A suppository is a medicated or non medicated solid

dosage form generally intended for use in the rectum,

vagina and urethra.

Drugs may be administered in suppository form for either

local or systemic effects. Such action depends on the

nature of the drug, its concentration, and the rate of

absorption.

Emollients, astringents, antibacterial agents, steroids,

and local

anesthetics are dispensed in suppository

for treating local conditions

Analgesics, antispasmodics, sed atives,

tranquilizers, and antibacterial agents

are dispensed in suppository for systemic action

1.Rectal suppositories are tapered to resemble a torpedo shape. weigh about 2 g for adults and I g for Children.

Types and shapes of suppositories

2.Vaginal suppositories molded in the

globular or oviform shape, or

compressed

on a tablet press into modified

conical

shapes. weigh about 3 to 5 g. 3.Urethral suppositories called bougies, are pencil shaped and pointed at one extremity. for males weigh about 4 g each and are 100 to 150 mm long; for females, they are 2 g each and usually 60 to 75 mm in length.

Factors Affecting Drug Absorption from Rectal Suppositories

Physiologic Factors

Many drugs cannot be administered orally Why?

Affected by the digestive juices

Their therapeutic activity is modified by the liver

enzymes after absorption from the small intestine.

The lower hemorrhoidal veins surrounding the

colon

and rectum enter into the inferior vena cava and

thus

bypass the liver.

More than (50 to 70%) of rectally administered drugs

can be absorbed from the ano rectal area into the

general circulation and still retain therapeutic values.

Why?1 The upper hemorrhoidal vein

does

connect with the portal veins

leading

to the liver.

The lymphatic circulation helps

also

in absorbing a rectally

administered

drug and in diverting the

absorbed

drug from the liver.

2 The pH of the rectal mucosa has a rate-

controlling role in drug absorption. The colon has a pH of ≈ 6.8, with no

buffer

capacity, thus the dissolving drugs

determine

the pH in the ano-rectal area.

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.

The diffusivity is influenced by:

The nature of the medicament, such as the

presence of

surfactant or the water-lipoidal solubility of the

drug

The physiologic state of the colon (the amount

and

chemical nature of the fluids and solids present).

The state of the anorectal membrane. This

membranous

wall is covered with a relatively continuous mucous

blanket, which can act as a mechanical

barrier for the free passage of drug through

the pore space where absorption occurs.

3 The diffusion of the drug to the site on

the

rectal mucosa at which absorption

occurs.

Physicochemical Characteristics o f the Drug

drug absorption from the anorectal area

Drug in vehicle- Drug in colon fluids- Absorption through the rectal mucosa

1.Release the drug from the suppository base.

2.Distribute by the surrounding fluids to sites of

absorption

3.Dissolve in the fluids

4.Contact of the drug with the lumen walls, and to a

large number of absorption sites.

1.Release the drug from the suppository base.

The lipid/water partition coefficient.

Solution of the drugs in solid water-soluble

bases and oleaginous bases resulted in

prolonged absorption times, because the drug is

slowly eluted into the surrounding fluids.

oFor fatty bases from which the drug

is released as the vehicle melts, water-soluble

oil-insoluble salts are preferred

o For water-soluble bases from which the drug is

released as the vehicle dissolves, the water-

soluble

type salt is the one of choice for quicker

drug absorption.

Ex. Ephedrine sulfate and quinine hydrochloride,

as well as sodium barbital and sodium

salicylate,

are preferred than their bases and acids to

increase

the absorption rate from suppositories.

The rate-limiting step in drug absorption from

suppositories is the partitioning of the dissolved

drug from the melted base and not the rate of

solution of the drug in the body fluids.

The rate at which the drug diffuses to the surface

of the suppository, the particle size of the

suspended drug and the presence of surface active

agents are factors that affect drug release from

suppositories.

Solution of the drugs in solid polyethylene glycol

and oleaginous bases resulted in prolonged

absorption times, because the drug is slowly eluted

into the surrounding fluids.

The particle size of the suspended drug

The larger the particle size, the slower the rate

of solution. Thus, the drug absorption rate is

decreased with an increase in drug particle size.

The concentration of the suspended drug

Marked increases in drug concentration play no

role in altering drug absorption rates but drug

concentration is related to release rates from

suppository bases.

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 rectal membrane is covered by a continuous

mucous blanket, which may be washed away by

colonic fluids that have reduced surface tension. The

cleansing action caused by the surfactant­containing

vehicle may make additional pore spaces available

for drug absorption, thus facilitating drug movement

across the rectal membrane barrier.

Ex. in the case of sodium iodide, absorption is

accelerated in the presence of surfactants and be

proportional to the relative surface tension lowering

of the vehicle.

N.B. In the case of phenol-type drugs, absorption rate

is decreased in the presence of surfactant, due to

the formation of a drug-surfactant complex.

2. Absorption from the lumen walls

The anorectal and colonic mucosae are selectively

permeable to the uncharged drug molecule. Thus,

lipid-soluble undissociated drug is the most readily

absorbed form.

• 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 Characteristics of the BaseFor Fatty Bases:

• The absorption rate is faster from fatty bases having

a lower melting range than from those with higher

melting ranges

• Since fatty bases may harden for several months

after molding, this rise in melting range certainly

would affect absorption

For Polyethylene Glycol Bases• The absorption rate increases along with hydroxyl

values.

The absorption rate is faster as the molecular mass of

the polyethylene glycols (PEGs) used increased.

1.Changes in the rheological properties of the base at body temperature Drug release from hvdrogels of hydropolyethyl

methacrylate decreased as increasing percentages

of the cross-linking agent ethylene glycol

dimethacrylate.

Addition of hydrophobic colloidal silicon oxide to fat

base Suppositories dramatically changes the

rheologic behavior of the mass.

Adjuvants

2. Affecting the dissolution of the drug

in the media of the dosage form.

In emulsion type bases. the amount of water-

soluble drug released increased with the water

content of the base, and that the rate of drug

released could be prolonged by the addition of an

aqueous polymer.

Salicylates improve the rectal absorption of water-

soluble antibiotics in lipophilic bases.

1. Origin and Chemical Composition.

A brief description of the composition of the base

reveals the source of origin (i.e., either entirely

natural, synthetic or modified natural products).

Physical or chemical incompatibilities of the base with

the other constituents may be pre dicted if the exact

formula composition is known, including

preservatives, antioxidants and emulsifiers.

Specifications for suppository bases

characteristics are expressed as a range indicating

the temperature at which the fat starts to melt and

the temperature at which it is completely melted.

2. Melting Range.

Since fatty suppository bases are complex

mixtures of triglycerides and therefore do

not have sharp melting points, their

melting

3. Solid-Fat Index (SFI).

A base with a sharp drop in solids over a short

temperature span proves brittle if molded too quickly.

This type of base requires a reduced differential

between mold temperature and mass temperature for

trouble-free molding. Suppository hardness can be

determined by the solids content at room

temperature. Since skin temperature is about 32°C,

one can predict a product that would be dry to touch

from a solids content over 30% at that temperature.

4. Hydroxyl Value.

This is a measure of

unesterified positions on

glyceride molecules and

reflects the monoglyceride

and diglyceride content of a

fatty base. The number

represents the milligrams of

KOH that would neutralize the

acetic acid used to acetylate

1 g of fat.

5. Solidification Point.

Is the time required for solidifying the base when it is

chilled in the mold. If the interval between the melting

range and solidification point is 10°C or more, the

time required for solidification may have to be

shortened by refrigeration to produce a more efficient

manufacturing procedure.

6. Saponification Value.

Is the number of milligrams of potassium hydroxide

required to neutralize the free acids and saponify the

esters contained in 1 g of a fat is an indication of the

type (mono-, di-, or tri-) glyceride, as well as the

amount of glyceride present.

7. Iodine Value.

Is the number of grams of iodine that

reacts with 100 g of fat or other unsaturated

material. The possibility of decomposition by

moisture, acids, and oxygen (which leads to rancidity

in fats) increases with high iodine values.

8. Water Number.

Is the amount of water, in grams, that can be

incorporated in 100 g of fat.

The "water number" can be increased by the addition

of surface active agents, monoglycerides, and other

emulsifiers.

9. Acid Value. Is the number of milligrams of potassium hydroxide

required to neutralize the free acid in 1 g of

substance. Low "acid values" or complete absence of

acid are important for good suppository bases.

Free acids complicate formulation work, because they

react with other ingredients and can also cause

irritation when in contact with mucous membranes.

Types of Suppository BasesThe Ideal Suppository Base for long shelf-life

1. Having reached equilibrium crystallinity.

The majority of components melt at rectal

temperature 36°C

Bases with higher melting ranges may be

employed for:

eutectic mixtures, addition of oils, balsams, and

suppositories intended for use in tropical

climates.

2. Completely nontoxic and nonirritating to sensitive

and inflamed tissues.

3. Compatible with a broad variety of drugs.

4. Has no metastable forms.

5. Shrinks sufficiently on cooling to release itself

from the mold without the need for mold

lubricants.

6. Has wetting and emulsifying properties.

7. High water number.

i.e. a high percentage of water can be

incorporated in it.

8. Stable on storage.

i.e. does not change color, odor, or drug release

pattern.

9. Can be manufactured by molding by either hand,

machine, compression, or extrusion.

If the base is fatty, it has the following

additional requirements:

10. Acid value below 3

11. Saponification value ranges from 200 to 245

12. Iodine value less than 7

13. The interval between "melting point (34oC)" and

"solidification (32oC) point" is small

14. Low melting ranges (30- 34oC) for incorporating

drugs

that increases the melting range of the base.

Ex. Silver nitrate or lead acetate

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.

Cocoa Butter (Theobroma Oil)

Cocoa butter is a yellowish white, solid, brittle fat.

Smells and tastes like chocolate.

Its melting point lies between 30°C and 35°C.

Its iodine value is between 34 and 38.

Its acid value is no higher than 4.

Oleogenous Suppository Bases

ADVANTAGES of CACAO BUTTER as SUPPOSITORY BASE

The most widely used suppository base

It satisfies many of the requirements for an ideal base

Safe, non reactive and melts at

body temperature.

Cocoa butter does not contain emulsifiers and

therefore does not take up large quantities of

water (maximum 20 to 30 g of water to 100 g

of cocoa butter).

The addition of emulsifiers such as Tween 60 (5 to

10%) increases the water absorption considerably.

Emulsifiers also help to keep insoluble substances

suspended in the fat. Suspension stability is further

obtained by the addition of materials (aluminum

monostearate, silica) that give melted fats thixotropic

properties. There is always the possibility that the

suppositories containing these additives will harden

on storage. Therefore, prolonged, careful stability

observations are recommended.

DISADVANTAGES of CACAO BUTTER as SUPPOSITORY BASE

Drugs as volatile oils, creosote, phenol, and chloral

hydrate lower the melting point of cocoa butter.

To correct this condition, wax and spermaceti are

commonly used.

Low contractility during solidification causes the

suppositories to adhere to molds and necessitates the

use of mold release agents or lubricants.

Cacao butter exhibits different polymorphisms

each

has different melting points

Each of the different forms of cocoa butter has

different melting points, and different drug release

rates.

When cocoa butter is heated above its melting

temperature (36°C) and chilled to its solidification

point (below 15°C), immediately after returning to

room temperature this cocoa butter has a melting

point of about 24°C, approximately 12° below its

original state.

Cocoa butter is primarily a triglyceride.

A phenomenon due to the high proportion

of unsaturated triglycerides is that it

exhibits polymorphism (the property of

existing in different crystalline forms).

Cocoa butter is thought to be capable of existing in four crystalline states:1.The α form

Obtained by suddenly cooling melted cocoa butter to 0°C. It melts at 24°C 2. The β’ form Crystallizes out of the liquefied cocoa butter with stirring at 18 to 23°C. Its melting between 28 and 31°C.3. The β’ form

Changes slowly into the stable β form which melts between 34 and 35°C. This change is accompanied by a volume contraction.

4. The γ form Melting at 18°C Obtained by pouring a cool (20°C) cocoa butter, before it solidifies, into a container which is cooled at deep freeze temperature.

The formation of various forms of cocoa butter

depends on:

The degree of heating

The cooling process

The conditions during this process.

At temperatures below 36°C, negligible amounts of

the

unstable forms are obtained

But prolonged heat above that critical temperature

causes

the formation of the unstable crystals with resulting

lowered melting points. Thus, prolonged heating in

the

process of melting the fats must be avoided

The reconversion to the stable β form takes one to

four

days, depending on the storage temperature, the

higher the

temperature, the faster the change.

The formation of the unstable forms can be

avoided by:

1. If the mass is not completely melted, the remaining

crystals prevent the formation of the unstable

form.

2. Small amounts of stable crystals added to the

melted

cocoa butter accelerate the change from the

unstable to

the stable form; this process is called “Seeding."

3. The solidified melt is tempered at temperatures

between

28 and 32oC for hours or days, causing a

comparatively

quick Change from the unstable to the stable form.

Cocoa Butter Substitutes

Cocoa butter substitutes maintain the desirable

properties of cocoa butter and eliminate the

undesirable ones.Treatment of Vegetable Oils to Produce Suppository Bases

Synthetic or natural oils as vegetable oils as coconut

or palm kernel oil are modified by:

Esterification, hydrogenation and fractionation at

different melting ranges to obtain the desired

product.

It is an inexpensive method

Hydrogenation of oil as corn oil to reduce the

unsaturation

and so increase the percentage of solid triglycerides

at

room temperature.

The triglycerides with lower melting points are

removed by

solvent extraction or by pressing.

This type of fat products are referred to as "hard

butter."

Hydrogenation

Interesterification of oils as coconut oil, palm

kernel oil,

and/or palm oil (all chosen for their high content of

lauric

acid moieties) are refined to remove free fatty

acids,

deodorized to remove volatiles, hydrogenated as

described previously, and then interesterified.

This final step, catalyzed by sodium methoxide,

more

equally distributes the fatty acid moieties among

the

glycerin molecules, creating more common

triglycerides,

and therefore a more narrow melting range.

Interesterification

First, the oil is split into fatty acids and glycerin by

treatment with high-pressure steam.

The glycerin is removed from the mixture, and the

remaining free fatty acids consist of C6-C18 chain

length compounds are (caproic, caprylic, capric,

lauric, myristic, palmitic, oleic, and stearic acids).

Caproic, caprylic, and capric acids are removed by

fractional vacuum distillation, because they are

readily rancidified and may cause irritation of mucous

membranes.

The remaining fatty acids, consisting mainly of

lauric acid, are hydrogenated to harden the mixture

and lower its iodine value.

Re-esterification

Hydrophilic Suppository Bases

Glycerin Suppositories Glycerinated gelatin suppositories do not melt at

body temperature but dissolve in the secretions of

the body cavity in which they are inserted (vaginal or

rectal).

Solution time is regulated by the proportion of

gelatin/glycerin/water used, the nature of the gelatin

used, and the chemical reaction of the drug with

gelatin.

Glycerinated gelatin suppositories support mold or

bacterial growth, thus, they are stored in a cool place

and often contain agents that inhibit microbial

growth.

Because glycerin is hygroscopic, these suppositories

are packaged in materials that protect them from

environmental moisture.

The Polyethylene Glycols (Carbowax and Polyglycols)

Long-chain polymers of ethylene oxide have the

general formula HOCH2 (CH2OCH2)X CH2OH

When their average molecular weight ranges from

200 to

600 they exist as liquids, and as wax-like solids

when

their molecular weights are above 1000.

Their water solubility, hygroscopicity, and vapor

pressure

decrease with increasing average molecular

weights.

The wide range of melting points and solubilities

makes

possible to formulate suppositories with various

degrees

of heat stability and different dissolution rates.

Several combinations of polyethylene glycols have

been prepared for suppository bases having different

physical characteristics .

Base 1

Polyethylene glycol 1000 96 %

Polyethylene glycol 4000 4 %

Base 2

Polyethylene glycol 1000 75 %

Polyethylene glycol 4000 25 %

This base has low-melting and require refrigeration.It is useful when rapid disintegration is desired.

More heat stable than Base 1 and stored at higher temperatures.It is useful when a slow release of active ingredients is desired.

Polyethylene glycol suppositories do not require a

mold lubricant and are easier to prepare than cocoa

butter suppositories.

They are physiologically inert, do not hydrolyze or

deteriorate and do not support mold growth.

ADVANTAGES of POLYETHYLENE GLYCOL

as SUPPOSITORY BASE

Most patients do not feel discomfort from the use

of these suppositories, because this type of Bases

cause irritation "sting“ to mucous membranes when

water drawn from the mucosa. This irritation may be

eliminated by dipping in water before insertion or by

addition of 10% water to facilitate solution of the

suppository after insertion.

DISADVANTAGES of POLYETHYLENE GLYCOL

as SUPPOSITORY BASE

The polyethylene glycol suppositories cannot be

prepared by hand rolling but prepared by both

molding and cold compression methods.

Special precautions are necessary in

preparing a molded suppository with the polyethylene

glycol bases.

The mold must be dry because the base is soluble in

water.

The suppository will be fissured owing to the

crystallization and contraction of the polymer. Such

suppositories may be easily fractured in packaging

or

handling. To solve this problem the melted mass

must be

allowed to cool to the congealing point before

pouring.

Water-Dispersible Bases

The surfactants most commonly used in suppository

formulations are the polyoxyethylene sorbitan fatty

acid esters (Tween), the polyoxyethylene stearates

(Myrj) and the sorbitan fatty acid esters (Span and

Arlacel). These surface active agents may be used

alone, blended, or used in combination with other

suppository vehicle materials to yield a wide range

of melting points and consistencies.

These are nonionic surface active materials, related

chemically to the polyethylene glycols.

Can be used for formulating both water-soluble

and oil-

soluble drugs.

Can be stored and handed at elevated

temperatures

Have broad drug compatibility.

Nonsupport of microbial growth, nontoxic and not

cause

sensitivity.

ADVANTAGES of WATER-DISPERIBLE BASES as SUPPOSITORY BASE

Caution must be taken in the use of surfactants

with drugs

due to the increase in the rate of drug absorption.

These surface active agents can show interaction

with

drugs and a consequent decrease in therapeutic

effects.

DISADVANTAGES of WATER-

DISPERIBLE BASES as SUPPOSITORY

BASE

Compressed Tablet Suppositories

Rectal suppositories usually are not compressed

as tablets, because the amount of liquid in the

rectal cavity is insufficient for tablet disintegration.

Effervescent tablets aid disintegration, as carbon

dioxide releasing laxative suppositories.

This compressed rectal suppository is coated

with water-soluble polyethylene glycol to aid

in insertion into the rectum.

The compressed tablet for vaginal use weighing

about 3 g with almond shape to ease insertion. The

moisture level of the vagina is sufficient for

disintegration and dissolution.

A typical vaginal tablet contains active ingredients,

with boric and/or phosphoric acid for adjusting the

acidity of the vagina to pH 5. Vaginal suppositories

are usually used for systemic or topical therapy, as

in the treatment of vaginitis, or as a spermatocide.

Soft gelatin capsules filled with liquid or solid

drugs used for vaginal use.

The suppositories are non-melting,

but dissolve in body fluids.

Unusual Types of Suppositories

Layered suppository has an outer shell with 37 to 38°C

melting point and a core with 34 to 35°C melting point.

This is prepared by dipping the suppository in the

coating solution until the desired coating thickness is

obtained. Each layer contains different drugs or used to

prevent coalescing of adjacent suppositories during

storage.

The layering also may be multilayering in the

horizontal plane. This is prepared by partially filling the

mold, allowing the mass to congeal, and pouring

additional layers. Multilayered suppositories used for

separating incompatible drugs in different layers and

providing different melting characteristics for

controlling the rate of drug absorption.

Glycerinated gelatin suppositories are hygroscopic,

they lose moisture by evaporation in dry climates

and absorb moisture under conditions of high

humidity.

Polyethylene glycol bases are hygroscopic, the rate

of moisture change in polyethylene glycol bases

depends on humidity, temperature and on the chain

length of the molecule. As the molecular weight

increases, the hygroscopicity decreases.

Hygroscopicity

Formulation of Suppositories

Use of water as a solvent for incorporating

substances in suppository bases should be avoided

for the following reasons.

1. Water accelerates the oxidation of fats.

2. If the water evaporates, the dissolved substances

would crystallize out.

3. Reactions between ingredients are more likely to

occur

in the presence of water.

4. Bacterial or fungal growth necessitates the

addition of

bacteriostatic agents as parabens.

Water in Suppositories

Polyethylene glycol are incompatible

with

silver salts,

tannic acid, aminopyrine, quinine, ichthammol,

aspirin,

benzocaine, iodochlorhydroxyquin, and

sulfonamides. Many chemicals have a tendency to crystallize out

of

polyethylene glycol, e.g. sodium barbital, salicylic

acid,

and camphor. Higher concentrations of salicylic acid soften

polyethylene

glycol to an ointment-like consistency, and aspirin

complexes with it. Penicillin G, although stable in cocoa butter and

other

fatty bases, decomposes in polyethylene glycol

bases. Fatty bases with significant hydroxyl values may

react

with acidic ingredients.

Incompatibilities

The viscosity of the melted suppository mass is

important in the manufacture of the suppository and

to its behavior in the rectum after melting.

Melted cocoa butter and some of its substitutes

have low viscosities, whereas the glycerinated gelatin

and polyethylene glycol type base have viscosities

considerably higher than cocoa butter.

Viscosity

In the manufacture of suppositories made with

low-viscosity bases, extra care must be exercised to

avoid the sedimentation of suspended particles. Poor

technique can lead to nonuniform suppositories,

particularly in the distribution of active ingredients.

To prevent segregation of particles suspended in

molten bases, the well-mixed mass should be handled

at the lowest temperature necessary to maintain

fluidity, constantly stirred without entrapping air, and

quickly solidified in the mold.

The following approaches may be taken to overcome

the

problems caused by use of low viscosity bases.

1. Use a base with a more narrow melting range that

is

closer to body temperature.

2.The inclusion of approximately 2% aluminum

monostearate not only increases the viscosity of the

fat base considerably, but also aids in maintaining a

homogeneous suspension of insoluble materials.

Cetyl, stearyl, or myristyl alcohols or stearic acid are

added to improve the consistency of suppositories.

Suppositories made from cocoa butter are elastic and do

not fracture.

Synthetic fatty bases with a high degree of hydrogenation

are more brittle. Fracturing of the suppository made with such bases is induced by rapid chilling (shock cooling) of the melted bases in an extremely cold mold.

Brittle suppositories have problems in manufacturing,

handling and wrapping.

To overcome this difficulty, the temperature differential between melted base and mold should be as small as possible. Addition of a small amount of Tween 80, Tween 85, fatty acid monoglycerides, castor oil, glycerin, or propylene glycol increases its plasticity and renders it less brittle.

Brittleness

To calculate the amount of drug per suppository,

the density of the base must be known.

The volume of the mold cavity is fixed, and therefore,

the weight of the individual suppository depends on

the density of the mass.

Knowledge of the suppository weight can be

obtained from a given mold and density of the chosen

base; the active ingredients can then be added to the

bulk base in such an amount that the exact quantity

of drug is present in each molded suppository.

Density

If volume contraction occurs in the mold

during cooling, additional compensation

must be made to obtain the proper suppository

weight.

Thus, density alone cannot be the sole criterion for

calculating suppository weight per fixed volume mold.

When volume contraction occurs, the suppository

weight is determined empirically by small batch runs.

This phenomenon occurs in many melted

suppository bases after cooling in the mold.

The results are manifested in the following two ways.

1. Good mold release. This is caused by the mass

pulling away from the sides of the mold. This

contraction facilitates the removal of the suppositories

from the mold, eliminating the need for mold release

agents.

Volume Contraction

2. Contraction hole formation at the

open end of the mold. This

undesirable feature results in

lowered suppository weight and

imperfect appearance of the

suppository. The contraction can be eliminated by pouring a mass

slightly above its congealing temperature into a

mold warmed to about the same temperature. In

volume production using standard molds, where

adequate control of temperature may not be

feasible, the mold is overfilled so that the excess

mass containing the contraction hole can be scraped

off.

Cocoa butter adheres to suppository

molds because of its low volume contraction.

These suppositories are difficult to remove from the

molds, and various mold lubricants or release agents

must be used to overcome this difficulty.

Mineral oil, an aqueous solution of sodium lauryl

sulfate, various silicones, alcohol, and tincture of

green soap are examples of agents employed for this

purpose.

They are applied by wiping, brushing, or spraying.

The release of suppositories from damaged molds

was improved by coating the cavities with polytetra

fluoroethylene (Teflon).

Lubricants or Mold Release Agents

The amount of base that is replaced by active

ingredients in the suppository formulation can be

calculated.

The replacement factor, f, is derived from the

following equation:

where: E = weight of pure base suppositories

G = weight of suppositories with X% active

ingredient

Dosage Replacement Factor

f = 100 (E - G) + 1

(G)(X)

The amount of active ingredient in each suppository

depends on:

Its concentration in the mass;

The volume of the mold cavity;

The specific gravity of the base;

The volume variation between molds, good

machining of

the molds should keep the volume of each cavity

within

2% of a desired value;

Weight variations between suppositories due to

the

inconsistencies in the manufacturing process,

e.g., incomplete closing of molds, uneven

scrapings.

Regardless of the reason for the variation in

weight, it

should be within ±5%.

Weight and Volume Control

The German and Russian Pharmacopeias state

individual weight variations of rectal suppositories

at ±5% of the average weight.

The Pharmacopeia Nordica allows ± 10% of the

average weight for 90% of the suppositories, but

these deviations must not exceed ±20%.

Confusion may take place between the acidity of

fats with rancidity.

The presence of free fatty acids is no indication of

rancidity or that such a product may become rancid.

Rancidity results from the autoxidation and

decomposition of unsaturated fats into low and

medium molecular weight

saturated and unsaturated aldehydes, ketones and

acids, which have strong, unpleasant odors.

Rancidity and Antioxidants

The lower the content of unsaturated fatty acid

constituents in a suppository base, the greater is its

resistance to rancidity.

Since this reaction begins with the formation of

hydroperoxides, the measure of autoxidation is the

peroxide value (active oxygen) which is a measure

of the iodine liberated from an acidified solution of

potassium iodide by "peroxide oxygen" of the fats.

Examples of effective antioxidants:

Phenols: such as m- or p-diphenols; α-naphthol;

Quinones: such as hydroquinone or β-

naphthoquinone;

Tocopherols: particularly the α and β forms;

Gossypol present in cottonseed oil;

Sesamol present in sesame oil;

Propyl gallate and gallic acid;

Tannins and tannic acid;

Ascorbic acid and its esters;

Butylhydroxyanisole (BHA) and butylhydroxytoluene

(BHT).

An Approach in Formulating SuppositoriesThe important considerations of the formulator are:

Is the medication intended for local or systemic use?

Is the site of application rectal, vaginal or urethral?

Is the desired effect to be quick or slow and prolonged?

Preliminary suppository bases to be studied are first

evaluated by measuring drug availability from the

suppository in water at 36 to 37°C.

Availability and cost of the suppository bases

Stability of both active ingredients and base at 4°C

and

room temperature.

Ease of molding and release in the manufacturing

equipment.

Toxicity (irritancy) and drug availability are measured

in

animals before the medication is ready for human

clinical trials.

Suppositories for Systemic Effect The drug should be homogeneously dispersible

in base used it, but releasable at the desired rate to

the aqueous body fluids surrounding the

suppository.

Therefore, the solubility of the active ingredient in

water or other solvents should be known.

If the drug favors water, a fatty base with low water

number may be preferred.

On the other hand, if the drug is highly fat-

soluble, a water-type base, with the addition of a

surfactant to enhance solubility may be the

preferred choice.

To enhance the homogeneity of drug in the desired

base, either a suitable solvent is used or the drug is

finely ground before incorporation.

A drug that is soluble in a minimal quantity of

water, or in another liquid miscible with the base,

can be dissolved and the solution added to the

molten base.

If the drug is to be incorporated directly into the

base, it should be finely ground so that 100% can be

passed through a 100-mesh USP screen.

Fragility, brittleness tests must be performed.

The theoretically desirable suppository formulations

are molded in the laboratory and stored at room

temperature (25 ± 3°C) for at least 48 hours before in

vitro testing for release rate.

In-vitro release rates as a quality control procedure

and the suppository formulation chosen yields the in

vitro release rate pattern that is to be used as the

desired standard.

Chemical and physical stability, consistency of in

vitro drug release patterns within theoretically desired

ranges, and animal toxicity are some characteristics

studied before suppository formulas are chosen for

human clinical trials.

The suppositories are stored at room

temperature (25 ± 3°C) and at 4°C for prolonged

stability tests. They are tested at regular intervals

(1- ,3-, and 6-month and 1- and 2-year periods) for

changes in appearance, melting and softening range,

drug stability, base stability, and in vitro drug

release pattern.

In vivo clinical findings in man are the last criteria

for choosing a desired formulation. The clinical

findings may be based on blood levels of the drug

and/or desired clinical effects in man.

Suppositories for Local Effect

Drugs intended for local action are generally non-

absorbable, e.g., drugs for hemorrhoids, local

anesthetics, and antiseptics.

The bases used for these drugs are virtually non-

absorbable, slow in melting, and slow in drug

release, as contrasted with suppository bases

intended for systemic drugs.

Local effects are generally delivered within

a half hour and last at least 4 hours.

The desired base should release an adequate

amount of drug within a half hour, and completely

melt with release of all drug between 4 and 6 hours.

A suppository that does not melt within the 6-hour

test period would probably not completely release

its drug, cause discomfort to the patient and be

expelled by the patient before it is fully utilized.

Tests in animals must show no irritancy if the

suppository is to be used in man.

Manufacture of SuppositoriesThree methods are used in preparing

suppositories:

Molding by hand

Compression molding

Pour molding

Hand Molding

The simplest and oldest method of preparing a

suppository is by hand, i.e. by rolling the well blended

suppository base containing the active ingredients into a

cylindrical rod of desired length and diameter, or into

vaginal balls of the intended weight.

Starch or talc powder on the rolling surface

and hands prevent the mass from adhering.

The rod is cut into portions, and one end is pointed.

This method is practical and economical for the

manufacture of small numbers of suppositories.

Compression Molding A more uniform and pharmaceutically elegant

suppository can be made by compressing the

cold

mass into a desired shape.

A hand turned wheel pushes a piston against

the

suppository mass contained in a cylinder, so

that the

mass is extruded into molds (usually three).

Advantages over hand molding method:

It avoids the possibilities of sedimentation of the

insoluble solids in the suppository base

Disadvantages:

Too slow for large-scale production.

Molding fat type base suppositories is air

entrapment.

This makes close weight control impossible and

also

favors the possible oxidation of both the base

and

active ingredients.

Pour MoldingThe most commonly used method for producing

suppositories on both a small and a large scale.

First, the base material is melted, preferably on a water

or

steam bath to avoid local overheating

Then the active ingredients are either emulsified or

suspended in it.

Finally, the mass is poured into cooled metal molds,

which

are usually chrome or nickel-plated.

Packaging of Molded Suppositories

Suppositories must be packaged so that each

suppository is overwrapped, or they must be placed

in a container in that they do not touch each other.

Suppositories usually are foiled in tin,

aluminum, paper and plastic strips.

Poorly wrapped and packaged suppositories can

cause:

Staining, breakage, or deformation by melting

caused by adhesion. Suppositories in direct contact

with one another are spoiled by

fusion resulting from changes in

temperature. Partially melted

suppositories stain the outer

package unless they are

overwrapped or are packaged with

some other barrier that prevents

contact with the outer container.

In-Package Molding Suppositories

It is a method for molding suppositories directly in

their wrapping material either plastic or aluminum

foil.

The tops of the molds are left open for the entrance

of filling nozzles. After the mass has been injected,

the tops are sealed. The strips are then passed in

an upright position through a

cooling station.

The advantages of in-package molding:

High production rates.

No bulk handling or storage of un wrapped

suppositories.

Disposable molds have the additional advantage of

being suited for suppositories intended for tropical

climates. If the mass should melt at the high

storage temperatures, the mold still retains its

proper shape, so that upon cooling it can be

dispensed without deformation.

The disadvantages of in-package molding:

Dependence on the shape of the formed mold