Semisolid Dosage form
Introduction
• Semisolid dosage forms are products of semisolid
consistency and applied to skin or mucous membranes
for therapeutic or protective action or cosmetic
function.
• Pharmaceutical semisolids include ointments, creams,
pastes, gels, and rigid foams.
• Their common property is the ability to cling to the
surface of application for reasonable duration before
they are washed or worn off.
ointment creams paste gels
Ideal properties of Semi-solid dosage forms
• Smooth texture
• Elegance appearance
• Non dehydrating
• Non gritty
• Non-greasy and non staining
• Non hygroscopic
• Easily applicable with efficient drug release
• High aqueous wash ability
• Non-irritating
• Do not alter membrane/ skin function
• Have low skin sensitization
Advantages
• Avoid of first pass metabolism
• Site specific action of drug on affected area.
• Convenient for unconscious patient or patient having
difficulty on oral administration
• Suitable dosage form for bitter drugs
• More stable than liquid dosage form
Disadvantages
• May cause staining
• They are bulky to handle
• Application with finger may cause contamination
• Physio-chemically less stable than solid dosage form
• May cause irritation
• Allergic to some patients
Types of semisolid dosage form
• Ointment
• Cream
• Paste
• Gels
• Poultices
• Plasters
Ointment
Homogeneous, translucent, viscous, semi-solid
preparation, most commonly a greasy, thick oil
(oil 80% - water 20%) with a high viscosity,
Applied to the skin or mucous membranes.
Uses
• Emollients
• application of active ingredients to the skin
• Occlusive
Creams
• They are viscous semisolid emulsion system
with opaque appearance compared with the
translucent ointments. Consistency and
rheological characters depend on weather the
cream is w/o or o/w.
• Properly designed O/W creams are elegant
drug delivery system, pleasing in both
appearance and feel after application.
• O/W creams are non greasy and are rinsable.
• They are good for most topical purposes.
Paste
• Pastes are basically ointments into which a
high percentage of insoluble solid has been
added. The extraordinary amount of
particulate matter stiffens the system.
• Pastes make particularly good protective
barrier when placed on the skin chemicals
before they ever reach the skin.
• Like ointments, paste forms an unbroken
relatively water – impermeable film. Unlike
ointments, the film is opaque and therefore, an
effective sun block accordingly.
Gels/ Jellies
• Gels are semisolid system in which a liquid phase is constrained
within a three-dimensional polymeric matrix (consisting of
natural and synthetic gums) in which a high degree of physical or
chemical cross-linking is introduced.
• The polymers used to prepare pharmaceutical gels include the
natural gums tragacanth, pectin, carageen,agar and alginic acid
and such synthetic and semisynthetic materials as
methylcellulose, hydroxyethylcellulose, carboxymethylcellulose
and the carbopols.
• Gels are aqueous colloidal suspensions of the hydrated forms of
insoluble medicaments. Gels are thicker than a solution.
• They can use for both external and internal purpose.
• Useful for the scalp and body folds. Avoid cuts and erossions due
to drying and stinging effect of alcohol bases
• Example: Aluminum Hydroxide Gel, used as an antacid.
Poultices
• It is soft, viscous, pasty preparation
for external use. They are applied to
skin while they are warm, after
spreading on or between layers of
cloth . Poultice must retain heat for a
considerable time because they are
intended to supply warmth to inflamed
parts of body.
• Poultices act by increasing blood flow,
relaxing tense muscles, soothing
inflamed tissues, or drawing toxins
from an infected area. Thus, they can
be used to relieve the pain and
inflammation associated with
abscesses; e.g. Kaolin poultice.
Transdermal patch
• Transdermal patches can be a very precise time released
method of delivering a drug. These are devices in the form of
adhesive patches of various shapes and sizes (5-20cm) which
deliver contained the drug at constant rate into the systemic
circulation via stratum corneum.
• The drug (in solution or in bound polymer) is held in a
reservoir between occlusive and baking film and rate
controlling microspore membrane, the under surface of which
smear with and adhesive impregnated with priming dose. The
adhesive layer is backed by another film that is to be peeled of
before been application.
Suppository
Suppositories are medicated, solid bodies of various sizes and
shapes suitable for introduction into body cavities for local or
systemic effect.
Drug delivery system where the medicament is incorporated
into a base (inert) such as cocoa butter which melts at body
temperature, or into one such as glycerinated gelatin PEG
(Polyethylene glycol) which slowly dissolves in the mucous
secretions.
Suppositories are suited particularly for
producing local action, but may also be
used to produce a systemic effect or to
exert a mechanical effect to facilitate
emptying the lower bowel.
Vaginal suppositories are known as
bougies.
Plasters
• Plasters are solid or semisolid masses
made by incorporating medicaments in
resinous or waxy bases which are melted
and spread on suitable backing material
they are mainly used to
– Afford protection and mechanical support.
– Furnish an occlusive and macerating action.
– Bring medication into close contact with the
surface of the skin.
Percutaneous absorption
Percutaneous absorption is defined as penetration of substances
into various layers of skin and permeation across the skin into
systemic circulations. The percutaneous absorption is a step-
wise process and can be divided into three parts:
1. Penetration is the entry of a substance into a particular layer.
2. Permeation is the penetration from one layer into another, and
is different both functionally and structurally from the first
layer.
3. Absorption is the uptake of a substance into systemic
circulation.
Mechanism of Drug Penetration through the skin
Structure of skin
• Epidermis:
o Stratum corneum (Horny cell layer)
o Stratum lucidum (Clear layer)
o Stratum granulosum ( Granular Layer)
o Stratum spinosum (Prickly layer)
o Stratum germinativum
• Dermis:
• Hypodermis or Subcutaneous layer:
Epidermis
The outer layer of skin is made up of Stratified Squamous epithelial
cells. Epidermis is thickest in palms and soles.
• The stratum corneum forms the outer most layer (10-15µm thick )
which consists of many layers of compacted, flattened,
dehydrated keratinized cells.
• The stratum corneum is responsible for the barrier function of the
skin and behaves as a primary barrier to the percutaneous
absorption.
• Water content of stratum corneum is around 20%.
• The moisture required for stratum corneum is around 10% (w/w)
to maintain flexibility and softness.
• It consists of Cermides and neutral lipids such as Sterols, free
fatty acids and triglycerides.
Dermis
• The dermis is made up of regular
network of robust collagen fibers
of fairly uniform thickness with
regularly placed cross striations.
• This network or the gel structure
is responsible for the elastic
properties of the skin.
• It is supplied by blood to convey nutrients, remove
waste & regulate body temp. Drug is well absorbed by
this route.
• Upper portion of the dermis is formed into ridges
containing lymphatics and nerve endings
Subcutaneous tissue
• This is a sheet of the fat containing areolar
tissue known as the superficial fascia, attaching
the dermis to the underlying structures .
Skin appendages
• Sweat glands produces sweat of pH 4-6.8 &
absorbs drugs, secretes proteins, lipids and
antibodies. Its function is to control heat.
Hair follicles
• They have sebaceous glands which produces
sebum and includes glycerides, cholesterol and
squalene.
Transfolicular route
• Fractional area available through this route is
0.1 %
• Human skin contains 40-70 hair follicles, 200
to 250 sweat glands on every [Link]. of skin
area.
• Mainly water soluble substance are diffused
faster through appendages than that of other
layers.
• Sweat glands and hair follicles act as a shunt
i.e. easy pathway for diffusion through rate
limiting stratum corneum .
Transepidermal route
• Epidermal barrier function mainly resides in
horny layer
• The viable layer may metabolize, inactivate or
activate a prodrug.
• Dermal capillary contains many capillaries so
residence time of drug is only one minute.
• Within stratum corneum molecule may
penetrate either transcellularly or intercellularly.
• Intracellular region is filled with lipid rich
amorphous material.
Factors affecting transdermal permeability
• Physiological and pathological condition of the
skin
• Physiochemical properties of drug substances
• Effects of vehicle
• Effects of additives
Physiological and Pathological Condition of Skin
– Reservoir effect of the Horney layer
– Skin condition
– Skin Hydration
– Skin Age
– Blood Flow
– Skin Temperature
– Cutaneous Biotransformation
– Regional Variation
– Lipid Film
Physicochemical properties of drug
substances
– Partition coefficient
– pH-condition
– Drug solubility
– Concentration
– Particle size
– Polymorphism
– Molecular weight
Effect of vehicles
– Viscosity
– pH
– Volatility
Effect of additives
– Surfactants
– Humectants
– Penetration enhancer
Formulation of semisolid dosage forms
Ingredients used in preparation of semisolid
– Active pharmaceutical ingredient (API)
– Bases
– Preservative
– Humectants
– Antioxidants
– Emulsifier
– Gelling agent
– Permeation enhancer
– Buffers
Bases
• It is one of the most important ingredient used
in formulation of semisolid dosage form.
• Ointment and suppository bases do not merely
act as the carriers of the medicaments, but they
also control the extent of absorption of
medicaments incorporated in them.
Ideal properties of a base
• They should be, Inert, non-irritating and non-
sensitizing.
• Compatible with skin pH and the drug.
• Good solvent and/or emulsifying agent.
• Emollient, protective, non-greasy and easily
removable.
• Release medicament readily at the site of
application.
• Pharmaceutically elegant and possess good
stability.
Types of bases
• Oleaginous bases.
• Absorption bases.
• Emulsion bases.
• Water soluble bases.
Oleaginous bases
• They consist of a combination of more than
one oleaginous material such as water-
insoluble hydrophobic oils and fats.
• Most of the early ointment bases used to be
exclusively oleaginous in nature but nowadays
the materials obtained from plant, animal, as
well as synthetic origin are employed as
oleaginous ointment bases.
• Combinations of these materials can produce a
wide range of melting points and viscosities.
Properties of Oleaginous bases
These bases are:
• Immiscible with water (they are difficult to wash off)
• Not absorbed by the skin, remain on the skin for
prolonged period of time without “drying out”
• Absorb very little water from formulation or from skin
exudates.
• Inhibit water loss from the skin by forming a water proof
film (Occlusive dressing).
• Improving hydration, may encourage penetration of the
medication through skin.
Examples: Vaseline, hard paraffin, liquid paraffin,
white ointment
Uses: protectants, emollient, and vehicle for solid
drugs
Absorption bases
Absorption bases (also called emulsifiable bases)
are mostly W/O type emulsions and have
capacity to absorb considerable quantities of
water or aqueous solution without marked
changes in consistency.
Properties of Absorption bases are:
- less occlusive than the hydrocarbon bases.
- Incorporation of aqueous solution is possible.
- easier to spread.
- good emollients
- They hydrate the stratum corneum.
- Not easily removed from the skin with water
washing (external phase is oleaginous)
Examples: Lanolin, anhydrous lanolin, wool fat, wool wax
(obtained from wool of sheep)
bees wax and cholesterol
Uses: protectants, emollient, and vehicle for
aqueous solutions and solid drugs
Emulsion bases
• They are either w/o or o/w.
• Hydrophilic Ointment
• Cold cream: W/O emulsions, emollient,
cleansing, not water washable, non occlusive,
shiny appearance, not need glycerin.
• Vanishing cream: O/W emulsion contains
large % of water and humectant. An excess of
stearic acid in the formula helps to form a thin
film when the water evaporates.
Properties of emulsion bases
– Water-washable, easier to remove
– Non/less greasy
– Can be diluted with water
– Non/less occlusive
– Better cosmetic appearance
– Better compliance; Patients prefer cream to an
– ointment because the cream spreads more readily,
– less greasy, evaporating water soothes the inflamed
tissue.
• Uses: Cleansing creams, emollients and vehicle
for solid and liquid drugs.
Water soluble bases
• These include both anhydrous and hydrous
dermatological non-emulsion bases which are
water soluble and contain no oil phase.
• Water soluble, water washable, greaseless.
• Because they soften with the addition of water,
large amounts of aqueous solutions are not
effectively incorporated into these bases.
• Examples: Carbowax compounds such as the
polyethylene glycol bases containing pectin,
cellulose, Bentonite, and gelatin.
Properties of water soluble bases
The water-soluble bases have the advantages of
being:
- Water soluble and washable
- Non-greasy, non-staining
- Non/less occlusive
- Lipid free
- Relatively inert
- Does not support mold growth
- Little hydrolysis, stable
-Disadvantages: May dehydrate skin and hinder
percutaneous absorption.
Ointment bases
Preservatives
• Some base, although, resist microbial attack
but because of their high water content, it
require an antimicrobial preservative.
• Commonly used preservatives include
– Methyl hydroxybenzoate
– Propyl hydroxybenzoate
– Chlorocresol
– Benzoic acid
– Phenyl mercuric nitrate
Antioxidants
• Oxygen is a highly reactive atom that is
capable of becoming part of potentially
damaging molecules commonly called “free
radicals.”
• Free radicals are capable of attacking the
healthy cells of the body, causing them to lose
their structure and function.
• To prevent this an antioxidants are added.
• E.g. Butylated hydroxy anisole, Butylated
hydroxy toluene.
Gelling agets
• Gelling agents, forms a gel, dissolving in the
liquid phase as a colloid mixture that forms a
weakly cohesive internal structure.
• These are organic hydrocolloids or hydrophilic
inorganic substances.
• E.g. Tragacanth, Sodium Alginate, Pectin, Starch,
Gelatin, Cellulose Derivatives, Carbomer, and
Poly Vinyl Alcohol Clays.
Permeation enhancers
Skin can act as a barrier. With the introduction of
various penetration enhancers, penetration of
the drug through the skin can be improved.
Emulsifier
An emulsifier (emulgent) is a substance that stabilizes an
emulsion by increasing its kinetic stability. One class of
emulsifiers is known as surface active substances, or
surfactants.
Ideal properties of emulsifier includes,
• Must reduce surface tension for proper emulsification.
• Prevents coalescence and should quickly absorb
around the dispersed phase.
• Ability to increase the viscosity at low concentration.
• Effective at low concentration
Emulsifiers
Humectant
• A humectant is a hygroscopic substance. It is often a
molecule with several hydrophilic groups, most often
hydroxyl groups.
• Since hygroscopic substances absorb water from the
air, they are frequently used in desiccation or for
humidity buffering.
• Humectants are used to
a) increase the solubility of the active ingredient.
b) to elevate its skin penetration.
c) To elevate the hydration of the skin.
Buffers
• Buffers are added for various purpose such as
a) Compatibility with skin.
b) Drug solubility.
c) Drug stability.
d) Influence ionization of drug.
• Skin, due to its weak acidic nature, tolerates
weak acidic preparations.
• E.g. sodium acetate, sodium citrate, potassium
metaphosphate.
Ointment manufacturing
• Trituration method
• Fusion method
• Chemical reaction method
• Emulsification technique
Trituration Method
• It is the most commonly
used method for the
extemporaneous
preparation of ointments.
• The medicaments which
are to be incorporated in
the base are generally
insoluble in it.
• Therefore it becomes
necessary to reduce the
medicament to fine powder
otherwise the distribution
of the medicament into the
base will not be uniform.
• In order to obtain the best results the
medicament is triturated with a small amount
of the base on an ointment slab with the help
of a stainless steel spatula with long broad
blade.
• To this the additional quantities of the base
are incorporated and triturated until the
medicament is homogenously mixed with the
base. To remove the gritty particles the
ointment should be passed through an
ointment mill.
Fusion method
• The ingredients of the base are melted together and
properly mixed to obtain a uniform product.
• On small scale, fusion method is carried out in a
porcelain dish, which is placed in a water bath.
• Initially the ingredient of high melting point is
melted.
• Then remaining ingredient of the base are added in
the decreasing order of their melting points and
melted with constant stirring.
• The above mixture is removed from the water bath
and stirred in order to cool it.
• If the drug is soluble in the base, then added slowly in
the melted ingredients and stirred thoroughly until the
mass cools down and a homogenous product is formed.
• If any liquid or aqueous substance is to be added, that
must be heated to about the same temperature as the
melted bases.
• After melting the ingredients and mixing the two
portions they should be stirred uniformly and
thoroughly until homogeneous mass is obtained.
• Rapid cooling should be avoided as this leads to the
formation of solid lumps and a uniform product will not
be obtained.
• Vigorous stirring should be avoided because this will
lead to excessive entrainment of air in the ointment.
Ointment Manufacturing plant
Chemical reaction method
• In this product is formed by chemical reaction, which
involves both fusion and mechanical mixing. Best
example of this method is Iodine ointment.
Procedure:
• Powder iodine in a mortar and pestle and add it to
arachis oil taken in a flask. Heat the mixture to 50oC
with occasional stirring until greenish black colour
appears. Add yellow soft paraffin to the above mixture
and heat it to 40oC with mixing. Cool the Ointment.
Manufacture of Emulsion
Preparation of Oil & Aqueous Phases
• Oil Phase
– Components of oil & fat mixtures are placed into a
SS steam-jacketed kettle, melted & mixed.
– Fatty acid (Stearic acid) and alcohol (Cetyl
alcohol) available in cake, flake and powder
forms. Flake form is preferable.
– Petrolatum to be transferred by pump or gravity &
through insulated pipes after melting (by heating
or keeping at heated room having 60-62C).
– Oil phase should be strained through several layers
of cheese cloth before keeping in emulsion mixing
kettle whose walls have been heated to the
temperature of the oil phase to prevent congealing
of its higher-melting components.
• Aqueous Phase
– Components of aqueous phase dissolved in
purified water & filtered.
– Water soluble drug can be added to the
aqueous phase provided high temperature
does not degrade the drug or emulsion is
not adversely affected.
– Otherwise, drug can be added in
solution/solid form after emulsion has
formed and has cooled.
Manufacture of Emulsion
Mixing of Phases
– Phases are mixed at 70-72C (Intimate mixing of
liquid phase occurs).
– Mixing temp can be lowered depending on temp
at which premature crystallization and
congealing of oil phase can occur.
– Sometimes higher than 70-72C like in borax –
beeswax due to high viscosity at this temp
– Phases mixing by 3 ways:
• Simultaneous blending of the phases
• Addition of discontinuous phase to the continuous
phase
• Addition of continuous phase to the discontinuous
phase
• Simultaneous blending
– Requires proportioning pump & continuous
mixer.
– Satisfactory for continuous or large-batch
operation.
• Addition of discontinuous phase to
continuous phase
– Suitable for system containing low vol of
discontinuous phase
• Addition of continuous phase to
discontinuous phase/phase inversion
– Mostly preferred due to fine dispersed phase
globules due to phase inversion.
Cooling of Semi-solid Emulsion
• Cooling should be gradual & at a rate consistent
with mixing of emulsion and scraping of the kettle
walls.
• Gradual cooling is done to prevent the formation of
congealed masses of the ointment or cream,
especially if the semisolid contains a large
percentage of high-melting substances.
• Perfume added at 43-45C in o/w but at near room
temperature in w/o.
• Drug can be added in this stage provided it
dissolves in continuous phase.
• Cooling is crucial as it is not uniform throughout
kettle (surface cooling rate is higher resulting
variation in physical properties).
• It is difficult to do vol adjustment in w/o emulsion.
Lost water vol should be added at first.
Conventional Emulsion Processing
Aqueous Phase Oil Phase
Finished Emulsion
Conventional Emulsion Processing
Storage
– The specified quality control tests have to be
completed before packaging into appropriate
containers like tubes, jars or single-dose packets are
used.
– Ointment are stored in well-closed containers to
protect against contamination and in a cool place to
protect against product separation due to heat
– To prevent water evaporation , the container is to be
closed until packaging. Storage tank # 316 SS
– When required light sensitive preparations are
packaged in light resistant containers.
– Should not have marked changes in consistency
– Protection from evaporation
Transfer for Packaging
• Two level operation – gravity feed; if not pumping to filling
equipment.
• Cleaning operation between batches:
– For kettle and tanks, High pressure (upto 1000 psi) Low
volume pump system using hot water with detergent.
– For homogenizer, filling equipment and pumps: disassembled,
cleaned, sanitized & dried.
Factors to be Evaluated in Semi-solid preparation
• Stability of the active ingredient/s
• Stability of the adjuvants
• Visual appearance
• Colour
• Odour (Development of pungent odour or loss of
fragrance)
• Viscosity, extrudability
• Loss of water and other volatile vehicle components
• Phase distribution (homogeneity or phase separation,
bleeding)
• Particle size distribution of dispersed
phases.
• pH
• Texture, feel upon application
– Stiffiness, grittiness, greasiness, tackiness
• Particulate contamination
• Microbial contamination & sterility
– In the unopened container & under
conditions of use)
• Release and bioavailability
Evaluation of Semi-solid dosage form
(1) Physical methods
– Test of rate of absorption
– Test of non-irritancy
– Test of rate of penetration
– Test of rate of drug release
– Test of rheological properties
– Test of content uniformity
(2) Microbiological methods
Test of microbial content
Test of preservative efficacy
Physical Method
Test of rate of Absorption
• The ointment should be applied over a definite
area of the skin by rubbing.
• At regular intervals of time, serum and urine
samples should be analyzed for the quantity of
drug absorbed.
Test of non-irritancy
• Non-irritancy of the preparation is evaluated by patch
test.
• In this test 24 human volunteers are selected. Definite
quantity of ointment is applied under occlusion daily
on the back or volar forearm for 21 days.
• Daily the type of pharmacological action observed is
noted. No visible reaction or erythema or intense
erythema with edema and vesicular erosion should
occur. A good ointment base shows no visible
reaction.
Test of rate of penitration
• Flow-through diffusion cell or
microdialysis method is used.
• Animal or human skin of
definite area should be collected
and tied to the holder present in
a diffusion cell. The diffusion
cell is placed in a fluid bath.
Measured quantity of the preparation is applied over the
skin and the amount of drug passed into the fluid is
measured at regular intervals by analyzing the aliquots
of fluid using a spectrophotometer.
Test of rate of drug release
• A clean test tube is taken and the internal
surface is coated with the preparation as a thin
layer. Saline or serum is poured into the test
tube.
• After a certain period of time, the saline is
analyzed for the quantity of the drug. The
amount of drug when divided by the time
period gives the rate of drug release.
Test of rheological properties
• The viscosity of the preparation should be such
that the product can be easily removed from
the container and easily applied to the skin.
• Using cone and plate viscometer the viscosity
of the preparation is determined.
Microbiological methods
Test of microbial contest
• Solutions of different samples of the
preparation are made. Each sample is
inoculated into separate volumes of 0.5 ml of
rabbit's plasma under aseptic conditions and
incubated at 37oC for 1-4 hours.
• No formation of the clot in the incubated
mass indicates the absence of the micro-
organisms.
Test of preservative efficacy
• Using pour plate technique the number of micro-
organisms initially present in the preparation are
determined.
• Solutions of different samples of the preparation are
made and mixed with Tryptone Azolectin (TAT) broth
separately. All cultures of the micro-organisms are
added into each mixture, under aseptic conditions. All
mixtures are incubated.
• The number of micro-organisms in each sample are
counted on 7th, 14th, 21st and 28th days of
inoculation.
Penetration Enhancers
• Skin penetration enhancement technique have been
developed to improve bioavailability & increase the
range of drugs for which topical & transdermal
delivery.
• Penetration enhancers (sorption promoters or
accelerants) penetrates through skin to decrease the
barrier resistance.
• Alternatively, physical mechanism such as
iontophoresis & phonophoresis can be used for certain
cases of drugs.
Chemical Enhancers
• Chemical enhancers or penetration enhancers
or absorption promoters are the agents that
interact with skin constituents to promote the
drug flux.
• Many agent have studied & evaluated for
enhancement properties.
• Yet their inclusion in skin formulation is
limited due to unknown mechanism & toxicity.
Mode of action of CPE
Penetration enhancers may act by one or more of
three main mechanisms
1. Disruption of the highly ordered structure of
stratum corneum lipid.
2. Interaction with intercellular protein.
3. Improved partition of the drug, coenhancer or
solvent into the stratum corneum.
Factors for Evaluation of Semi-solids
• Particle size distribution of dispersed
phases.
• pH
• Texture, feel upon application
– Stiffiness, grittiness, greasiness, tackiness
• Particulate contamination
• Microbial contamination & sterility
– In the unopened container & under
conditions of use)
• Release and bioavailability
Evaluation of Semi-solid dosage form
(1) Physical methods
– Test of rate of absorption
– Test of non-irritancy
– Test of rate of penetration
– Test of rate of drug release
– Test of rheological properties
– Test of content uniformity
(2) Microbiological methods
Test of microbial content
Test of preservative efficacy
Physical Methods
Test of rate of absorption
• The ointment should be applied over a definite
area of the skin by rubbing.
• At regular intervals of time, serum and urine
samples should be analyzed for the quantity of
drug absorbed.
Test of non-irritancy
• Non-irritancy of the preparation is evaluated by patch
test.
• In this test 24 human volunteers are selected. Definite
quantity of ointment is applied under occlusion daily
on the back or volar forearm for 21 days.
• Daily the type of pharmacological action observed is
noted. No visible reaction or erythema or intense
erythema with edema and vesicular erosion should
occur. A good ointment base shows no visible
reaction.
Test of rate of penetration
• Flow-through diffusion cell or microdialysis method
is used.
• Animal or human skin of definite area should be
collected and tied to the holder present in a diffusion
cell. The diffusion cell is placed in a fluid bath.
• Measured quantity of the preparation is applied over
the skin and the amount of drug passed into the fluid
is measured at regular intervals by analyzing the
aliquots of fluid using a spectrophotometer.
Test of rate of drug release
• A clean test tube is taken and the internal
surface is coated with the preparation as a thin
layer. Saline or serum is poured into the test
tube.
• After a certain period of time, the saline is
analyzed for the quantity of the drug. The
amount of drug when divided by the time
period gives the rate of drug release.
Test of rheological properties
• The viscosity of the preparation should be such
that the product can be easily removed from
the container and easily applied to the skin.
• Using cone and plate viscometer the viscosity
of the preparation is determined.
Test of Microbial content
• Solutions of different samples of the
preparation are made. Each sample is
inoculated into separate volumes of 0.5 ml of
rabbit's plasma under aseptic conditions and
incubated at 37oC for 1-4 hours.
• No formation of the clot in the incubated
mass indicates the absence of the micro-
organisms.
Test of preservative efficacy
• Using pour plate technique the number of micro-
organisms initially present in the preparation are
determined.
• Solutions of different samples of the preparation are
made and mixed with Tryptone Azolectin (TAT) broth
separately. All cultures of the micro-organisms are
added into each mixture, under aseptic conditions. All
mixtures are incubated.
• The number of micro-organisms in each sample are
counted on 7th, 14th, 21st and 28th days of
inoculation.
Penetration Enhancers
• Skin penetration enhancement technique have been
developed to improve bioavailability & increase the
range of drugs for which topical & transdermal
delivery.
• Penetration enhancers (sorption promoters or
accelerants) penetrates through skin to decrease the
barrier resistance.
• Alternatively, physical mechanism such as
iontophoresis & phonophoresis can be used for certain
cases of drugs.
Chemical Enhancers
• Chemical enhancers or penetration enhancers
or absorption promoters are the agents that
interact with skin constituents to promote the
drug flux.
• Many agent have studied & evaluated for
enhancement properties.
• Yet their inclusion in skin formulation is
limited due to unknown mechanism & toxicity.
Mode of action of CPE
Penetration enhancers may act by one or more of
three main mechanisms
1. Disruption of the highly ordered structure of
stratum corneum lipid.
2. Interaction with intercellular protein.
3. Improved partition of the drug, coenhancer or
solvent into the stratum corneum.
Classification of CPE’s
1. Surfactants :
a) Ionic: SLS, Na laureate, etc.
b) Non ionic : Tween 80, Polysorbates, etc.
2. Bile Salts & Derivatives :
E.g.. Na glyacolate, Na deoxycholate
3. Fatty Acid & Derivatives :
E.g.. Oleic acid, Caprylic acid, etc.
4. Chelating Agents :
E.g.. EDTA, Citric acid, etc.
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5. Sulphoxide :
E.g.. DMSO, DMA, DMF, etc.
6. Polyols :
E.g. : PG, PEG, Glycerol, etc.
7. Monohydric Alcohols :
E.g. : Ethanol, 2- Propanol, etc.
8. Miscellaneous :
E.g. : a) Urea & its derivatives
b) Terpenes & Terpenoids
c) Phospholipids
d) Water
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Physical Enhancers
• Iontophoresis
–Iontophoresis is the process of enhancing the permeation of
topically applied therapeutic agents through the skin by the
application of electric current. The drug is applied under an
electrode of the same charge as the drug, and an indifferent
counter electrode is positioned elsewhere on the body.
• Electroporation
–It involves the application of short (microsecond or
millisecond), high voltage (50-1000 volts) pulses to the skin.
The mechanism of penetration is the formation of transient
pores due to electric pulses that subsequently allow the
passage of macromolecules from the outside of the cell to
the intracellular space via a combination of processes such
as diffusion and electrophoresis.
• Ultrasound
– Sonophoresis is a technique which involves the use of
ultrasonic energy to enhance skin penetration of active
substances. The mechanism of transdermal skin
permeation involves the disruption of the stratum
corneum lipids by the formation of gaseous cavities,
thus allowing the drug to pass through the skin.
• Microneedles
– The solid silicon needles(coated with drug) or hollow
metal needles (filled with drug solution) penetrate the
horny layer without breaking and without stimulating
nerves in the deeper tissues.
• Magnetophoresis
– It involves the application of a magnetic field as an
external driving force to enhance drug delivery
across the skin. It induces alteration in the skins
structure that could contribute to an increase in
permeability
• Photomechanical wave
– Pressure waves generated by intense laser radiation,
can permeabilize the stratum corneum as well as the
cell membrane. PW is only applied for a very short
time (100ns-1µs). It is thought that the pressure
waves form a continuous or hydrophilic pathway
across the skin due to expansion of lacunae domains
in the stratum corneum.
