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Semisolid Dosage

Forms :

Definitions,
Types,
Mechanisms Of Drug Penetration,
Factors influencing Penetration,
Semisolid Bases And Their Selection,
General Formulation Of Semisolids & Clear Gels
Manufacturing Procedure,
Evaluation And
Packaging.

Introduction
Semisolid dosage forms usually are intended for localized drug delivery.
In the past few years, however, these forms also have been explored for
the systemic delivery of various drugs.

Semisolids constitute a significant proportion of pharmaceutical dosage


forms.
They also have major applications in cosmetics.

They can be applied topically to the skin, cornea, rectal tissue, nasal
mucosa, vagina, buccal tissue, urethral membrane, and external ear
lining.

Definitions
Semisolid dosage forms are dermatological
preparations intended to apply externally on
the skin to produce local or systemic effect.
Semisolid dosage forms are dermatological products of semisolid
consistency which are applied to skin or mucous membrane for
therapeutic or protective action or cosmetic function.
Pharmaceutical semisolid preparations may be
defined as topical products intended for
application on the skin or accessible mucous
membranes to provide localized and sometimes
systemic effects at the site of application or for
cosmetic functions.

Ex: Ointments , creams , pastes , gels etc

IDEAL PROPERTIES OF SEMISOLIDS


PHYSICAL PROPERTIES

Smooth texture
Elegant in appearance
Non dehydrating
Non gritty
Non greasy and non staining
Non hygroscopic

PHYSIOLOGICAL PROPERTIES

Non irritating
Do not alter membrane / skin functioning
Miscible with skin secretion
Have low sensitization index

APPLICATION PROPERTIES

Easily applicable with efficient drug release.


High aqueous wash ability.

THE SKIN : Structure of skin

SKIN: Summery
Largest multilayer organ.
In adults weighs about 8 lbs.
Covers a surface area exceeding 20,000cm 2 .
Function:
Serves as an barrier for physical and chemical attack.
Plays a role in regulation of blood pressure.

Layers of Skin: 3 tissue layers.


Epidermis.
Dermis.
The subcutaneous fat layer.

Functions of the skin


Protection: an anatomical barrier from pathogens and damage
between the internal and external environment in bodily
defence; Langerhans cells in the skin are part of the adaptive
immune system.
Sensation: contains a variety of nerve endings that react to
heat and cold, touch, pressure, vibration, and tissue injury.
Heat regulation: the skin contains a blood supply far greater
than its requirements which allows precise control of energy loss
by radiation, convection and conduction. Dilated blood vessels
increase perfusion and heatloss, while constricted vessels
greatly reduce cutaneous blood flow and conserve heat.
Control of evaporation: the skin provides a relatively dry and
semi-impermeable barrier to fluid loss . Loss of this function
contributes to the massive fluid loss in burns.

Functions of the skin.


Aesthetics and communication: others see our skin and can assess
our mood, physical state and attractiveness.
Storage and synthesis: acts as a storage centre for lipids and water,
as well as a means of synthesis of vitamin D by action of UV on certain
parts of the skin.
Excretion: sweat contains urea, however its concentration is 1/130th
that of urine, hence excretion by sweating is at most a secondary
function to temperature regulation.
Absorption: the cells comprising the outermost 0.250.40mm of the
skin are "almost exclusively supplied by external oxygen", although the
"contribution to total respiration is negligible".
In addition, medicine can be administered through the skin, by
ointments or by means of adhesive patch, such as the nicotine
patch or iontophoresis. The skin is an important site of transport
in many other organisms.
Water resistance: The skin acts as a water resistant barrier so essential
nutrients aren't washed out of the body

The layers of epidermis


Epidermis is divided into
the following 5
sublayers or strata:
o Stratum corneum
o Stratum lucidum
o Stratum
granulosum
o Stratum spinosum
o Stratum
germinativum (also
called "stratum
basale").

STRATUM GERMINATIVUM: THE BASAL OR


GERMINAL LAYER

Right Above the Dermis.


Basal cells are nucleated, columner and about 6 m wide,
connected by cytoplasmic intercellular bridges.
It is often described as one cell thick, though it may in fact
be two to three cells thick in glabrous (hairless) skin.
Metabolically active Layers of epidermis.
The stratum basale is primarily made up of basal
keratinocyte cells, which can be considered the stem cells of
the epidermis.
They divide to form the keratinocytes of the stratum
spinosum, which migrate superficially.
The cells flatten and shrink as they slowly die from lack of
oxygen and nutrition.
Other types of cells found within the stratum basale
are melanocytes (pigment-producing cells),
Langerhans cells (immune cells), and Merkel cells
(touch receptors).

STRATUM SPINOSUM (Prickly Cell Layer)


Cells of this later are produced by morphological and
histochemical alteration of the cells of basal layer as
they move upward.
Cells are interconnected by fine prickles.
Each prickle encloses an extension of cytoplasm.
Opposing tips of the prickles of the adjucent
cells adhere to form intercellular bridges or
desmosomes.
This link maintains the integrity of epidermis.
The cells flatten and their nuclei shrinks.

THE STRATUM GRANULOSUM (OR GRANULAR LAYER)

It is a thin layer of cells in the epidermis.


Keratinocytes migrating from the underlying
stratum spinosum become known as granular
cells in this layer.
These cells contain keratohyalin granules, which
are filled with histidine- and cystine-rich proteins that
appear to bind the keratin filaments together.
Therefore, the main function of keratohylain
granules is to bind intermediate keratin filaments
together.
At the transition between this layer and the stratum
corneum, cells secrete lamellar bodies (containing
lipids and proteins) into the extracellular space.
This results in the formation of the hydrophobic
lipid envelope responsible for the skin's barrier
properties.

STRATUM LUCIDUM
The stratum lucidum (Latin for "clear layer") is a thin, clear layer of
dead skin cells in the epidermis named for its translucent
appearance under a microscope.
It is readily visible by light microscopy only in areas of thick skin,
which are found on the palms of the hands and the soles of the feet.
Located between the stratum granulosum and stratum corneum
layers, it is composed of three to five layers of dead, flattened
keratinocytes.
The keratinocytes of the stratum lucidum do not feature distinct
boundaries and are filled with eleidin, an intermediate form of keratin.
The thickness of the lucidum is controlled by the rate of mitosis
(division) of the epidermal cells.
In addition, melanocytes determine the darkness of the stratum
lucidum.
The cells of the stratum lucidum are flattened and non-nuclear.
They are surrounded by an oily substance that is the result of the
exocytosis of lamellar bodies accumulated while the
keratinocytes are moving through the stratum spinosum and
stratum granulosum.

STRATUM CORNEUM
The stratum corneum (Latin for 'horny layer') is the
outermost layer of the epidermis, consisting of dead
cells (corneocytes).
The purpose of the stratum corneum is to form a barrier
to protect underlying tissue from infection, dehydration,
chemicals and mechanical stress.
Desquamation, the process of cell shedding from the
surface of the stratum corneum, balances proliferating
keratinocytes that form in the stratum basale.
These cells migrate through the epidermis towards the
surface in a journey that takes approximately fourteen
days.
In the human forearm, about 1300 cells per cm 2 per hour
are shed.
New cells appear on the surface of SC in every 28-30
days.

STRATUM CORNEUM.
Consists of compacted, flattened, dead, keratinized
cells in stratified layers with a density of 1.55.
Rate limiting barrier for inward and outward
movement of chemical substances.
Generally 10 m thick when dry, 40-50 m thick
when fully hydrated, several hundred m thick in
palms of the hands and the soles of the feet.
Dry state composition: 75-85% protein, 15-20% lipid
and 15% water.
Occlusive dressings or creams applied over the skin
prevents natural evaporation of water making SC
highly hydrated and some substances become more
soluble in it.

Dermoepidermal Junction
Situated Below basal cell layer.
The junction serves 3 functions:
1.
Dermal-epidermal adherence
2.
Mechanical Support for epidermis.
3.
Control of passage of cells and some large molecules

.
1.
2.
3.

across the junction.


Barrier function of the junction
For small molecules
For Large molecules
For Cells
No evidence that the junction significantly inhibits the
passage of water, electrolytes and other low molecular
weight materials.

DERMIS or CORIUM

Situated beneath epidermis.


1/8 thick.
Constitutes the main mass of the skin.
Consists of about 80% of protein in a matrix of
mucopolysaccharide ground substance.
Contains and support numerous:
Blood vessels.
Lymphatics.
Nerves.
Epidermal appendages like hair follicles,
sebaceous glands and sweat glands.
Sweat glands are of two types eccrine and apocrine.
Hair follicles covers 1/1000 of total surface roughly.

The subcutaneous fat layer


The subcutaneous tissue also called the hypodermis,
subcutis, or superficial fascia, is beneath dermis which
is beneath epidermis. It is used mainly for fat storage.
The types of cells found in the hypodermis are
fibroblasts, adipose cells, and macrophages.
It acts as padding and as an energy reserve, as well as
providing some minor thermoregulation via insulation.
Quite elastic layer contains arteries and veins in
superficial regions but rest of the portion
contains limited number of capilaries and no
vital organs.

SUBCUTANEOUS TISSUE CONSISTS OF:


Fibrous bands anchoring the skin to the deep fascia
Collagen and elastin fibers attaching it to the dermis
Fat, except in the eyelids, clitoris, penis, much of pinna, and
scrotum
Blood vessels on route to the dermis
Lymphatic vessels on route from dermis
The glandular part of some sweat glands; mammary gland
lie entirely within the subcutaneous tissue (which are modified
apocrine sweat glands)
Cutaneous nerves and free endings
Hair follicle roots
Ruffini and Pacinian corpuscles (mechanoreceptor)
Mast cells
Bursae, in the space overlying joints in order to facilitate smooth
passage of overlying skin
Fine, flat sheets of muscle, in certain locations, including the
scalp, face, hand, nipple, and scrotum, called the panniculus
carnosus

What is penetration ?
Skin penetration is differs from skin
permeation.
skin penetration is the former describes
the passage of an ingredients into the
skin ( to target skin layer).
Skin permeation is the passage of an
ingredient through the skin to the
circulatory system.

Skin Appendages
Skin appendages(ofadnexa) are skin-associated
structures that serve a particular function including
sensation, contractility, lubrication and heat loss.
Hair Follicles.
Sebaceous glands like pilosebaceous glands.
Sweat Glands (Eccrine and apocrine)

Drug Penetration Through Skin


Dermatologic Drug therapy: To produce a desired
therapeutic action at specific sites on the
epidermal tissue.
While certain tropical drugs act primarily on
the surface of the skin.
Like: emollients, antimicrobials and
deodorants.
The target area of most dermatological disorders
lies in the viable epidermis and the upper dermis.
This requires diffusive penetration of the skin or
percutaneous absorption.

PERCUTANEOUS
ABSORPTION.
Skin (percutaneous, dermal) absorption is
a term that describes the transport of
chemicals from the outer surface of the skin
both into the skin and into the systemic
circulation.
Skin absorption is a route by which substances
can enter the body through the skin.
Along with inhalation, ingestion and injection,
dermal absorption is a route of exposure for
toxic substances and route of administration for
medication.

Routes of Penetration
When a drug system is applied tropically,
the drug diffuses out of its vehicle onto
the surface tissues of the skin.
From there, there are 3 portals of entry:
1. Through the follicular region.
2. Through the sweat ducts.
3. Through the unbroken stratum corneum
between these appendages.

Percutaneous absorption
TRANSCELLULAR
PENETRATION (across the cells)
INTERCELLULAR PENETRATION
(between the cells)
TRANSAPPENDAGEAL
PENETRATION (via hair follicles,
sweat and sebaceous glands, and
pilosebaceous apparatus) offers
0.1-1% of total skin area.

Routes of Penetration
Epidermal appendages: hair follicles, sebaceous
glands and sweat glands are scattered sparsely
through out the skin.
Their cross-sectional area 0.1-1% of the skin area.
Sweat glands are of two types eccrine and
apocrine.
Little evidence regarding eccrine glands role in
cutaneous permeability.
Hair follicles covers 1/1000 of total surface roughly.
Thus epidermis represents an area 100-1000 times
more than other routes of entry.

Routes of Penetration
Between transepidermal and
transappendageal the former is the
principle portal of entry for the drugs
absorbed through both the pathways as
pilosebaceous units offer relatively smaller
absorbing surface.

For substances absorbed primarily by


transepidermal route , penetration is rapid
but lesser than GIT absorption and always
followed by some degree of pilosebaceous
penetration.

Interaction between a
given compound and the
skin is physicochemical
in nature and depends
on the condition of the
skin

Thus under the appropriate


conditions, each of the
contending routes of
permeability may change and
may be the overwhelmingly
dominant one.

Mechanism of Penetration
After the application of a substance to the surface of
the skin.
Transient diffusion is shown to be potentially far
greater through the appendages than through the
matrix of stratum corneum.
When Steady state diffusion is reached.
Then diffusion through the matrix of the stratum
corneum is dominant.
Transient diffusion occurs primarily via follicles
and ducts and steady state diffusion primarily
via intact stratum corneum.

Again flux through the


appendegial pathway or
the shunts is difficult to
measure experimentally ,
except possibly through
hair.

Mechanism of Penetration
Diffusion through the stratum corneum is a
passive process with little evidence for the
presence of specialized active transport mechanisms.
This passive diffusion depends upon the
substance being absorbed, dispersion medium
and ambient conditions.
Percutaneous absorption depends :
Epidermal diffusion -> Dermal clearance -> effective
blood flow, interstitial fluid movement, lymphatics
and certain other factors related to dermal
constituents.

Mechanism of Penetration:
Properties of absorbed substance
Hydrophilic drugs and ions undergo absorption through
the polar pathways of the skin.
The polar or porous pathways includes the deformities
in the lipid bilayers and appendegial pathways or
shunt pathway.
The dry skin is positively charged at physiological pH,
thus negatively charged molecules may diffuse more
rapidly across the skin than negatively charged molecules
followed by non-ionic molecules.
For most lipophilic molecules (MW <500 Da) , the
predominant pathway is via the lipid domains.
The drug needs to partition through the lipid region of
the intercellular space or the transcellular lipids to
diffuse across the SC.

The intrafollicular pathway and the


sebaceous glands pathway

*(Mainly for lipid and surprisingly it is for


a charge and large polar molecule) .
sebaceous gland on the total skin surface
represent not more than 0.1% , but some
time it will be the target such as acne
*Delivery System Handbook for Personal Care and Cosmetic Products. By Meyer

Follicle distribution

The polar pathway


This route is believed to be
hydrophilic in natural , it is
composed of aqueous region
surrounded by polar lipids
that create the walls of
microchannels.

The polar pathway


The localization of the
hydrophilic pores is unclear,
but they think that :
1- it is intercellular .
2- it is intracellular keratin .

The polar pathway


We need 3-10 corneocytes to create a
columns that form a cluster.
Corneocytes edges inside each cluster
were found to intercalate extensively
, but neighboring cluster were
separated by gaps of a few
micrometers.

The polar pathway


So know we will say that we have
2 different hydrophilic pathway :
1- inter-cluster rout (within low
penetration resistant)
2- inter-coreocyte pathway (higher
penetration resistance), it is
twisted between coreocyte ,may
be act as an actual channel in
the skin.

it is also thought to be
the route by whitch
water evaporates
through the skin

Factors in Skin Penetration


Absorption of substances through the skin depends on a number
of factors:
Physicochemical properties of the drug, pH, vehicles.
Concentration
Duration of contact
Solubility of medication
Water/Lipid Partition coefficient of the drug.
Molecule size.
Physical condition of the skin: age, area, intact/broken
Part of the body exposed including the amount of hair on the skin.
Small molecules penetrate rapidly than large molecules.
In general the rate of absorption of chemicals through skin
follows the following scheme from fastest to slowest: Scrotal >
Forehead > Armpit Scalp > Back = Abdomen > Palm = under
surface of the foot

OTHER FACTORS AFFECTING


PERCUTANEOUS ABSORPTION
Thickness of skin
Surface area applied

Friction and heat


Occlusion (SC 5-10% water
to 50% water)
- Cover skin surface easily,
mix readily with sebum
-Promotes hydration of skin
Hair follicles.

State of the diseased


skin(pathologic
changes)
Age of the patient
Type of vehicle
Method of
application,
temperature.
A defined duration of
use that maximizes
efficacy and
minimizes adverse
side effects.

Study Methods for Skin Penetration

In vitro Technique:

Diffusion cell. The


passage of drug molecules through the animal or
human skin into the fluid bath below.
Alcohol-water /receptor phase or Sink (Chloroform
and isopropyl myristate) model depending upon the
solubility of the drug in the vehicle and its partition
coefficient into the skin imitating sink.

In Vivo Technique:

Dyes, fluorescence,
radioactive labelling, substance producing specific
chemical reaction, urine analysis but with
disadvantages of their own.

Semisolid dosage forms :


Types

Semisolid dosage forms meant for external application


Semisolid dosage forms subcategorized are as-

Ointments
Creams
Jellies / Gels
Suppositories
Poultices
Plasters
Pastes
Glycero-gelatins
Rigid foams

The suppositories are also included in this category but it is a unit


dosage forms.

Ointments
Ointments are homogenous, translucent, viscous, semi solid
preparation intended for external application to skin or
mucous membranes.
Ointment may be medicated or not.
composed of fluid hydrocarbons meshed in a matrix of
higher melting solid hydrocarbons.
Applied to mucous membrane or skin

Ointment
Medicated ointments: It may be defined as a medicament or
medicaments dissolved, suspended or emulsified in ointment
base.
Use of Medicated ointments: Application of active
ingredients to the skin
Ointment Bases provides Occlusive action.
unmedicated ointment: The ointments are mainly used for
their protective or emollient properties
Uses of unmedicated ointment: Emollient, protectants or
lubricants.
There is no single ointment base which possesses all the
qualities of ideal ointment base, so it become necessary to use
more than one ointment base in the preparation of ointment.

Qualities of ideal ointment


base
It should be inert, odourless & colourless & smooth.
It should be physically & chemically stable.
It should be compatible with the skin & with incorporated
medicaments.
It should be of such consistency that it spread & soften
when applied to skin with stress.
It should not retard healing of wound.
It should produce irritation or sensitization of the skin.

CREAMS
A semisolid dosage form containing one or more drug
substances dissolved or dispersed in either a water-in-oil
emulsion or an oil-in-water or in an other type of waterwashable base.
Viscous semi solid emulsion with opaque appearance as
Contrasted with translucent ointments
Consistency depends on whether the cream is W/O or
O/W
W/O Creams
O/W Creams
Contain lipophyllic
emulsifying agent

Contains hydrophilic
emulsifying agent

Used as emollient or as
cleansing agent

O/W creams are elegant


drug delivery system

creams

These are viscous semisolid emulsions which are meant


for external use.

Cream is divided in to two types namely as


I) Aqueous creams
II) Oily creams

In case of aqueous creams the emulsions are o/w type &


it is relatively non greasy. The emulsifying waxes are
anionic, cationic & non ionic used. Generally
polysorbate, triethanolamine soap are used as
emulsifying agent.

In case of oily creams w/o type & it is relatively greasy.


The emulsifying agent such as wool fat, wool alcohols,
beeswax & calcium soap is used.

The cream should be store in collapsible tube & supplied


in well closed container to prevent evaporation &

pastes

Pastes
are
semisolid
preparations
intended
for
external application to skin.

The pastes are generally very


thick & stiff.

They do not melt at ordinary


temperature & thus forms a
protective coating over the
area where they are applied.

pastes

Pastes are differ from ointment as they


contain a high proportion of finely
powdered medicaments.

Pastes are basically ointments into


which a high percentage of insoluble
solids have been added.

Contains high percentage of insoluble


solid(usually 50% or more)

Pastes are usually prepared by


incorporating solids directly into a
congealed system by levigation with a
portion of base to form paste like mass.

Pastes
They have good adhesion on skin and less greasy.
They function as a protective barrier on the skin for treating deeper rash
or protecting the face or lips from the sun.
They are mainly used as a antiseptic, protective, soothing dressings.
Pastes should be stored & supplied in containers made of materials which
do not allow absorption or diffusion of content.

Gels
i.

Gels are semisolid systems in which a liquid phase is constrained


within a 3D polymeric matrix (consisting of natural or synthetic
gums) in which a high degree of physical/chemical cross-linking has
been introduced.

ii. Gels are aqueous colloidal system of hydrated forms of insoluble


medicaments.

jellies
Jellies are transparent or translucent, non greasy, semi solid
preparations mainly used for external application to skin.
These are also used for lubricating catheters, surgical
gloves & rectal thermometer.
The substance like gelatin, starch, tragacanth, sodium
alginate & cellulose derivatives are used for the formulation
of jellies.
Jellies are of three types namely as
Medicated jellies
Lubricating jellies
Miscellaneous jellies
carrier for spermicidal agents to
be used intra vaginally with diaphargm.

Gels and Jellies


.

Jellies contain more water than


gels.

Poultices
1. These are also known as cataplasams.
2. They are soft viscous wet masses of solid substances applied to skin in order to
reduce inflammation and in some cases to act as a counter irritant.
3. Poultices must retain heat for a considerable time.
4. After heating the preparation is spread on dressing and applied to
the affected area .
5. E.g: Kaolin poultice (B.P.C)

Plasters
These are solid or semi solid masses adhere to the skin when spread up on cotton felt line
or muslin as a backing material.
made by incorporating medicaments in the resinous or waxy bases
which are melted or spread on suitable baking material..
They are generally used to,
Afford protection and medicinal support.
Furnish on occlusive and macerating action.
Bring medication in to close contact with the surface of skin.
Medicated Plaster for Muscle and Joint Pain

Suppositorie
s

It is solid or stiffened semi solid dosage form intended to


insertion on body orifices other than mouth where they
melt , soften and dissolve
and exert local or systemic effect.

Types
Rectal suppositories
Pessaries
Urethral bougies
Nasal bougies
Ear cones

Glycerogelatins
Glycero-gelatins: Glycerogelatins are plastic masses containing
gelatin (15%) , glycerin (40%) , water (35%) and an added medicinal
substance (10%) such as zinc oxide.
Soften the gelatin in water bath for 10 minutes, then heat it on steam
bath until gelatin is dissolved.
Mix the medicinal substance with glycerin and mix with gelatin.
Cool by stirring and congeal.
Before application it is melted and then cooled just above body
temperature and applied on the affected area with a fine brush.
Covered with bandage and allowed to remain in place for weeks.
Example: zinc gelatin boot or pressure bandage.

Rigid Foams
Rigid foams: These are systems in which air or some other gas is
emulsified in liquid phase to the point of stiffening.

Raw Materials in Semisolid


Preparations
The following are the necessary raw materials to
prepare a semisolid dosage form.

Hydrocarbons
Hydrocarbon waxes
Oleaginous Substances
Fatty acids and alcohols
Emulsifiers
Polyols/ Humectants
Insoluble Powders

Hydrocarbons
Hydrocarbons used in semisolid dosage form
preparation are:
Petrolatum: mixture of semisolid hydrocarbons
containing aliphatic, cyclic, saturated, unsaturated,
branched and unbranched substances in varying
proportion.
Available in form of short or long fiber.
Mineral oil obtained from petrolatum: lower
viscosity of oils than petrolatum results in less
tackiness and greasiness and thus preferred in
semisolid dosage form preparation.

Hydrocarbon waxes
Used to increase the viscosity of mineral oil in order
to prevent its separation from an ointment.
Natural waxes include: Paraffin wax, ozokerite,
ceresin a mixture of paraffin and ozokerite wax.
Ceresin has the property to retain oil within a matrix
like structure without the sweating or oozing of oils.
Synthetic waxes have been developed from
vegetable oils and naturally occurring waxes.
They have long hydrocarbon chans C18-C36 long..
Used together with natural waxes.
Ex: Synchrowaxes with gelling characteristics.

Oleaginous Substances
Mono-, di- and Tri- glycerides of mixtures of
unsaturated and saturated fatty acids.
Ex: Peanut oil, almond oil, sesame oil and olive oil.
Trace metal contaminants in the oils may catalyze
oxidation reaction.
Prevented by addition of antioxidants like BHA, BHT
etc.
Anti-oxidants may cause drug imcompatibiliy or
dermal sensitivity.
The exact chemical composition of a particular
vegetable oil varies due to its natural origin, soil,
rainfall, storage, climate etc.

Fatty acids and alcohols


Mixture of related fatty acids.
Like Stearic and palmitic acids and other fatty acids.
A slide change in the ratio of the saturated fatty acids
changes the structure and size of fatty acid crystals thus
solubility.
Thus stearic acid of rigidly controlled purity is used
in many topical preparations.
Steraic acid is used as an emusifier in o/w emulsions.
Stearate soaps of KOH or triethanolamine of 8-20% is also
an emulsifier and the rest increases the consistency.
Creams formed with sodium stearate are much firmer.
Stearyl alcohols, cetyl alcohols are used as auxillary
emulsifiers.

Emulsifiers
Mixed emulsifier systems are preferred.
The combination of a surfactant and an oil soluble
auxiliary emulsifier.
O/W: Triethanolamine stearate soap with cetyl alcohol
W/O: Beeswax and water soluble surface active agent.
The clay, Mg-Al-Silicate has been used as a thickener,
suspending agent and o/w emulsion stabilizers.
Cationic or nonionic emulsifiers for drugs requiring
acid pH .
Nonionic emulsifiers are used in both w/o and o/w
semisolid preparations.

Polyols or Humectants

Protects moisture on the semisolid preparation.


Gives better texture and viscosity of the preparation.
Prevent cream from drying out.
Prevent the formation of crust when the cream is
packed in a jar.
Improves consistency and rub-out qualities when
the cream is applied on the skin.
Increasing amount of humectants content tends to
increase tackiness/stickiness.
Example: Sorbitol 70%>Glycerine>Propylene Glycol
and polyethylene glycol.

Insoluble Powders
Should be uniformly dispersed to ensure homogeneity.
No grittiness.
Decrease in size provides more surface area of the
drug for contact with the dermal site.
Sub-micron size powders show aggregation problem
due electrically charged surface condition after
milling.
Choice of proper crystalline form is important for use
in semisolids.
The maintenance of the selected polymorphic form in
the semi solids.
The components of vehicle and the method of
preparation of the semisolid dosage form affect the
stability of the polymorphic form

SKIN PENETRATION ENHANCERS


Materials that are experimentally studied to increase percutaneous
absortion are know as penetration enhancers or accelerants.
Ex: DMSO, DMA, DMF.
They are hygroscopic , thus swells and increases the hydration of the
Stratum Corneum and permeability.
Surfactants increase the permeability of water through skin by
altering the physical state of water in the skin and increases the
permeation of charged hydrophilic substances.
Ex: Laurate ion (anionic, highest penetration),
Penetration: Anionic>Cationic>Nonionic surfactants.
Salts of fatty acids: carbon length of 10 or less and pH lower than 11.

Vehicles: Mechanism
Vehicles alters the activity of water in the stratum
corneum and influences the stratum corneum/vehicle
partition coefficient.
Grease and oils, occlusive, greatest hydration through
sweat accumulation at the skin-vehicle interface.
Humectants and powders decreases the hydration of
SC thus decreases penetration.
Paraffin prevents trans-epidermal water loss by
diffusion.

Vehicles: Ideal Properties


Low affinity for the penetrant.
Least solubility for the drug.
High vehicle to receptor phase (Stratum
Corneum) partition coefficient.
High activity coefficient.
Solutes held firmly by vehicle (high affinity of the
vehicle), have low activity coefficient and exhibits
slow rate of drug release.
Solute held loosely by the vehicle (less affinity of
the vehicle for the drug substance), have high
activity coefficient and thus faster drug release.

Semisolid Bases: Selection


Criteria

Vehicles/Bases should posses the following


selection criteria.
Desired release rate of the drug substance from
the ointment base.
Desirability of tropical or percutaneous drug
absorption.
Desirability of occlusion of moisture from the skin.
Stability and solubility of the drug in the base.
Effect if any of the drug on the consistency or
other features of the ointment base.
Desire for a base that is easily removed by
washing with water.
Characteristics of the surface to which it is
applied.

Concept

Definition: semisolid preparations


intended for external application are
termed ointments.
Ingredient: drug substance +bases+
adjuvants

Ointment Bases
The earliest ointment bases consisted of fats and
the mixture with other substances.

But modern bases are mostly non-greasy, water


miscible and water washable.

Ointment Bases
Ideal ointment base It should be
1. inert, odourless and smooth.
2. Chemically and physically stable.
3. compatible with skin and incorporated
medicament .
4. Easy to compound and remain stable on storage.
5. Release the medicament efficiently at the site of
application.
5. low sensitization and irritation index.
7. Should not retard healing of the wound.

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

Semisolid: Types of
ointment Bases
The following are the types of ointment bases as
per USP:

Classification of Ointment base

Hydrocarbon/Oleaginous bases.
Absorption Bases.
Emulsion bases.
Water Soluble bases.

Hydrocarbon/Oleaginous bases.
Salient characteristics:
They are: 1. Anhydrous
2. hydrophobic (do not absorb water
easily)
3. insoluble in water.
4. not removable by water.
They consisted of vegetable and animal fats as
well as petroleum hydrocarbons.

(1) hydrocarbon
bases
Hydrocarbon bases (oleaginous bases) are water-free, and aqueous preparations
may be incorporated into them only in small amounts and then with difficulty.
Hydrocarbon bases are retained on the skin for prolonged periods, do not permit
the escape of moisture from the skin to the atmosphere, and are difficult to wash
off.
As such they act as occlusive dressings. They do not "dry out" or change
noticeably upon aging.

Oleaginous/hydrocarbon bases
These bases consist of water soluble hydrocarbons,
vegetable oils, animal fats & wax.
The constituents of hydrocarbon bases are soft paraffin,
hard paraffin & liquid paraffin.
The vegetable oils are mainly used in ointment to lower the
melting point or to soften the bases.
These bases serve to keep the medicaments in prolonged
contact with the skin & also act as occlusive dressings.
They have a low capacity to absorb water & are used
chiefly for their emollient effect.
These bases losing their importance now a days for the
many reason.

hydrocarbon bases : materials

A list of commonly used materials are:


1. Hydrocarbons: Petrolatum (White and yellow),
Liquid paraffin,
Paraffin wax, Microcrystalline
wax, ceresin,
Plastibase.

Hydrocarbons

Petrolatum:
purified mixture of semisolid hydrocarbons from petroleum.
Types: 2. yellow and white soft paraffin (Bleached yellow paraffin).
Melting Point: 38-560C

Hard paraffin:
purified mixture of solid hydrocarbons obtained from petroleum.
colourless, white, translucent, odourless, tasteless wax like
substance.
used to harden or soften ointment base.

Liquid paraffin:
mixture of liquid hydrocarbons obtained by distillation from
petroleum.
Colourless, odourless, tasteless and tranceparent oily liquid.
Soluble in ether and chloroform but insoluble I water and alcohol.

Liquid paraffin is used along with hard and soft paraffin to get a
desired consistency of the ointment.

Petrolatum

a mixture of semisolid
hydrocarbons obtained from
petroleum
an unctuous mass, varying in color
from yellow to white
It may be used alone or in
combination with other agents as
an ointment 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-inoil 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
drug into an oleaginous base.

Mineral Oil
a mixture of liquid hydrocarbons.
It is useful as a levigating
substance to wet and to
incorporate solid substances into
the preparation of ointments that
consist of oleaginous bases as
their vehicle.

hydrocarbon bases: materials

2. Vegetable oils and Animal Fats: Coconut,


peanut, sesame,
almond oil, Bees wax, Lanolin,
Spermaceti Wax
(Sperm Whale).

Anhydrous Lanolin (refined wool fat)


may contain no more than
0.25% of water.
insoluble in water, but mixes
without separation with about
twice its weight of water
The incorporation of water
results in the formation of a
water-in-oil emulsion.

Lanolin (hydrous Wool


Fat
)
a semisolid,
fatlike
substance obtained
from the wool of
sheep.

a water-in-oil
emulsion that
contains between 25
and 30% water.
Additional water may
be incorporated into

Beeswax and spermaceti


They are weak sufactants (W/O) and
used as stabilization agents in O/W
emulsive ointment.

hydrocarbon bases: materials

3. Hydrogenated and Sulphonated oils:


Hydrogenated castor,
cotton seed, soybean, corn
oil.
Hydrogenated sulphonated
castor oil.

hydrocarbon bases bases: materials


Alcohols, Acids and esters:
cetyl alcohol, Stearyl alcohol, Oleyl
alcohol, Lauryl
alcohol, Myristyl Alcohol.
Palmatic Acid, Stearic acid, Oleic acid,
Lauric acid,
Myristic acid.
Glyceryltristearate, Ethyl oleate, Isopropyl
myristicate, Ethylene glycol,
dilaurate/dioleate/distearate
Silicones: polysiloxanes. Ex: Dimethy polysiloxanes.

Disadvantages of oleaginous
bases
They are greasy.
They are sticky & are difficult to remove both from skin &
clothing.
They retain body heat which may produce an
uncomfortable feeling of warmth.
They do not help in the absorption of medicaments.

(2) Absorption
bases
These bases are generally anhydrous substance which
have the property of absorbing considerable quantities
of water but still retaining their ointment like
consistency.
Absorption bases may be of two types:
(1) Non emulsified bases/Anhydrous Bases: those that permit
the incorporation of aqueous solutions, resulting in the
formation of water-in-oil emulsions , e.g. Hydrophilic
Petrolatum and Anhydrous lanolin i.e., Wool fat, wool
alcohol, beeswax & cholesterol.
(2)Water in oil emulsion : those that are already water-in-oil
emulsions (emulsion bases) that permit the
incorporation of small, additional quantities of

These bases are useful as emollients


although they do not provide the
degree of occlusion afforded by the
oleaginous bases.
Absorption bases are not easily
removed from the skin with water
washing.
They are also useful pharmaceutically to
incorporate aqueous solutions of drugs,

Absorption Bases: Raw Materials


Having hydrophilic or water absorbing properties.
Generally anhydrous on w/o emulsion
Has the capability to absorb water more than their
weight.
Ultimately forms w/o emulsion.
Wool fat. (can absorb 50% of its weight of water)
Hydrous wool fat. (contains 30% water, emollient)
Wool alcohol. (contains 30% cholesterol, other alcohols,
emulsifying agent producing w/o emulsion, improves
texture, stability and emollient property of o/w emulsion)
Bees wax. (Yellow or white bees wax, used as a
stiffening agent in ointments and pastes)

Advantages of Absorption bases:


Compatible with large number of medicaments.
Can absorb a large quantity of water or aqueous
substance.
Relatively heat stable.
May be used in their emulsified form or
anhydrous form.
Quite greasy but can be easily removed from skin
compared to hydrocarbon bases.

(3)Water-Removable
Bases
The water removable bases are o/w emulsions
and are referred to as Vanishing Creams.
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

Water Removal
Bases

Absorption
Bases

They are Oil-in water


emulsions.
Example: Vanishing
Cream

They are Water-in-Oil


Emulsions.
Example: Cold Cream

(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 incorporation of nonaqueous or solid

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

Water Soluble bases


Prepared from mixture of low and high molecular
weight polyethylene glycol which range in their
consistency from liquid to solid.
Non-volatile and inert.
Possess the ability to form an emollient surface.
Neither hydrolyze nor deteriorate nor support
mold growth.
Medicaments: Benzoic acid, salicylic acid etc.

Water soluble bases


These are commonly known as greaseless ointment bases.
Selection of appropriate carbowaxes is depend on their
molecular weight.

Adjuvant
s
Antioxidants
Antimicrobial
preservatives

Antioxida
nts
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 antimicrobial preservatives to
the formulation to inhibit the growth of
contaminating microorganisms
These preservatives include: parahydroxybenzoates (parabens), phenols,
benzoic acid, sorbic acid, quaternary
ammonium salts and other compounds.

Preparation of
BothOintments
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

(1)
the
components of the ointment are
incorporation
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

(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.

(3)
emulsification
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.

the water-immiscible components such as the oil and


waxes are melted together in a steam bath to about 70 to
75C
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

Notic
e:
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

ophthalmic
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 eye.
Ointment bases utilized for ophthalmics have a melting or softening 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 permits water and waterinsoluble drugs to be retained within the delivery system.

The advantage and


disadvantage of Ophthalmic
Ointment:
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

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
(a) the desired
release
rate of the
factors,
including
:
particular drug substance from the
ointment base
(b) the desirability for enhancement by
the base of the percutaneous

(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

Selection of The Ointment Base


Dermatological Factor
1.
2.
3.
4.
5.
6.
7.

Absorption and Penetration


Effect on Skin Function
Miscibility with Skin secretion and Serum
Compatibility with Skin Secretion
Freedom from irritant effect.
Emollient properties.
Ease of application and removal.

. Pharmaceutical Factor
1.
2.
3.
4.

Stability
Solvent Properties.
Emulsifying Properties.
Consistency.

Evaluation Of Topical Dosage Form

Creams: bases
These bases are semisolid or have cream like
consistency.
Both o/w or w/o emulsions are used as a
base.
The o/w emulsion base is more popular now
days because ease of application will easily
achieved.
The w/o type of emulsion bases are greasy
& sticky.
The emulsifying ointment is prepared from
emulsifying wax, white soft paraffin & liquid
paraffin.

Creams: Formulation
Cold Cream

Bees Wax. 25 gm
Borax
. 1.25 gm
Mineral Oil . 25.0 gm
Water .. 48.75 gm
Perfume QS
Preservative QS

Vanishing Cream

Stearic Acid . 17.0 gm


Lanolin ..
1.0
Triethanolamine .. 2.0 gm
Borax
4.0 gm
Glycerine
5.0 gm
Water
.. 70.5 gm
Perfume . QS
Preservatives .
qs

Emulsion bases: Creams


Either o/w or w/o emulsions.
W/O emulsion like cold creams are used as emollients.
The aqueous phase hydrates the skin while the oily
phase forms and occlusive covering and prevents water
loss by evaporation.
Serves as bases for medications like ZnO, sulphur etc.
Greasy and sticky.
O/W emulsions like vanishing cream are used as
vehicles for medicinal agents.
Water being external phase they are easy to remove
with water and non-sticky and non-greasy are more
acceptable than W/O emulsions.

Emulsifying agents:
sodium
lauryl sulfate :O/W emulsion
Creams
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:
Monovalent soaps form O/W emulsions while
polyvalent soaps form W/O emulsions.

Sometimes either an amine (such as


triethanolamine) or ammonium hydroxide is
used to neutralize stearic acid to form the
O/W emulsifier triethanolaminestearate/ammonium-stearate.
Bancrofts Rule: the phase where the emulsifier is
most soluble will become the external phase.

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


oleaginous bases.
propylene glycol and water representing the aqueous
phase
Methylparaben and propylparaben are used to preserve
the ointment against microbial growth

Evaluation Of Topical Dosage Form

Pastes: Formulation
Bases Used For Pastes
Hydrocarbon Bases
Water miscible Bases
Water Soluble Bases
Pastes

ointment

Contains large amount of


finely powdered Solids

Contains dissolved/
suspended/emulsified
medicaments

Very thick and stiff

Soft semisolid preparation

Less greasy

More greasy

Forms a protective coating on


the skin

Used both as protective or


emollient

Applied with a spatula or on


lint

Simply applied on skin

Less soft/macerating

More macerating in action

Contains a large amount of


porous powders which allows

Used for the protection of


lesions

Pastes: Bases
1. Hydrocarbon Bases
.
.

Formulated by using liquid and soft Paraffin


Example: Zinc Oxide Paste
ZnO.. 25 gm (Finely
Sifted)
Starch.. 25 gm
(Finely Sifted)
White Soft Paraffin .. 50 gm

Method:
.
.
.
.
.

Melt the white soft paraffin on a water bath.


Separately pass the zinc oxide and starch through sieve no.
20.
Mix the required amount of powder in a mortar.
Add small amount of melted base with continuous trituration
until smooth paste is obtained.
Add the remaining base, triturate until cold and a uniform
paste is obtained.

Pastes: Bases
2. Water Miscible Base
Emulsifying ointment or glycerin is also used as a
water miscible base for the preparation of a paste.
Example:

Resorcinol .. 2.5 gm
Precipitated Sulphur .. 2.5 gm
Zinc oxide finely sifted 20 gm
Emulsifying ointment .. 25 gm

Method
Triturate the fine powders with a small amount of
emulsifying base until smooth and gradually
incorporate the remaining base.

Pastes: Bases
3. Water Soluble Bases
Suitable combination of high and low molecular weight
polyethylene glycols are mixed to obtain desired
consistency.
Example : PEG 400. 60 gm
PEG 4000.. 40 gm
Softens or melts when applied on the skin.
Bases are water soluble.
Water soluble dental paste containing neomycin
sulphate with macrogol base (PEG Base)

Pastes: Preparation and Storage


Method of Preparation: Prepared by
1. Trituration.
2. Fusion.
Trituration is used when the base is semisolid or liquid.
Fusion method is used when the base is solid or
semisolid.
Storage:
1. The pastes should be stored in a well closed container
and in a cool place to prevent loss of moisture.
2. Container should be made up of materials which do
not allow absorption or diffusion

Evaluation Of Topical Dosage


Form
Particle size
Evaluation
of paste

Gels/Jellies: Gelling Agents


Gelling agents are generally organic hydrocolloids.
Gelling agents are:
1.
2.
3.
4.

Natural Gums (Tragacanth, pectin, alginates)


Gelatin.
Cellulose Derivatives (MC, HPC, HPMC, EC)
Carbomers/Carbopols (934, 940, 974, 980)

. Preparation:
.
.
.
.

The gelling agent is added in the aqueous solution of drugs.


The mass is triturated in a mortar until a uniform product is
obtained.
Glass mortar and pestle is used in case of dark colored
drugs.
Whole gum should be preferred over powdered gum for a
clear gel and uniform consistency.

Clear Gels: Formulation and


Manufacturing
Clear Transparent semisolids containing the solubilized
active substances.
Formed by the aid of an gelling agent.
Example: Carbopol 934, 940, 974. Methyl cellulose
Gelling agents like carbopol swells when dispersed in water
and generally in the presence of an alkaline substance like
triethanolamine.

Formulation: Methyl cellulose . 2 gm


carbopol 934.. 500 mg
propylene glycol. 5 gm
Triethanolamine. 2 gm
water
.. Qs upto 100 gm
Method
Disperse Methyl cellulose and carbopol 934 (Triturated with
propylene glycol) in water. Add triethanolamine in carbopol.
Allow the gelling agents to swell and the mix to obtain gel.

Evaluation Of Topical
Dosage Form

Gels: Preservation and Storage


Preservation:
As the Gels contain large amount of water so it is prone
to bacterial and fungal growth.
Antimicrobial agents used to preserve the gels are:
Methyl p-hydroxybenzoate (0.1-0.2%)
Propyl p-hydroxybenzoate (0.05%)
Benzalkonium Chloride (0.02%)
Phenyl Mercuric Nitrate (0.001%)
Storage of Jellies:
Well filled and well closed containers to
minimize evaporation of water, stored n a cool place to
prevent drying out, sterile gels like catheter lubricants
are packed in collapsible tubes.

INDUSTRIAL PROCESSING

Pilot plant or small scale production equipment is


essential in developing a manufacturing procedure for a
production size batch.
The preparation of many batches ranging in size from 2.5
to 25 or more kilograms, for product evaluation and clinical
testing provides opportunity to observe, improve and
correct the variations.
Mixing and stirring operations are critical in the
preparation these can be controlled in 0.5- 1.0kg batches of
finished product.

The electrically operated propeller type mixer can


be manually adjusted and positioned in the laboratory
mixing vessel to achieve maximum turbulence.
The angle of entry of the propeller shaft and the
depth of the propeller can be easily varied in the
laboratory to prevent aeration.
A metal spatula can be held or positioned in the
beaker during mixing to serve as a baffle to increase
turbulence with out entrainment of air.

Aeration should be avoided, since it may lead to


emulsion instability and variation in density with in a
batch.
Entrainment can occur
Homogenizing
Milling stage
Filling equipment
Packaging operation.

Aeration maybe prevented at the primary emulsion step


if one phase is introduced into the other in such a
manner that splashing and streaming are avoided.
Splashing can overcome by careful adjustment of the
mixing conditions and liquid flow pattern.
The incoming liquid should enter the mixing kettle below
the surface of the other liquid.
Completely enclosed kettles are available for the
manufacturing of semisolids which tend to aerate
excessively.
The sealed vessels can also operate under vacuume.
Full feeding hopper is needed otherwise auger will drive
air into the semisolid.

Rheological changes:
Homogenization frequently increases the
consistency of a semisolid emulsion because it
increases the number of emulsified particles.
consistency is affected by
1. Number of passes through the homogenizer.
2. Pressures used for homogenization.

PREPARATION OF OIL AND


AQUEOUS PHASES

The components of the oil mixtures are placed into a


stainless steel steam jacketed kettle,melted and
mixed.
Some of the solid components e.g. stearic acid,cetyl
alchol are available in many different forms like
cakes,flakes or powder. The flakes are more
preferable because of the convenience of handling.
Petrolatum is inconvenient to handle unless it is melted
and transferred by pumping or pouring from its drum.

The oil phase is then strained through several layers


of cheese cloth to remove any foreign matter.
If petrolatum is used as oil phase then it should be
passed through filter medium particularly in
ophthalmic preparations.
The oil phase is transferred by gravity or pump to
the emulsion mixing kettle.

The components of the aqueous phase are dissolved in


the purified water and filtered.
A soluble drug may be added to this aqueous phase.

MIXING OF PHASES
The phases are usually mixed at a temperature of 70
to 720C,because at this temperature intimate mixing
of the liquid phases can occur.
The properties of some emulsions depend on the
temperature at which the phases are mixed.The
initial mixing temperature must be raised above 70 to
72 0C.

Three ways of mixing the phases:


1.Simultaneous blending of the phases.
2.Addition of the discontinuous phase to the continuous phase.
3.Additon of the continuous phase to the discontinuous phase.

The simultaneous blending of the phases requires the


use of a proportioning pump and a continuous mixer.
This method is used for continuous or large batch
operation.
The second method is used for emulsion systems that
have a low volume of dispersed phase.
The third process is preferred for many emulsion
systems.

Low Energy Emulsification


Limited utilization of
thermal and mechanical
energy.
The use of minimum
amount of emulsion
phase in the
emulsification stage can
result in considerable
reduction in energy
requirements and
processing time without
compromising the quality
of the product.
The balance of the
aqueous phase is added
during cooling period thus
saving the cost of heating
the aqueous phase.

Internal
Phase/Disperse
d Phase

Concentrated
Emulsion

Finished
Emulsion

External
Phase Part
(1)

External
Phase Part
(2)

Low Energy Emulsification.


Procedure : In Oil-in-Water emulsion the oil
phase (oil, waxes, fats, preservatives and perhaps
an emulsifier) and a small portion of the water
phase is heated together and mixed.

Atleast 70% of the water phase can be at the cool


dilution stage thus saving energy.

Low Energy Emulsification.. Factors


The quality, stability, rheology and particle size
distribution of the internal phase of the finished
product prepared by low energy mixing will
depend upon:
1. Temperature required to form conc. Emulsion.
2. The ratio of internal and external phase forming the
conc. Emulsion.
3. The phase inversion temperature.
4. Type and intensity of mixing.
5. The rate of addition of the external phase

Equipments used for mixing of phases:


1. Agitator mixers :Sigma mixer and planetary mixer.
2. Shear mixers: Triple roller mill and Colloidal mill.

Sigma blade mixer:


The mechanism of mixing is shearing. The sigma shaped
blades creates high shear.
Advantages:
It creates a minimum dead space during mixing.
.
Disadvantages:
It works at a fixed speed.

Colloidal mill:
It consists of two steel discs.Here one disc rotates and another
one is stationary. When the material is passed through these
discs they get sheared.Thus coarse particles are break down
to small particles due to shear.
Advantages:
1.It can be used in the production of sterile products.
Disadvantages:
1.It is not used for dry milling.
2.Heat is generated during milling.

COOLING THE SEMISOLID EMULSION:


The rate of cooling is generally slow to allow for
adequate mixing while the emulsion is still liquid.
The temperature of the cooling medium in the
equipment should be decreased gradually and at a rate
consistent with the mixing of the emulsion and
scrapping of the kettle walls to prevent formation of
congealed masses of the ointment or cream.

Perfume should be added at 43 to 450c to avoid


chilling the emulsion in case of oil in water type
emulsion.
Perfume should be added at room temperature in
water in oil type emulsion.
If the drug is not added in the aqueous phase then it
should be added in solution form or in the form of
crystals.

STORAGE OF SEMI-SOLIDS
Unless rapid in process methods of analysis are
developed, it is the usual practice to store the
semisolid until the specified quality control tests have
been completed before packaging into appropriate.

containers: tubes, jars, or single dose packets.


A product is considered to be in process until it has
been packaged.

The active substance in the cream or ointment


may react with the storage container unless a
Highly resistant, stainless steel, is used for bulk
storage.
Evaporation of water from a cream must be
retarded; this can be effectively accomplished by
placing non-reactive plastic sheeting in direct contact
with the cream, as well as covering the storage
container with a tight-fitting stainless steel lid.

TRANSFER OF MATERIAL FOR PACKAGING


The semi-solid may be gravity fed, if it is a two-Level
operation or pumped to the filling equipment.
It must be able to resist the shear stress developed
in the transfer of the product, as well as that due to
the mechanical action of the filling equipment.
Once a formal manufacturing procedure has been
established, there should be no deviation from it.
The manufacturing and packaging equipment should be
sanitized following thorough cleaning with detergents.

They should be flushed with chlorinated water,


formalin, or other suitable sterilant followed by a
bacteria-free water rinse.
Water and swab samples should be taken to verify
microbial elimination.

EVALUATION OF
OINTMENTS/SEMISOLIDS
Content uniformity of drug

Penetration

Rate of release of medicament


Absorption of medicament in blood stream
Irritant effect:

OTHER EVALUATION PARAMETERS


FOR SEMI SOLIDS

Packaging & storage


Minimum Fill
Water content
Metal particles
Leakage test
Sterility test
Microbial screening
In Vitro and In Vivo studies

Content uniformity of drug


A known weight of ointment is taken and assayed for amount
of the drug.

Penetration
A weighed quantity of ointment is rubbed over skin for a
given period of time and unabsorbed ointment is collected and
weighed.
The differences in weights represent the amount absorbed.

In Vitro Skin Penetration


Flow through cell
Franz diffusion cell
They mainly have two compartments
1) Donor
2) Receptor
Method:
mouse skin or human cadaver skin.
Placed in between the two compartments.
The passage of semisolid preparation through the epidermal
surface to receptor compartment is measured by,
Detector ( Flow through type )
Sampling ( Franz diffusion cell )

RATE OF RELEASE OF MEDICAMENT


To assess rate of release of medicament, small amount of the
ointment can be placed on the surface of nutrient agar
contained in a Petri dish or alternately in a small cup cut in
the agar surface.
If the medicament is bactericidal the agar plate is
previously seeded with a suitable organism like s.aureus.
After a suitable period of incubation, the zone of inhibition
is measured and correlated with the rate of release.
Another method for finding out release rate is to smear
internal surface of test tubes with thin layers of ointment, fill
the tubes with saline/serum and after a gap of time
estimating the amount of drug present in the serum/saline.

ABSORPTION OF MEDICAMENT INTO BLOOD STREAM

The diadermatic ointment should be evaluated for the


rate of absorption of drug into the blood stream. This
test can be run in-vivo only.
Definite amount of ointments should be rubbed
through the skin. Under standard conditions and
medicaments are estimated in the blood plasma or
urine.

IRRITANT EFFECT
In general no ointment should possess irritant effect on the
skin or mucous membranes the tests for irritancy can be
carried out on the skin and eyes of rabbits or the skin of
human beings.
The irritant effect can also be judged to a certain extent by
injecting the ointment into thigh muscles and under the
abdominal skin of rats. Reaction are noted at intervals of
24,48,72 and 96 hours. Lesions on cornea, iris, conjunctiva
are used for judging the irritancy to the eyes. Presence of
patches on the skin within 2 weeks indicate irritancy to
pressing skin.

DRAIZE TEST
Draize skin irritation test:

A known amount of test substance is introduced


under a one square inch gauge patch,
The patch is applied to skin of 12 albino rabbits, (6
with intact skin) and (6 with abraded skin),
The patch is secured in place with adhesive tape
and the entire trunk of the animal is wrapped with
an impervious material for a 24 hour period,
After 24 hours the patches are removed and
resulting reaction is evaluated for erythema and
edema formation.
The reaction is again scored at the end of 72 hours
and the two readings are averaged.

CONCLUSION FROM DRAIZE TEST

CATEGORY
DRAIZE

CODE

SKIN REACTION

Mild

MLD

Well defined erythema and slight


edema ( edges of area well defined
by definite raising)

Moderate

MOD

Moderate to severe erythema and


moderate edema (area raised
approximately 1 mm)

Severe

SEV

Severe erythema (beet redness to


slight eschar formation (injuries in
depth ) and severe edema ( raised
more than the 1 mm and extending
beyond area of exposure.

DRAIZE EYE IRRITATION


TEST
A known amount of test material is placed in one eye
of each of 6 albino rabbits the other eye remains
untreated, serving as a control.
The eyes are not washed after instillation and are
examined at 24,48 and 72 hours for ocular reaction.
The test is considered positive if ulceration, opacity of
the cornea , inflammation of the iris, swelling of the
conjunctiva occurs.
A substance is an eye irritant if,
4 of six rabbits score positive
it is considered a non irritant if none or only one of the 6
animals exhibit irritation.

CONSISTENCY TEST

PENETROMETRY:

PROCEDURE:
Preparation of test sample: 3 methods (A,B,C)
A: Carefully and completely fill three containers without
forming air bubbles. Level if necessary to obtain a flat
surface.
B: Apply a suitable shear to the samples for 5 min
carefully and completely fill three containers without
forming air bubbles. Level if necessary to obtain a flat
surface.
C: melt 3 samples carefully and completely fill three
containers without forming air bubbles. Level if necessary
to obtain a flat surface.
CAUTION: Store the samples at 25 0.5oC foe 24 hours
unless otherwise prescribed.

Determination Of Penetration :
Place the test sample on the basis
of the penetrometer. Verify that its
surface is perpendicular to the vertical
axis of the penetrating object. Bring the
temperature of the penetrating object to
25 0.5oC and then adjust its position
such that its tip just touches the surface
of the sample . Release the penetrating
object and hold it free for 5 sec. clam the
penetrating object and measure the
depth of penetration. Repeat the test
with 2 remaining containers.

RESULT:
The penetration is expressed in
terms of mm as the arithmetic mean of
the three measurements. If any of the
individual results differ from the mean by
more than 3%,repeat the
test and
express the results of the 6 measurements
as the mean

EVALUATION OF CREAMS
As these products are used widely and for various parts of the
body, stringent evaluation and quality control is essential.
Appearance spread ability, wash ability.

Rheology
Rheology is very important as these creams are marketed in tubes
or containers. The rheology or viscosity should remain constant.
As these products are normally non-Newtonian in nature, the
viscosity can be measured using viscometers used for such liquids.

Rheologic measurements are utilized to characterize the ease


of pouring from a bottle, squeezing from a tube or other
deformable container, maintaining product shape in a jar or
after extrusion rubbing the product onto and into the skin and
pumping the product from mixing and storage to filling
equipment.

Sensitivity
As various types of ingredients are used with occasional use
of antiseptics hormones etc. there is a possibility of
sensitization or photosensitization of the skin. This should be
tested before hand. This test is normally done by patch test
on and can be either open or occlusive. The test sample is
applied along with a standard market product at different
places and effect is compared after a period of time.

Universal
Tests Tests For Creams & Ointments
Quality
Control

1.Universal Tests:
Description:
This includes visual examination to identify changes in color, separation,
crystallization etc., in the final appearance of the product.
The description should specify the content or label claim of the product.

2.Identification:
Quantitative identification of active ingredients in the finished dosage
form.
Methods:
IR
Raman spectroscopy
Chromatography

3.ASSAY:
The quantity of drug present in unit weight or volume of ointment or
cream is determined by:
Spectrophotometric method
Titrimetric method
Chromatographic method
Microbial assays

4.MICROBIAL ASSAYS
Microbial assays are recommended for preparations containing
antibiotics such as:
Amphotericin-B
Bacitracin
Chlortetracycline HCl
Gentamycin sulphate
Method:
Cylindrical plate or plate assays
Turbidimetric or tube assays
5.IMPURITIES:
The impurities arising from degradation of drug substance and during
the manufacturing process of drug product should be assessed and
controlled

II.SPECIFIC TESTS:
1.PH
Creams and ointments contain very limited quantities of water or
aqueous phase,
Hence this test is not always warranted.
Formulation dependent.
Not included in compendia drug product monograph.

2.APPARENT VISCOSITY:
Formulation and/or process dependent.
Not included in compendia drug product monograph.

3.UNIFORMITY OF DOSAGE UNIT:


This test is applicable for dosage forms packaged in single unit containers.
4.Water Content:
Determined by Titrimetric methods.
Reagent: KF reagent

Preparations

Max., allowable Limit of water

Ointments

0.5 to 1.0%

Bacitracin, Nystatin,

NMT 0.5%

Chlortetracycline HCl ointment


Amphotericin-B, Gentamycin
sulphate, Neomycin sulphate,
Erythromycin sulphate, Tetracycline
HCl

Upto 1%

5.ANTIMICROBIAL PRESERVATIVE EFFECT:


Method: Pour plate technique

Solns of different samples

On 14thday

No.of vegetative cells NMT 0.1%


of intial conc

On 28th day

No, of organisms should be below


or equal to intial conc

6.PARTICLE SIZE DETERMINATION:


Dilute preparation with equal volume of glycerol/ liquid paraffin as per
monograph.
Mount on glass slide.
Observe through microscope.
Calculate the no. of particles having max., diameter within stated limit.

III.SPECIFIC TESTS FOR SEMISOLID DOSAGE FORMS:


1.PHASE SEPARATION TEST:
Visual tests.
Done by measuring the volume of separated phases.
2.UNIFORMITY IN CONTAINERS:
Type

Assay Limit

Multiple dose products containing

90-110% of product label

>5gm
Multiple dose products containing
<5gm

90-110% of product label

Procedure:
Expose the product in tube.
Visually inspect product.
Remove a sample of product from top, middle and bottom portions
of the tube.
Perform assay separately
Products Packaged In Containers Other Than Tubes:
Select a syringe such that it reaches bottom of the container.
Remove plunger & cut of bottom of syringe barrel.
Sample from one side of container is slowly withdrawn by slowly
inserting syringe barrel into container until it reaches bottom.

Twist syringe barrel containing sample core and remove barrel.


Insert the syringe plunger and carefully extrude the equal portions
representing Top, middle, bottom of container.
Perform assay separately for each portions

INVITRO DRUG RELEASE STUDIES:


These studies are conducted in order to ascertain the release of drug from
the formulation matrix.
Apparatus: Franz diffusion cell

CONCLUSION:
From this it can be concluded that, though a no. of quality control
tests have been assigned for sold & semisolid dosage forms in IP, BP,
USP yet there occurs some difference between them.
Hence in order to overcome that, the different tests & limits
specified in different pharmacopoeias have to be streamlined and
harmonized in such a way that, tests meets specified limit as per
harmonized one and later meets regulatory requirements of that
particular country.