the citric acid crystals are
powdered and then mixed with the other powders of the
same sieve to ensure uniformity of the mixture.
Size reduction, sieving ,mixing
2- The sieves and the mixing equipment should be made of
stainless steel or other materials resistant to the effect of
the acids.
3- The mixing of powders is performed as rapidly as
possible, preferably in an environment of low humidity to
avoid the absorption of moisture and a premature
chemical reaction.
4- After mixing step, the powder is placed on a suitable
dish in an oven at 34 °C - 40 °C.
5- The aim of the heating step is to liberate the water of
crystallization from the citric acid, which in turn dissolves a
portion of the powder mixture, setting of the chemical
reaction and the consequent release of some carbon
dioxide.
• This causes the softened mass of powder
to become somewhat spongy, and when
of the proper consistency (as bread
dough), it is removed from the oven and
rubbed through a sieve to produce
granules of the desired size.
6- The granules are dried at a temperature
not exceeding 54 °C and immediately
placed in containers and tightly sealed.
Wet Method
• The wet method differs from the fusion method in that
the source of binding agent is not the water of
crystallization from the citric acid but hydro-alcoholic
solution is used as the moistening agent.
• In this method, all of the powders may be anhydrous as
long as water is added to the moistening liquid.
• Just enough liquid is added (in portions) to prepare a
mass of proper consistency; then the granules are
prepared and dried in the same manner of fusion
method.
• Drying of effervescent granules is a shorter process than
drying conventional granules granulated with water,
because of very small amount of water involved in the
process compared to normal granules.

• The dried effervescent granules must have moisture


content, after drying phase, equal to or less than 0.1%.
Packaging Materials of Effervescent Granules:
• Although paper is one of the oldest pharmaceutical
packaging materials, it is not the best packaging material for
effervescent granules when used alone. This is due to
several disadvantages;
• No barrier properties against moisture, gases and odors.
• Moisture sensitive.
• No heat- or cold-seal properties and hence cannot be sealed
without adhesives and special coatings.
• Poor transparency and gloss compared to certain plastic
films.
• To overcome such disadvantages, paper can be
combined with other materials:-

• For example, paper can be further coated by polymers


or laminated to plastic or to aluminum foil to:-
1- Improve its barrier properties to gases and moisture.
2- Create heat-sealing ability when used in the primary
pack.
Laminates:-
• A laminate is made by bonding together two or more layers
of different materials, such as paper, plastic and metal.
• The aim of this combination is to obtain a single packaging
structured material that has the desirable properties of the
different layers.
• By this approach, a minimum amount of material is used and
the laminate is cost-effective.
• Example:-Laminates are used to produce pharmaceutical
packs such as sachets for effervescent.
•An example is a structure consisting of
paper/metal foil/polythene layers, used for
sachet packaging.
•The paper provides strength, printability and the
ability to easily tear the package, the foil
provides an excellent barrier to light, moisture
and gases and the polythene enables heat
sealing.
2:Coated granules
• Coated granules are usually multi-dose
preparations consist of granules coated with
one or more layers of mixtures of various
excipients.
• The substances used as coatings are usually
applied as solution or suspension in
conditions in which evaporation of the
vehicle occur.
Coated granules
3:Gastroresistant granules
• These are delayed release granules that are
intended to resist the gastric fluid and to
release the active substance in intestinal fluid
• These properties are achieved by covering
the granules with the gastro-resistant
material or by other suitable means.
Gastro-resistant granules
4:Modified release granules
• They are coated or uncoated granules which
contain special excipients or which are
prepared by special procedure are both ,
designed to modified the rate , the place or
the time at which the active substance or
substances are released.
• Modified release granules include prolonged
release granules and delayed release
granules.
Modified release granules
Shelf life and storage:
• Shelf life of granules is 2-3 weeks.
• Granules should be stored in airtight
containers.
• Granules should be placed at cool and dry place.
Container

• Granules should be kept in air tight container.


Container:
Label and advice

• Dissolve or mix with water before taking.


• A normal dose is 1-5 g of the powder taken in liquid,
when required.
• Antacids are usually taken b/w meals and at bedtime.
Powders VS Granules
Powders Granules
• Comparatively poor flow properties • Flow well compared to tablets, good
choice for compressing tabs
• Relatively less stable (physically and • Has less surface area, more stable to atm.
Chemically) due to inc. S.A & Atm. Effect effect
• More likely to hardening / cake formation • Less likely
on long storage
• For some powders, drugs float on the • More easily wetted by the solvents, good
surface, difficult to make solution choice reconstitution liquids
• Relatively poor compressibility • Good compressibility
• Chances of non uniform dosing are more • Relatively more uniformity of contents in
case of granules
• More dust due to small particle size • Generate less dust on handling
• Comparatively less appealing • Have a more elegant appearance
• Relatively simple method of • It involves more processing, exposure to
processing/formulation heat and contact with solvents
Pharmaceutical Technology

Suppositories
Learning objectives:

At the end of this chapter the students will be able to:

1. Compare an contrast various suppositories dosage forms in


terms of physical appearance, size, and shape.

2. Describe the advantages and disadvantage of rectal drug


delivery system vs. oral drug delivery.

3. Identify and explain physiological factors which influence the


drug absorption from rectal suppository administration.
4. Identify and explain physicochemical factors of the drug and
suppository base as these influence the rectal absorption.

5. Compare and contrast the various classes of suppository bases

6. Describe the three methods of suppository preparation

7. Generate a listing of key counseling points a pharmacist should


share with the patient prescribed a drug in a suppository.

8. Determine the density factor of the drug in polyethylene glycol


suppositories
Suppositories definition
• Definition: Suppositories are unit solid dosage forms intended for
insertion into body orifices where they melt, soften, or dissolve and
exert local or systemic effects.
• The derivation of the word suppository is from the Latin supponere,
meaning to place under.
• Suppositories are commonly used rectally and vaginally (pessaries)
and occasionally urethral (bougies), rarely nasal (bougies and through
ear (ear cones).
They have various shapes and weights.
Therapeutic uses

Suppository can be used for local or systemic effect.

The action depends on nature of drug, concentration and rate


of absorption

For treating local conditions: Emollients, astringents,


antibacterial agents, steroids, and local anesthetics

For treating systemic conditions: analgesics, antispasmodics,


sedative, antibacterials & tranquilizers).
1) Local action
Rectal suppositories intended for localized action are most
frequently used to relieve constipation or the pain using local
anesthetic, irritation, itching, and inflammation associated
with hemorrhoids or other ano-rectal conditions.

A popular laxative, glycerin suppositories promote laxation


by the local irritation of the mucous membranes.

Vaginal suppositories or inserts intended for localized effects


are employed mainly as contraceptives, antiseptics in
feminine hygiene.
2) Systemic action
For systemic effects, the mucous membranes of the rectum and
vagina permit the absorption of many soluble drugs.

Although the rectum is used frequently as the site for the


systemic absorption of drugs, the vagina is not as frequently
used for this purpose.

Examples include paracetamol (acetoaminophen), diclofenac.


Routes of Administration that Utilize Suppositories

Suppositories have various shapes, sizes, and weights because


they are used in many different routes of administrations (body
cavities).
Rectal Suppositories
• Rectal Suppositories About 32 mm (1.5 inches) in length, cylindrical,
one or both ends tapered and some are bullet, torpedo, or little
finger shaped. Depending on the density of the base and the
medicaments in the suppository, the weight may vary

• Adult rectal suppositories weigh about 2 grams when cocoa butter


(theobroma oil) is used as a base. (varies according to base)

• Rectal suppositories for use by infants and children are about half
the weight and size of the adult suppositories and assume a more
pencil-like shape.

• Intended for both local (soothing inflamed hemorrhoids, laxatives)


and systemic actions

Small scale production of supp


Using rectal administration to achieve systemic activity is
preferred when:
• The drug is destroyed in the GIT
• Oral administration is not possible because of vomiting
• The patient is unconscious or incapable of swallowing oral
formulation
Cases such as: Asthma, nausea, motion sickness, anxiety, and
bacterial infections.
Advantages of rectal
suppositories:
• It avoid first pass effect. (inferior, • It can be given to unconscious
middle superior hemorrhoidal veins) patient or patients with nausea and
• Melt at body temperature.
vomiting.
• It gives localized and systemic action.
• Useful for rapid and direct effect in rectum.
• Drug stability
• Convenient for those drug causes GIT irritation,
• Large dose drug vomiting etc.
• Unpleasant tasting or smell drugs • Unit dosage form of the drug.
• It is easy to use for pediatric and geriatric patients. • The presence of disease in the upper GIT
• Useful to produce local effect. (ulcers or part of the stomach was removed) that
• Useful to promote evacuation of bowel may interfere with drug absorption
Disadvantages of suppositories rectal administration:

• Irritant drug can`t administered


• They are not preferred by the patient, not convenient
• Need to store at low temp.
• Cant easily prepared
• Cost-expensive
• Defecation may interrupt the absorption process.
• absorbing surface area of the rectum is much smaller than that of the
small intestine.
• fluid content of the rectum is much less than that of the small
intestine; this may effect dissolution rate, etc.
• Some drug may be degraded by the microbial flora present in the
rectum.
• Rectal absorption of most drugs is frequently erratic and unpredictable
• Some suppositories leak (oily supp.) or are expelled after insertion ( 1
Vaginal suppositories
• Called pessaries,(they are used for certain conditions,
don’t replace rectal supp.)are usually globular, oviform,
or cone-shaped and weigh about 5 g when cocoa butter
is the base.
• Depending on the base and the manufacturer's product,
the weights of vaginal suppositories may vary widely.
• They are employed as contraceptives, feminine hygiene
antiseptics, bacterial antibiotics, antifungal or to restore
the vaginal mucosa (dryness).
• Vaginal suppositories are inserted high in the vaginal
tract with the aid of a special applicator (plunger).
• The disadvantages of vaginal administration is not suitable for
systemic action why?
Vaginal administration does lead to variable absorption since
the vagina is physiologically and anatomically dynamic organ
that causes pH and membrane permeability to change over time
(hormones effect). There is also some tendency of some dosage
forms to expelled after insertion into the vagina.
Urethral suppositories

• called bougies, are slender, pencil-shaped suppositories intended for insertion


into the male or female urethra. Nowadays, they are rarely used but were applied
as local anesthetics and antiseptics
• Male urethral suppositories may be 3 to 6 mm in diameter and approximately
140 mm long, cocoa butter is employed as the base, weigh about 4 g.
• Female urethral suppositorie are about half the length and weight of the male
urethral suppository, being about 70 mm long and weighing about 2 g when
made of cocoa butter.
• Commercially available: marketed as pellets (3 or 6 mm in length)
• Not encountered in compounding practice
How to insert suppositories
Some factors of drug absorption from rectal
suppositories
Rectum is about 150 mm in length, terminating in the anal
opening. Its surface area is about 0.02-0.04 m2 (lung S.A 500
m2, small intestine 200 m2), and in the absence of fecal matter
the rectum contains small amount of fluids (1-3ml).
The factors that affect rectal absorption of a drug may be divided
into two main groups:
a. Physiologic factors
b. Physicochemical factors of the drug and suppository base
Physiologic factors

• Colonic content
- The physiologic state of the colon (the amount and pH of the fluids,
and solids present). In order to increase the absorption, the colon
should be empty to increase contact of the drug with the absorption
surface.
- The state of the ano-rectal membrane. This membranous wall is
covered with a relatively continuous mucous blanket, which can act as
a mechanical barrier for the drug absorption.
Physiologic factors
• Circulation route
- The lower hemorrhoidal veins surrounding the colon receive the
absorbed drug and initiate its circulation throughout the body,
bypass the liver.

- Lymphatic circulation also assists in the absorption of rectally


administered drugs.
Physiologic factors
• pH and lack of buffering
• The colon has a pH of ≈ 6.8 (neutral), with no buffer capacity (no
resistance in pH change), thus the dissolving drugs determine
the pH in the ano-rectal area.
• The suppository base employed has a marked influence on the
release of active constituents incorporated into it.
• Colonic lumen is permeable to the unionized forms of drugs.
Thus, weaker acids and bases are more readily absorbed than
the stronger, highly ionized ones. Thus, the absorption of a drug
would be enhanced by a change in the pH of the rectal mucosa
that would increase the proportion of unionized drug.
**So absorption of acidic drugs can be increased when the pH of the
surrounding fluids was lowered.
The absorption of salicylic acid rises from 12% at a pH 7 to 42% at pH 4.
In contrast, with a basic drug like quinine, which becomes more ionized
at the lower pH values, the absorption is decreased from 20% at pH 7
to 9% at pH 4.
**For systemic action using cocoa butter base (oleaginous base):
ionized drug or unionized?
**PEG or glycerinated gelatin (water miscible bases): ionized drug or
unionized?
Formulation of Suppositories
1. Drug
2. Additives
• Suppositories base
• Surfactants
• Preservatives
• Anti oxidants: Antioxidants (to avoid autooxidation of unsaturated fatty acids
into saturated aldehydes ketones and fatty acids) with strong unpleasant
odor Therefore the lower the content of unsaturated fatty acids, the higher
its resistance to rancidity
• Buffers
• Penetration enhancers
• Lubricants
• anti-settling agents (blend of higher m.p waxes & fatty acids )
Physicochemical factors of the drug and suppository base
• Lipid-water solubility (Partition Coefficient)
- A lipophilic drug that is distributed in a fatty suppository base in low
concentration has less of a tendency to escape to the surrounding
aqueous fluids than would a hydrophilic substance present in a fatty
base to an extent approaching its saturation.

- Water soluble bases, for example, PEG, which dissolve in the anorectal
fluids, release for absorption both water-soluble and oil-soluble drugs.

- Naturally, the more drug a base contains, the more drug will be
available for potential absorption.
Physicochemical factors of the drug and suppository base
The pKa of the drug
The pKa of the drug determines if it’s going to be ionized or unionized in the
pH of the colon. In order to achieve absorption the drug should be
unionized.
- For maximum absorption the drug should be unionized and lipid soluble
(high log P)
•Completely ionized drugs like quaternary ammonium compounds and
sulfonic acid derivatives are poorly absorbed.
• Unionized substances that are lipid-insoluble are poorly absorbed.
Thus, drug absorption can be increased by the use of buffer solutions or salts
that convert the pH of the anorectal area to a value that increases the
concentration of unionized drug.
Physicochemical factors of the drug and suppository base
• Particle size
- For drugs present in a suppository (suspended particles),
the size of the drug particle will influence its rate of
dissolution and its availability for absorption.

- The smaller the particle size (specific surface area??), the


more readily the dissolution of the particle and the greater
the chance for rapid absorption.
Physicochemical factors of the drug and suppository base
The presence of Surfactants in the formulation [surfactant-
containing vehicle]
Surfactants increase drug absorption rate due to:
1. Surface tension lowering
2.The mucus-peptizing action
The cleansing action caused by the surfactant-containing vehicle may
make additional pore spaces available for drug absorption, thus
facilitating drug movement across the rectal membrane barrier.
Physicochemical factors of the drug and suppository base
• Nature of the base
- The base must be capable of melting, softening, or dissolving to
release its drug for absorption

- The possibility of chemical and/or physical interactions


between the medicinal agent and the suppository base, which
could affect the stability and/or bioavailability of the drug.

- If the base (glycerinated-gelatin) is irritating to the mucous


membranes of the rectum, it may initiate a colonic response
and prompt a bowel movement, negating the prospect of
complete drug release and absorption.
The ideal suppository bases
One of the first requisites for a suppository base is that (ideal
suppository base)
• it remains solid at room temperature
• Release medicament readily soon after insertion.
• Easily formed by compression and molding.
• Easily melt at body temperature and dissolve or disperse and swell in
the presence of the mucous membrane.
• Retain shape while handling moldable, non adhering
• Inert, Non-toxic & non-irritant (enhance defecation)
• Stable on storage & compatible with a broad variety of drugs (no
drug intrxn)
• High water number :i.e. does not change color, odor, or drug release
pattern
Suppository base composition plays an important role in both the rate
and extent of the release of the medications
If the base is fatty, it has the following additional requirements:

• Acid value below 0.2


• Saponification value ranges from 200 to 245
• Iodine value less than 7
• The interval between "melting point“ and "solidification point" is small (less
than 10 degrees): Solid Fat Index (SFI) curve is sharp
• Low melting ranges (30- 34°C) for incorporating drugs that increases the
melting range of the base.
Ex. Silver nitrate or lead acetate
And High melting ranges (37-41°C) for incorporating drugs that lower melting
points of the base.
Ex. Camphor, chloral hydrate, menthol, phenol, thymol, and several types
of volatile oils or for formulating suppositories for use in tropical climates.
Classification of suppository bases

I. Oleaginous (fatty-lipophilic) bases


a) Natural - cocoa butter or their substitutes (suitable for inflamed
mucosa because of the soothing effect)
b) Synthetic – hydrogenated vegetable oils (to make them more solids).
Adv: stability no polymorphisms?

II. Hydrophilic (water soluble/miscible) bases


a) Natural - glycerol-gelatin (Glycerinated gelatin)
b) Synthetic –PEG- macrogols

III Others (miscellaneous): Hydorgels (macromolecular network/swelling)


1) Fatty or oleaginous base
Cocoa butter or Theobroma Oil
• is defined as the fat obtained from the roasted seed of Theobroma
cacao.
It is the most widely used suppository base (oldest base).
It satisfy many requirement for ideal suppository base :
1) Bland (fluffy). 2) Non reactive. 3) Melt at body temperature.
- Cacao Butter is a triglyceride (combination of glycerin and one or
different fatty acids, primarily of oleopalmitostearin and oleodistearine).
, yellowish white, solid, brittle fat (fragile), smells and taste like chocolate.
Its melting point between 30-35° C, and at ordinary room temperatures
of 15° to 25° C it is a hard, amorphous solid. Its iodine value is “between”
34-38 and its acid value is no higher than 4, because cacao butter can
melt and rancid. So it must be stored in cool dry place protected from
light.
- Two factors when preparing suppositories with cocoa butter
base. First, this base must not be heated above 35C because
cocoa butter is a polymorphic compound and if overheated
will convert to a metastable structure that melts in the 25 to
30C range. Thus, the finished suppositories would melt at
room temperature and not be usable. (Seeding)
- The second factor is the change in melting point caused by
adding certain drugs to cocoa butter suppositories. For
example, chloral hydrate and phenol tend to lower the
melting point. It may be necessary to add beeswax
(solidifying material)to raise the melting point of finished
suppositories back to the desired range.
Limitations:
- Polymorphism – unstable alpha/gamma/beta prime form
- Adhere to mould due to contractility on solidification
- Softening point too low for hot climates or with certain drugs
(beeswax may be added)
- Batch to batch variation in composition
- Becomes rancid on storage
- Immiscible in body fluids and poor water absorption
- Tendency to leak, immiscibility makes it not suitable for vaginal and
urethral route
- Costly
Cacao butter exhibited polymorphism (exist in different crystalline forms). Cacao
butter is thought to exist in 4 crystalline states:
1) α - crystal ‫ ــ‬melt at 22oC ‫ ــ‬unstable
2) γ - crystal ‫ ــ‬melt at 18oC ‫ ــ‬unstable
3) β’ - crystal ‫ ــ‬melt at 27oC ‫ ــ‬unstable
4) β – stable crystal ‫ ــ‬melt at 34-36oC ‫ ــ‬stable

Various forms of cacao butter depend on:


1- Degree of heating.
2- Cooling process.
3- Conditions during this process.
The re-conversion to the stable B- form takes form one to four days depending
on the storage temperature, the higher the temperature the faster the change.
Synthetic lipophilic bases

• Hydrogenated fatty acids of vegetable oils (palm oil and cottonseed


oil). More solid
• Fat-based compounds containing higher molecular weight fatty acids,
such as palmitic and stearic acids with glycerin the (glyceryl
monostearate and glyceryl monopalmitate, (Witepsol®) )
Synthetic lipophilic bases advantages & disadvantages:
- readily available
- do not become rancid
- chemically more inert
- rapid solidification
- do not exhibit polymorphism
- good water absorption and emulsification properties
- lubrication can be avoided
- white, smooth & odorless
- can incorporate drugs with low melting points
- may become brittle & fracture if cooled rapidly
- They are not very viscous on melting, so the medicaments incorporated
with the base settle down rapidly
- more expensive than cocoa butter
2. Hydrophilic bases

 It is a mixture of glycerin (70%) and water (10%) which


is made stiff by the addition of gelatin (20%).
 Properties:
 It is colourless, transparent, translucent in nature.
 It is soft to touch.
 It melts at 30 - 350C.
 Type of gelatin bases: to avoid incompatibility.
 Type A or Pharmagel A: acidic in nature and used for
acidic drugs.
 Type B or Pharmagel B: alkaline in nature and used for
basic drugs.
 Used for vaginal suppositories (rectally : irritant).
Gelatin
• Gelatin is a purified protein produced by the hydrolysis of the
collagenous tissue, such as skins and bones, of animals.
• Two types of gelatin are used for pharmaceutical purposes, Type A,
which is prepared by acid hydrolysis and is cationic, and Type B,
which is prepared by alkaline hydrolysis and is anionic.
• Type A is compatible with substances such as boric acid and lactic
acid while Type B is compatible with substances like zinc oxide.
Glycero- Gelatin Base
Advantages:
• It melt at body temperature. It mix with body fluid.
• Not rancid.
• It can be used to prepare suppositories using boric acid, chloral hydrate
bromides, iodides, iodoform opium etc.
• Release drugs over long period of time.
Disadvantages:
• Difficult to prepare and handle.
• Chance of bacterial growth/ Preservatives addition e.g methyl
parabens and/or propyl parabens.
• Glycerin is hygroscopic in nature. (become hard on drying and soft in contact with
moisture) should be stored in air tight container
• The solution time depends on the content and quality of the gelatin and also the age of the
suppository.
• Laxative in action.
• Incompatible with tannic acid, gallic acid, ferric chloride etc.
Polyethylene Glycols/ Macrogols:
• Water-miscible bases are composed of PEGs possessing a
molecular weight greater than 1000 g/mol.(HOCH2(CH2OCH2)xCH2OH)
• The melting point of these higher grades of PEGs increases as the
molecular weight increases, e.g. the melting points of PEG 1000 and
PEG 8000 are 370–400C and 600– 630C, respectively.
• Typically the melting point of PEG suppository bases is 420C; this
is generally achieved and controlled using the appropriate
mixtures of grade of this polymer.
• In addition to controlling the melting point and drug release, different
molecular weights of this polymer may also be blended to control the
mechanical properties of PEG based suppositories. (When their
average molecular weight ranges from 200 to 600 they exist as
liquids, and as wax like 600 to1500 and solids up to 20 000)
• Their water solubility and hygroscopicity decrease with increasing average
molecular weights Since they are hydrophilic bases, they dissolve and don’t melt at
body temperature
• The wide range of melting points and solubilities allows the formulation of
suppositories with various degrees of heat stability and different dissolution rates
• In this scenario, the lower-molecular-weight PEGs, e.g. PEG 400, will act to reduce
the brittle behaviour of these suppository bases.
• PEG is known to enhance the solubility of therapeutic agents and therefore this
interaction between the drug and polymer may affect the subsequent release of
the drug from the liquefied base.
• Secondly, the solubility of the drug in the solid base may change as functions of
both storage conditions and time and this may result in crystal growth within the
suppository.
Polyethylene Glycols/ Macrogols:
Advantages:
1. They are chemically stable.

2. Physiologically Inert, Non-irritant.

3. Do not allow bacterial growth.

4. Physical properties changes according to molecular weight.

5. Provide prolonged action.

6. Do not stick to mould (Take care that the mold should be dry because this
base is water soluble).
7. Suppositories are clean and smooth in appearance.

8. Their melting point is above body temperature therefore they are easily
stored
Polyethylene Glycols:
• Disadvantages:
• Hygroscopic in nature (Depends on the Mw).
• Incompatibility with some drugs tannins phenol etc.
• Most patients feel discomfort from the use of these
suppositories, because this type of Bases cause irritation"
to mucous membranes when water drawn from the
mucosa This irritation may be eliminated by dipping in
water before insertion or by addition of water to facilitate
solution of the suppository after insertion
• In addition crystal growth occurs with some drugs causing
irritation to the rectal mucosa and, if the crystals are large,
prolonged dissolution times
3. Water - dispersible base (Others)

Several non-ionic surface active materials, closely related chemically to PEG as


suppository bases. The bases can be used for formulation both water-soluble and
oil-soluble drugs such asTween (polyoxyethylene sorbitan fatty acid
Esters) & Span (sorbitan fatty acid esters). These surface active agents may be
used alone, blended or used in combination with other suppository vehicle.
Another type of water dispersible suppository vehicle is based on the use of
water soluble cellulose derivatives (e.g. methylcellulose & sodium
carboxymethylcellulose ).

Advantages of Water Dispersible Bases:


1. Stable on storage at elevated temperature (don’t melt).
2. Compatible with many drugs
3. Can be used for formulating both water and oil soluble drugs.
3. Non support of microbial growth, non toxic and non sensitive.

45
Specifications for Suppository Bases :

1- Origin & Chemical Composition:


A brief description of the composition of the base reveals the source of
the origin (natural or synthetic or modified natural products). Physical
or chemical in- compatibilities with other constituents may be
predicted if the exact formula composition is known including
preservatives, antioxidants and emulsifiers

46
2- Melting Range :
Suppository bases (complex mixtures of triglycerides) don't have a
sharp melting point, 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
determination by "Capillary melting point“ or " thaw point".
The lower the melting range, the higher the absorption of the drug
from the base

47
3- Solidification Point:
This test allow to determine the time required for solidifying the
base, when it is chilled in the mold 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 amore efficient
manufacturing procedure by refrigeration, if melting point 33° C
and solidifying point 20° C then it will be liquid for 13° C, then the
drug will sediment and the apex of the suppository will contain all
the drug.

48
4- Hydroxyl Value:
"It is the number of milligrams.of KOH (Potassium hydroxide) that
would neutralize the acetic acid used to acetylate 1g of fat. It
reflects the mono- and di-glyceride content of a fatty base.

5- Saponification Value:
The number of milligrams of KOH (Potassium hydroxide) required
to neutralize the free fatty acids and saponify the ester
contained in 1 g of a fat. From saponification value we can know
the type of glyceride present (mono-, di- or tri-) and also amount
present.

49
7- Iodine Value:
It is the number of grams of Iodine that reacts with l00 g of fat or other unsaturated
material.
The possibility of decomposition by moisture, acids, oxygen (which leads to rancidity of
fats) increases with higher iodine value.

8- Water Number:
It is the amount of water in grams that can be incorporated in l00g of fat. The "water
number" can be increased by the addition of surface- active agents.

9- Acid Value:
It is the number of milligrams of KOH (Potassium hydroxide) required neutralizing the
free fatty acids in I g substance (fat). Low acid value or absence of acid value is
important for good suppository bases. (less rancidity, irritation, intrxn with
ingredients)
50
Formulation consideration
 Consider the following points
1. Medication intended for local or systemic use.
2. Site of application-rectal, vaginal and urethral.
3. Desired effect- quick, slow or prolonged.
 First preliminary evaluation (by measuring drug availability
from the suppository in water at 36 to 37°C).
 Availability of the base and the cost
 Ease of moulding and release in the manufacturing
 equipment
 . at 4oC and at room temp.
Stability
 Following parameter are studied:
 Irritation (toxicity on animals)
 Drug availability. Etc
Method of Preparation

 Hand rolling.
 Compression moulding.
 Fusion method.

The method most frequently employed


both on a small scale and on an
industrial scale is molding.
Hand rolling
It is the oldest and simplest method of
suppository preparation and may be
used when only a few suppositories
are to be prepared in a grated cocoa
butter base.

It has the advantage of avoiding the


necessity of heating the cocoa
butter.

A plastic-like mass is prepared by


triturating grated cocoa butter and
active ingredients in a mortar.
Hand rolling

 The mass is formed into a ball in the palm of the hands, then
rolled into a uniform cylinder with a large spatula or small flat
board on a pill tile.
 Starch or talc powder on the rolling surface and hands
prevent the mass from adhering
 The cylinder is then cut into the appropriate number of pieces
which are rolled on one end to produce a conical shape.
 Effective hand rolling requires considerable practice and skill.
The suppository "pipe" or cylinder tends to crack or hollow in the
center, especially when the mass is insufficiently kneaded and
softened.
Compression moulding
Compression molding is a method of preparing
suppositories from a mixed mass of grated
suppository base (PEG) and medicaments
which is forced into a special compression
mold using suppository making machines.

The suppository base and the other ingredients


are combined by thorough mixing.

The friction of the process causing the base to


soften into a past-like consistency.

Pressure is applied from one end to release the


mass from the other end into the suppository
mold or die.
Compression moulding
 When active ingredients are added, it is necessary to omit a
portion of the suppository base, based on the density factors of
the active ingredients.
 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 fusion molding method, compression permits
no likelihood of insoluble matter settling during manufacture.
 Suppository is simple and more elegant appearance than hand
molding.
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.
• Too slow for large scale production
• Air entrapment may take place, this causes weight variation in
suppositories and also causes the possible oxidation of both the base
and active ingredients
Fusion Method
1. Melting the suppository base
2. Dispersing or dissolving the drug in the melted base.
3. The mixture is removed from the heat and poured into a suppository
mold.
4. Allowing the melt to congeal
5. Removing the formed suppositories from the mold. (mineral oil vs soap
and glycerin)
The fusion method can be used with all types of suppositories (Cocoa
butter, glycerinated gelatin, polyethylene glycol, and most other bases)
and must be used with most of them.
Fusion Method

 Small scale molds are capable of


producing 6 or 12 suppositories in a
single operation.
 Industrial molds produce hundreds
of suppositories from a single
molding.
Suppository Molds

• Molds in common use today are made from stainless steel, aluminum,
brass, or plastic.
• 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.
LUBRICANTS FOR USE WITH
SUPPOSITORY BASES
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.
Determination of the Amount of Base Required
• Knowing the amount of drug substances provided in each suppository
subtracted from the total volume of the mold will give the volume of base
required.
• if considerable quantities of other substances are to be used, The total volume
of these materials is subtracted from the volume of the mold, and the
appropriate amount of base is added.
• Because the bases are solid at room temperature, the volume of base may be
converted to weight from the density of the material.
• Example,
if 12 mL of cocoa butter is required to fill a suppository mold and if the
medicaments in the formula have a collective volume of 2.8 mL, 9.2 mL of cocoa
butter will be required. By multiplying 9.2 mL times the density of cocoa
butter,0.86 g/ mL, it may be calculated that 7.9 g of cocoa butter will be required.
The most used method of calculating the
quantity of base that the active medication
will occupy and the quantities of
ingredients required is by using the
density factors
Density factors
• Ratio give the amount of base displaced by the active drug obtained
by dividing the density of the active drug by the density of the base

• From table Aspirin density Factor 1.3 Mean each 1.3g Aspirin displace
1 g of cocoa butter
Density factors for a selected number of ingredients are shown in
Table .
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.
Preparing and Pouring the Melt
- The melt is poured carefully and continuously into each cavity of the mold, which
has been previously equilibrated to room temperature.

- If any undissolved 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,

- The mold is usually placed in the refrigerator , after harding , 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.

- Generally, little or no pressure is required, and the suppositories simply fall out
of the mold when it is opened.
2-8 °C

Cool dry place/ protect from light


Many commercial supp. are wrapped individually in
aluminum foil or PVC-polyethylene, strip packaging is
commonplace
IN- PACKAGE 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.
https://www.youtube.com/watch?v=AwrDsrvbE88

Primary package = Mould

*ADVANTAGE OF PACKAGE MOLDING:


1. high production rate.
2. no generation of scraping.
3. no bulk handling.
4. maintenance of strict temperature control
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Labels for suppositories
Special Label: Stored in a cool place, for rectal/vaginal use only
The patient should be advised to unwrap the suppositories before use
Some countries use the red label for the suppositories and use a special
label For external use ””, since it is not intended for oral administration.
Quality control of suppositories:
1- Appearance:
This includes odour, colour, surface condition and shape.
2- Weight Uniformity:
- Weigh 20 suppositories individually. w1, w2, w3….w20
- Weigh all the suppositories together = W.
- Calculate the average weight = W/20.

Limit: Not more than 2 suppositories differ from the average weight by more than
5%, and no suppository differs from the average weight by more than 10%.
Quality control of suppositories:
3- Melting range test: (affect the drug release, done mainly for hydrophobic bases
supp.)

- Determines the time taken by an entire suppository to melt when it is


immersed in a constant temperature bath at 37°C.
-The experiment done by using the USP Tablet Disintegration Apparatus.
Procedure:
1-The suppository is completely immersed in the constant temperature water
bath, and the time for the entire suppository to melt or disperse in the
surrounding water is measured.

- The suppository is considered disintegrated when:


A- It is completely dissolved or
B- Dispersed into its component part.
C- Become soft “change in shape” with formation of core which is not
resistant to pressure with glass rod.
Quality control of suppositories:
4- Liquefaction Time or Softening Time Test:
- In this test a U tube is partially immersed in a constant
temperature bath and is maintained at a temperature between
35 to 37°C.
There is a constriction in the tube in which the suppository is kept
and above the suppository, a glass rod is kept. The time taken for
The glass rod to go through the suppository and reach the
constriction is known as the liquefaction time or softening time.
- Another apparatus is there for finding “softening time” which
mimics in vivo conditions. It uses a cellophane tube, and the
temperature is maintained by water circulation. Time taken for the
suppository to melt is noted
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Quality control of suppositories:
5- Breaking Test (Hardness): (1.8 – 2 kg)
- The breaking test is designed as a method for measuring the
fragility or brittleness or elasticity of suppository mainly oleaginous base
supp.
1-The suppository is placed in the instrument with control temp.
2- Add 600 g; leave it for one min. (use a stop watch).
3- If not broken, add 200 g every one min. until the
suppository is broken.

Calculations:
The hardness of the suppository is calculated by adding the weights
together.
But if the suppository is broken before the end of the last min. the last
weight is canceled.
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Quality control of suppositories:

6- Dissolution test:
- By using different types of apparatus such as wire mesh
basket, or dialysis tubing is used to test for in vitro
release from suppositories.
Quality control of suppositories:
7- Stability testing:
SPECIFIC PROBLEMS IN FORMULATING SUPPOSITORIES :
1- Water in suppositories:
Use of water as a solvent for drug should be avoided for the following
Reasons:
a- Water accelerates oxidation of fats.
b- If water evaporates, the dissolved substance crystallizes out.
c- 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 .
d- Reaction between ingredients (in suppository) are more likely to occur in the presence of water.
e- The incorporation of water or other substances that might be contaminate with bacteria or fungi
necessitates the addition of bacteriostatic agents (as parabens)

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2- Hygroscopicity:
a- Glycerinated gelatin suppositories lost moisture by
evaporation in dry climates and absorbed moisture
under conditions of high humidity
b- PEG bases are also hygroscopic.

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

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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:


a- Use base with a more narrow melting rang that is closer to body
temperature.
b- The inclusion of approximately 2% aluminum monostearate not only
increase the viscosity of the fat base but to maintain homogenous
suspension of insoluble material.
c- Cetyl , stearyl or myristyl alcohols or stearic acid are added to improve the
consistency of suppositories .

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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 a higher solids content
at room temperature are usually more brittle.
To overcome, 1) the temperature difference between
the melted base & the mold should be minimal.
2) Addition of small amount of Tween 80,
castor oil, glycerin imparts plasticity to a fat

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6- Volume contraction:
Occurs in many melted suppository base after cooling the mold, result in:
a- Good mold release (contraction facilitate the removal of the suppository from
the mold , eliminating the need for mold release agents).
b- 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.

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Lubricant or mold releasing agent:
Cocoa butter adhere 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). The release of suppository
from damaged mold was improved by coating the cavities with
polytetrofluoroethylene (Teflone).

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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. Example of effective antioxidant are
phenols such as " hydroquinone or B-
naphtholquinone.

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