Semisolid dosage form

Murat Kizaibek

Ointments

Ophthalmic ointments

Suppository

ointments

Concept

Ointment base

Adjuvants

Preparation of ointments

Quality control of ointments

Concept

• Definition: semisolid preparations intended for exter

nal application are termed ointments.

• Ingredient: drug substance +bases+ adjuvants

Classification

According to the

dispersion system:

(1) solutions type

(2) suspension type

(3) emulsions type

According to the bases:

(1) oleaginous dosage form

(2) emulsions dosage form

(3) pastes dosage form

(4) collodions dosage form

(5) ophthalmic dosage form

Quality requirement

the product is required smooth and uniform with

certain stickiness to skin

the drug in bases even distributed

stability of the ointment

Skin infection preparations are designed to be sterile

Ointment bases

Ointment bases are classified into four general groups:

• (1) Hydrocarbon bases

• (2) Absorption bases

• (3) Water-Removable Bases

• (4) Water-Soluble Bases

(1) hydrocarbon bases

Hydrocarbon bases (oleaginous bases) are water-free, and a

queous preparations may be incorporated into them only in s

mall amounts and then with difficulty.

Hydrocarbon bases are retained on the skin for prolonged pe

riods, do not permit the escape of moisture from the skin to t

he atmosphere, and are difficult to wash off.

As such they act as occlusive dressings. They do not "dry ou

t" or change noticeably upon aging.

• Petrolatum

a mixture of semisolid hydrocarbo

ns obtained from petroleum

an unctuous mass, varying in color

from yellow to white

It may be used alone or in combina

tion with other agents as an ointme

nt base

Commercial product is Vaseline

• Paraffin

A purified mixture of solid hydrocarbons obtained from petroleum.

A colorless or white, more or less translucent mass that may be used

to harden or stiffen oleaginous semisolid ointment bases.

• Liquid paraffin• a colorless, odorless

oily liquid consisting of a mixture of hydrocarbons obtained from petroleum

• has the same character with paraffin

• be used in combination with paraffin to adjust viscosity

•Hydrophilic Petrolatum is composed of cholesterol, stearyl alcohol, white wax, and white

petrolatum

has the ability to absorb water, with the formation of a water-in-o

il emulsion.

Aquaphor is a highly refined variation of Hydrophilic Petrolatum

and because it can absorb up to 3 times its weight in water, it has

proven useful to incorporate extemporaneously a water-soluble d

rug into an oleaginous base.

may contain no more than 0.25

% of water.

insoluble in water, but mixes wi

thout separation with about twi

ce its weight of water

The incorporation of water resu

lts in the formation of a water-i

n-oil emulsion.

Anhydrous Lanolin (refined wool fat)

a semisolid, fatlike substance

obtained from the wool of she

ep.

a water-in-oil emulsion that c

ontains between 25 and 30%

water.

Additional water may be inco

rporated into lanolin by mixi

ng.

Lanolin (hydrous Wool Fat )

• Beeswax and spermaceti

They are weak sufactants (W/O) and used as stabilizati

on agents in O/W emulsive ointment.

Mineral Oil

• a mixture of liquid hydrocarbons.

• It is useful as a levigating substan

ce to wet and to incorporate solid

substances into the preparation o

f ointments that consist of oleagin

ous bases as their vehicle.

(2) Absorption bases

Absorption bases may be of two types:

(1)those that permit the incorporation of aqueous solut

ions, resulting in the formation of water-in-oil emuls

ions (e.g. Hydrophilic Petrolatum and Anhydrous lan

olin) and those that are already water-in-oil emulsio

ns (emulsion bases) that permit the incorporation of

small, additional quantities of aqueous solutions (e.g.

lanolin and Cold Cream).

These bases are useful as emollients although they do

not provide the degree of occlusion afforded by the ol

eaginous bases.

Absorption bases are not easily removed from the ski

n with water washing.

They are also useful pharmaceutically to incorporate

aqueous solutions of drugs, e g., sodium sulfacetamid

e, into oleaginous bases.

(3)Water-Removable Bases

oil-in-water emulsions that are capable of being washed from skin or clothing with water. For this reason, they are frequently referred to as "water-washable" ointment bases

may be diluted with water or with aqueous solutions.

have the ability to absorb serous discharges in dermatologic conditions.

Certain medicinal agents may be better absorbed by the skin when present in a base of this type than in other types of bases.

•Emulsifying agents

sodium lauryl sulfate :O/W emulsion

stearyl alcohol and cetyl alcohol representing the oleaginous phase of the W/O emulsion to improve the stabilization and viscosity.

sodium stearate and calcium stearate.

Glyceryl monostearate: weak W/O emulsifying agents and used as stabilization agents and emollient in the O/W emulsion.

• Spans: W/O emulsifying agents

• Tweens: O /W emulsifying agents

• Peregal O and emulsive OP: O/W

• Stearic acid, beewax and paraffin are the main oleaginou

s bases.

• propylene glycol and water representing the aqueous ph

ase

• Methylparaben and propylparaben are used to preserve t

he ointment against microbial growth

(4) Water-Soluble Bases

• contain only water-soluble components.

• are water washable

• Because they soften greatly with the addition of water,

aqueous solutions are not effectively incorporated into

these bases. Rather, they are better used for the incor

poration of nonaqueous or solid substances.

•Polyethylene Glycol Ointment

Polyethylene glycols are polymers of ethylene oxide

and water

The chain length may be varied to achieve polymers

having desired viscosity and physical (liquid,

semisolid, or solid) form.

The general formula for this base calls for the

combining of polyethylene glycol 3350(a solid) and

polyethylene glycol 400 (a liquid) to prepare base.

Adjuvants

• Antioxidants

• Antimicrobial preservatives

•Antioxidants

preparations Antioxidants

aqueous Sodium sulfite(Na2SO3)

sodium bisulfite(NaHSO3), hypophosphorous acid(H3PO2)

ascobic acid( vitamin C)

oleaginous Alpha tocopherol(vitamin E)

Butylhydroxyanisole(BHA)

ascorbyl palmitate

•Antimicrobial preservatives

frequently require the addition of chemical antimicr

obial preservatives to the formulation to inhibit the

growth of contaminating microorganisms

These preservatives include: para-hydroxybenzoates

(parabens), phenols, benzoic acid, sorbic acid, quater

nary ammonium salts and other compounds.

Selection of the Appropriate Base

The selection of the base to use in the formulation of an

ointment depends upon the careful assessment of a

number of factors, including :

(a) the desired release rate of the particular drug subst

ance from the ointment base

(b) the desirability for enhancement by the base of the

percutaneous absorption of the drug

(c) the advisability of occlusion of moisture from the

skin by the base

(d) the short-term and long-term stability of the drug

in the ointment base

(e) the influence, if any, of the drug on the consistency

or other features of the ointment base.

(f) patient factors also play an important role in a

base's selection

Preparation of Ointments Both on a large and a small scale, ointments are

prepared by three general methods:

(1) incorporation method

(2) fusion method

(3) emulsification method

The method for a particular preparation depends

primarily upon the nature of the ingredients

(1) incorporation the components of the ointment are mixed together by

various means until a uniform preparation has been

attained.

On a small scale, the pharmacist may mix the

components of an ointment in a mortar with a pestle,

or a spatula and an ointment slab (a large glass or

porcelain plate) may be used to rub the ingredients

together.

(2) fusion

By the fusion method, all or some of the components of an

ointment are combined by being melted together and cooled

with constant stirring until congealed.

Those components not melted are generally added to the

congealing mixture as it is being cooled and stirred.

Naturally, heat-labile substances and any volatile components

are added last when the temperature of the mixture is low

enough not to cause decomposition of volatilization of the

components.

• In the preparation of ointments having an emulsion type of

formula, the general method of manufacture involves a

melting process as well as an emulsification process.

(3) emulsification

the water-immiscible components such as the oil and

waxes are melted together in a steam bath to about 70 to

75°C

Meantime, an aqueous solution of all of the heat-stable,

water-soluble components is being prepared in the

amount of purified water specified in the formula and

heated to the same temperature as the oleaginous

components.

Then the aqueous solution is slowly added, with

constant stirring (usually with a mechanical stirrer),

to the melted oleaginous mixture, the temperature is

maintained for 5 to 10 minutes to prevent

crystallization of waxes

the mixture is slowly cooled with the stirring

continued until the mixture is congealed.

Notice:

• If the aqueous solution were not the same

temperature as the oleaginous melt, there would

be solidification of some of the waxes upon the

addition of the colder aqueous solution to the

melted mixture.

Emulsification ointments

Ⅱophthalmic ointments

• Concept

semisolid preparations intended for

application to the eye are specially prepared

and are termed ophthalmic ointments.

•Preparation of ophthalmic ointments

The methods of preparation just like

ointments,but under the aseptic condition

for prevent eye infection.

•The bases

must be non-irritating to the eye and must permit the diffusion of

the medicinal substance throughout the secretions bathing the e

ye.

Ointment bases utilized for ophthalmics have a melting or softeni

ng point close to body temperature.

In most instances, mixtures of petrolatum and liquid petrolatum

(mineral oil) are utilized as the ointment base.

Sometimes a water-miscible agent as lanolin is added. This per

mits water and water-insoluble drugs to be retained within the del

ivery system.

•The advantage and disadvantage

The primary advantage of an ophthalmic ointment

over an ophthalmic solution is the increased ocular

contact time of the drug.

One disadvantage to ophthalmic ointment use is the

blurred vision which occurs as the ointment base

melts and is spread across the lens.

Suppositories

Suppositories are semisolid dosage forms intended for

insertion into body orifices where they melt, soften, or

dissolve and exert localized or systemic effects.

1.Definition

Suppositories are commonly employed rectally, vagi

nally and occasionally urethrally.

They have various shapes and weights depending up

on the density of the base and the medicaments prese

nt in it, and the individual manufacturer's product.

2. Body orifices for using

Rectal using

Vaginal using

Shape of suppositories

3.character of action

Rectal suppositories are most frequently employed to relieve

constipation or the pain, irritation, itching, and inflammation a

ssociated with hemorrhoids or other anorectal conditions.

Vaginal suppositories or inserts are employed mainly as cont

raceptives, antiseptics in feminine hygiene, and as specific a

gents to combat an invading pathogen.

Urethral suppositories may be used as antibacterial and as a

local anesthetic preparative to urethral examination.

1)Local Action

(a) for the relief of nausea and vomiting and as a tranquilizer

(b) for narcotic analgesia

(c) for the relief of migraine syndrome

(d) anti-inflammatory analgesic and antipyretic.

2)Systemic Action

administered rectally in the form of suppositories for

systemic effects include:

3) advantages over oral therapy(rectal route for achieving systemic effects )

(a) drugs destroyed or inactivated by the pH or enzymatic

activity of the stomach or intestines need not be exposed

to these destructive environments;

(b) drugs irritating to the stomach may be given without

causing such irritation;

(c) drugs destroyed by portal circulation may bypass the liver

after rectal absorption (drugs enter the portal circulation

after oral administration and absorption);

(d) the route is convenient for administration of drugs

to adult or pediatric patients who may be unable or

unwilling to swallow medication;

(e) it is an effective route in the treatment of patients

with vomiting episodes.

4.Quality control of suppository

the medicaments and base mixed uniformly with certain

hardness under condition of shipment and storage

capable of being easily inserted into the intended body

orifice without causing undue distension.

once inserted, the base melts, softens, or dissolves,

distributing the medicaments it carries to the tissues of the

region. It must be retained for the appropriate period of time

for local effects or quickly absorbed for systemic effects .

The shape and size of a suppository must be such that

contains drug,base and other adjuvant ,which the affec

ting factors for preparation are the physicochemical n

ature of the drug, the nature of the suppository vehicle

and its capacity to release the drug and clinical desired

effects from administration 。

Drug

properties as the relative solubility of the drug in lipid

and in water , the particle size of a dispersed drug.

Ⅱ Ingredients of suppositories

1.requisites for a suppository base is that :

1)it remains solid at room temperature but softens, melts,

or dissolves readily at body temperature so that the dru

g it contains may be made fully available soon after inse

rtion

2)with certain hydrophilic or hydrophobic character

3)melting point near to solidifying point

4) easily ejectable from mold

5) don’t irritate to the mucous membranes

Base

2.Classification of Suppository Bases

According to bases physical characteristics the

bases can be classified into

(1) fatty or oleaginous bases

(2)water-soluble or water-miscible bases

(1) fatty or oleaginous bases:

Fatty bases are perhaps the most frequently employed s

uppository bases . A lipophilic drug that is distributed i

n a fatty suppository base in low concentration has less o

f a tendency to escape to the surrounding aqueous fluids

than would a hydrophilic substance present in a fatty ba

se to an extent approaching its saturation.

fatty bases contains:

(a) Cocoa Butter and (b) compounds of glycerin

the fat obtained from the r

oasted seed of theobroma c

acao.

At room temperature it is

a yellowish, white solid hav

ing a faint, agreeable choco

late-like odor.

(a) Cocoa Butter

Chemically, it is a triglyceride (combination of gly

cerin and one or different fatty acids) primarily of

oleopalmitostearin and oleodistearin.

It melts between 30 to 36 , an ideal supposito℃ ℃

ry base, melting just below body temperature and

yet maintaining its solidity at usual room tempera

tures.

because of its triglyceride content, cocoa butter exhibi

ts marked polymorphism, or different crystalline for

ms α, β,β’,γ.

Because of this, when cocoa butter is hastily or careles

sly melted at a temperature greatly exceeding the min

imum required temperature and then quickly chilled,

As a result a metastable crystalline form (α crystals)

with a melting point much lower than the original coc

oa butter that the cocoa butter will not solidify at roo

m temperature.

Since the form represents a metastable condition, ther

e is a slow transition to the more stable β form of cryst

als having the greater stability and the higher melting

point.

Cocoa butter must be slowly and evenly melted. Prefe

rably over a water bath of warm water, to avoid the fo

rmation of the unstable crystalline form and ensure th

e retention in the liquid of the more stable β crystals t

hat will constitute nuclei upon which the congealing m

ay occur during chilling of the liquid.

Substances such as phenol and chloral hydrate have a

tendency to lower the melting point of cocoa butter wh

en incorporated with it.

If the mp is lowered to such an extent that it is not feas

ible to prepare a solid suppository using cocoa butler

alone as the base, solidifying agents like cetyl esters w

ax (about 20%) or beeswax (about 4%) may be melted

with the cocoa butter to compensate for the softening

effect of the added substance.

However, the additions of hardening agents must

not be so excessive as to prevent the melting of

the base after the suppository has been inserted

into the body,

nor must the wax material interfere with the

therapeutic agent in any way so as to alter the

efficacy of the product.

The higher molecular weight fatty acids, such a

s palmitic and stearic acids, may be found in fa

tty suppository bases.

Such compounds as glyceryl monostearate and

glyceryl monopalmitate are examples of this ty

pe of agent.

(b) compounds of glycerin

This base is slower to soften and mix with the physiologic fluids , therefore provides a more prolonged release;

Because it have a tendency to absorb moisture due to the hygroscopic nature of glycerin, the suppository must be protected from atmospheric moisture in order for them to maintain their shape and consistency

Due also to the hygroscopicity of the glycerin, the suppository may have a dehydrating effect and be irritating to the tissues upon insertion.

(2) water-soluble or water-miscible bases

(a) Glycerinated gelatin

The water present in the formula for the suppositories

minimizes this action; however, if necessary, the

suppositories may be moistened with water prior to

their insertion to reduce the initial tendency of the

base to draw water from the mucous membranes and

irritate the tissues.

A glycerinated gelatin base is most frequently used in the

preparation of vaginal suppositories, where the prolonged

localized action of the medicinal agent is usually desired.

vaginal suppositories are much more easily inserted than

suppositories with a cocoa butter base, owing to the

brittleness of cocoa butter and its rapid softening at body

temperature.

They are available in a number of molecular weight

ranges, the more commonly used being polyethylene

glycol 200,400, 600,1000,1500,1540, 3350, 4000,6000,

and 8000. The numerical designations refer to the

average molecular weights of each of the polymers.

(b) Polyethylene glycols

Various combinations of these polyethylene glycols

may be combined by fusion, using two or more of the

various types to achieve a suppository base of the

desired consistency and characteristics.

Polyethylene glycol suppositories do not melt at

body temperature but rather dissolve slowly in

the body's fluids.

If the polyethylene glycol suppositories do not

contain at least 20%of water to avoid the irritation

of the mucous membranes after insertion, they

should be dipped in water just prior to use.

a surface-active agent with the average polymer l

ength being equivalent to about 40 oxyethylene u

nits.

The substance is a waxy, white to light tan solid t

hat is water-soluble. Its melting point is generally

between 39℃ and 45 ℃ .

(c) polyoxyl 40 stearate

Ⅲ Preparation of Suppositories

Suppositories are prepared by two methods:

(1) Preparation by compression

(2) Fusion or preparation by mold

(1) Preparation by Compression:

Suppositories may be prepared by forcing the mixed

mass of the suppository base and the medicaments int

o special molds using suppository making machines.

In preparation for compression into the molds, the su

ppository base and the other formulative ingredients a

re combined by thorough mixing, the friction of the p

rocess causing the base to soften into a paste-like consi

stency.

(a)cold Compression:

The process of compression is especially suited for the

making of suppositories containing medicinal

substances that are heat labile and for suppositories

containing a great deal of substances insoluble in the

base.

(b) hand rolling and shaping:

With the ready availability of suppository molds of

accommodating shapes and sizes, there is little

requirement for today's pharmacist to shape

suppositories by hand.

Hand rolling and shaping is a historic part of the

art of the pharmacist.

(2) Fusion or preparation by mold

The method is most frequently employed in the

preparation of suppositories both on a small scale and

on an industrial scale.

Mold shape

Molds in common use today are made from stainless

steel.

The molds, which separate into sections, generally

longitudinally, are opened for cleaning before and

after the preparation of a batch of suppositories.

Care must be exercised in cleaning the mold for the

desired smoothness of the resulting suppositories.

LUBRICATION OF THE MOLD

Depending upon the formulation, suppository molds may require lubrication before the melt is poured to facilitate the clean and easy removal of the molded suppositories.

Lubrication is seldom necessary when the suppository base is cocoa butter or polyethylene glycol.

Lubrication is usually necessary when glycerinated gelatin suppositories are prepared.

Any materials which might cause irritation to the mucous membranes should not be employed as a mold lubricant.

(a) the melting of the base

(b) incorporating of any required medicaments

(c) pouring the melt into molds

(d) allowing the melt to cool and congeal into suppositories

(e) removing the formed suppositories from the mold.

Notice:Suppositories of cocoa butler, glycerinated gelatin,

polyethylene glycol, and most other suppository bases are

suitable for preparation by molding.

the steps in molding

pouring the melt into molds

removing the formed suppositories

Each individual mold is capable of holding a specific volume of material in each of its openings.

If the material is changed, the weight of the resulting suppositories will differ from the weight of suppositories prepared in the same mold because of the difference in the densities of the materials.

Similarly, any added medicinal agent would further alter the densities of the bases, and the weights of the resulting suppositories would be different from those prepared with base material alone.

CALIBRATION OF THE MOLD

It is important that the pharmacist calibrate each of

his suppository molds for the suppository bases that

he generally employs in order that he may prepare

medicated suppositories each having the proper

quantity of medicaments.

First step : to prepare molded suppositories from

base material alone. After removal from the mold,

the suppositories are weighed, and the total weight

and the average weight of each suppository are

recorded as G

Second step :

to prepare molded suppositories from base and

drug. After removal from the mold, the

suppositories are weighed, and the total weight

and the average weight of each suppository are

recorded as M

Third step : to calculate the displacement

value by the equation below:

G

G-(M-W)

W

M

)( WMG

WDV

n

DV

yGx )(

For example:

Prepare the suppositories using cocoa buffer. The

average weight of each blank suppository is 3.5g. Then

adding 1.5g drugs into cocoa buffer and preparing a

medicated suppository. The weight of the medicated

suppository is 4.2g.

Please calculate the dosage of cocoa buffer if 10

medicated suppositories, every medicated

suppositories contain 1.0g drug, want to be prepared.

individually wrapped in either foil or a plastic material. Some

are packaged in a continuous strip with suppositories being

separated by tearing along perforations placed between

suppositories

Suppositories are also commonly packaged in slide boxes or

in plastic boxes.

maintain in a cool place.

stored in environments of fitting humidity

Ⅳ Packaging and Storage

Most commercially available suppositories are:

flash1 flash2

Ⅴ Treating role and Clinical applying

systemic action: medicaments may be intended to be

absorbed for the exertion of systemic effects

local action :medicaments may be intended for

retention within the cavity for localized drug effects.

Systemic Action

For systemic effects, the mucous membranes of

the rectum and vagina permit the absorption of

many soluble drugs. Although the rectum is

utilized quite frequently as the site for the

systemic absorption of drugs, the vagina is not as

frequently used for this purpose.

Absorption route:

According to the course of venous flow, a drug

absorbed in the lower part of the rectum should

enter the vena cava;

A drug placed in the upper part of the rectum

should diffuse into blood vessels which lead to the

liver.

The factors affecting the rectal absorption of a drug admini

stered in the form of a suppository may be divided into :

(1)physiologic factors: colonic contents, circulation route, and

the pH and lack of buffering capacity of the rectal fluids

(2) physicochemical factors of the drug and the base: The lipi

d-water partition coefficient;particle size; nature of the bases

Affecting factors for absorption

GlossaryOintments bases; oleaginous; hydrocarbon bases; absorptio

n bases; water-removable bases;water-soluble bases ; Petrol

atum ; Vaseline; Paraffin ; Anhydrous lanolin ; Hydrophilic;

Antioxidants; incorporation method; fusion method; emulsif

ication method; ophthalmic ointments;

Suppositories; Body orifices ; Rectal; Vaginal; melting point ;

Cocoa Butter ; polymorphism; hygroscopicity; Glycerinated

gelatin ; Polyethylene glycols; polyoxyl 40 stearate; displace

ment value