Anatomy of skin
The skin is very effective as a selective penetration
barrier. The epidermis provides the major control
element for drug penetration.
Mechanism of drug penetration through skin
Three potential entry MACRO ROUTES to the viable tissue:
1. Via the sweat ducts
2. Across the continuous stratum corneum
3. Through the hair follicles with their associated sebaceous
Low molecular weight molecules penetrate through stratum
conium to some extent.
Skin appendages are main route for Electrolytes, polar
steroids, antibiotics and colloidal particles.
Particles of 3-10 µ penetrate through hair follicle and particles
less than 3µ penetrate through stratum conium.
Hair follicle route may be important for ions and large
Topically applied agents such as steroids,
hexachlorophane, griseofulvin, sodium fusidate and fusidic
acid may form a depot or reservoir by binding within the
Once drug permeates through horny layer it readily enters living
tissue and systemic circulation.
The average residence time of drug in dermis may be 1 min
before it is washed away by blood.
NSAIMS reach far down to muscles to form depots.
Structure of Skin showing routes of penetration
1. Across the intact horny layer
2. Through the hair follicles with the associated sebaceous gland
3. Via the sweat glands
Factors influencing dermal penetration of drugs
I. Biological factors:
1. Skin condition
2. Skin age
3. Blood flow
4. Regional skin site
5. Skin metabolism
6. Species difference
II. Physicochemical factors:
1. Skin hydration
2. Temperature and pH
3. Diffusion coefficient
4. Drug concentration
5. Partition coefficient
6. Molecular size and shape
1. Skin condition
The intact, healthy skin is a tough barrier but acids and alkalis
injure barrier cells and thereby promote penetration.
Mixtures of non-polar and polar solvents, such as chloroform and
methanol, remove the lipid fraction and molecules pass more easily.
Disease alters skin condition, skin inflamed, with loss of stratum
corneum thus permeability increases.
If organ thickened, with corns, calluses and warts, drug permeation
2. Skin age
Skin of the young and the elderly is more permeable than
Children are more susceptible to the toxic effects of drugs
and chemicals, because of their greater surface area per unit
body weight; thus potent topical steroids, Causes severe side-
effects and death.
An increased blood f;low could reduce the amount of time a
penetrant remains in the dermis, and also raise the concentration
gradient across the skin.
In clinically hyperaemic disease damages the skin barrier and
4. Regional skin sites :
Variations in permeability depend on the thickness and nature of the stratum
corneum and the density of skin appendages.
Absorption changes with substance, volunteer and site.
Permeabilities depend on thickness of stratum corneum and the overall
thickness of the tissue.
Plantar and palmar callus may be 400-600 µm thick compared to 10-20 µm
for other sites.
The hyoscine Transderm system employs in postauricular skin (i.e. behind
the ear) because the layers of stratum corneum are thinner
Facial skin in general is more permeable than other body sites
5. Skin metabolism:
The skin metabolizes steroid hormones, chemical
carcinogens and some drugs.
This is advantage to prodrugs.
Skin can metabolize 5% of topical drugs.
6. Species differences:
Mice, rats and rabbits are used to assess percutaneous
absorption, but their skins have more hair follicles than human
skin and they lack sweat glands.
Hairless mouse, monkey and pig skins are most like
that of humans.
Hairless rat and fuzzy guinea pig may be better
models for humans.
To obtain skin penetration data it is best to use human skin
1. Skin hydration:
When water saturates the skin the tissue swells, softens and
and hydration of the stratum corneum increases permeability.
Dusting powders or lotions, provide a large surface
area for evaporation and therefore dry the skin
2. Temperature and pH:
The penetration rate of material through human skin can
change tenfold for a large temperature variation.
Occlusive vehicles increase skin temperature and
According to pH-partition hypothesis, only unionized molecules
pass readily across lipid membranes.
Weak acids and bases dissociate to different degrees,
depending on the pH and their PKa or Pkb values.
Stratum corneum is resistant to alterations in pH, range of 3-9.
3. Diffusion coefficient:
The diffusional speed of a molecule depends mainly on the
state of matter of the medium.
In gases, diffusion coefficients are large than liquids
In skin, the diffusivities reach their lowest values within
the compacted stratum corneum matrix.
The diffusion coefficient of a drug in a topical vehicle
depends on the properties of the drug and the diffusion
medium and on the interaction between them.
4. Drug concentration:
Drug permeation and flux of solute is proportional to the
concentration gradient across the barrier.
drug permeation follows Fick's law, saturated donor solution
gives maximum flux.
pH change, complex formation, or the presence of
surfactants, micelles or cosolvents modify the effective
5. Partition coefficient(K):
The partition coefficient is important in establishing the flux
of a drug through the stratum corneum.
Drug (K<1) are water soluble, (K>1) are oil soluble.
Polar cosolvent mixtures, such as propylene glycol with
water, produce saturated drug solutions and maximize the
concentration gradient across the stratum corneum.
Surfactants disruption of intercellular lipid packing in the
stratum corneum, act as penetration Enhancers.
Complex formation of drug increases the apparent
partition coefficient may promote drug absorption.
6. Molecular size and shape:
Absorption is apparently inversely related to molecular
Small molecules penetrate faster than large ones.
It is more difficult to determine the effect of molecular shape,
as it is related to partition coefficient.
• Semi solids are the topical dosage form used for
the therapeutic, protective or cosmetic function.
They may be applied to the skin, or used nasally,
vaginally, or rectally…
Advantage of semi-solid dosage form:
• It is used externally
• Probability of side effect can be reduce
• First pass gut and hepatic metabolism is avoided.
• Local action and Site specific action of drug on
• Convenient for unconscious patient or patient
having difficulty on oral administration.
• Suitable dosage form for bitter drugs.
• More stable than liquid dosage form
Disadvantages of semi-solid dosage forms:
• There is no dosage accuracy in this type of dosage
• The base which is used in the semi-solid dosage form
can be easily oxidized.
• May cause staining.
They are bulky to handle.
Application with finger may cause contamination.
Physico-chemically less stable than solid dosage
May cause irritation or allergy to some patients
IDEAL PROPERTIES OF
• PHYSICAL PROPERTIES:
• Smooth texture
• Elegant in appearance
• Non dehydrating
• Non gritty
• Non greasy and non staining
• Non hygroscopic
IDEAL PROPERTIES OF
• 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.
PREPARATION OF SEMISOLIDS DOSAGE
INGREDIENTS USED IN PREPARATION:
• Gelling agent
• Permeation enhancer
1.OINTMENT: these are semi solid preparations meant
for external application to the skin/ mucous membrane.
2.PASTE: these are semisolid preparations intended for
external application to skin.
3.CREAM: these are viscous semisolid emulsions meant
for external use.
4.GELS: these are semisolid dispersion systems which may
contain suspension of either small /large organic molecules
dispersed in a
Classification of ointments
1. Based on penetration
•Epidermic- Meant for action on epidermis
•Endodermic- Action on deeper layers of cutaneous tissue
•Diadermic- Meant for deep penetration
2. According to therapeutic uses
Classification of Pastes:
1. Fatty paste
2. Aqueous gel paste
3. Hydrocolloid paste
Classification of Creams:
1. Aqueous creams (O/W creams)
anionic emulsifying agent
cationic emulsifying agent
non-ionic emulsifying agent
Classification of Gels:
1. Based on use
2. Oily creams (W/O creams)
2. Based on nature of colloidal system
Single phase system
Two phase system
3. Based on
Excipients in semisolid dosage forms
Ointment Paste Cream Gel
Ointment base Paste base Penetration
Preservatives Preservatives Oil/oleaginous
Anti-oxidant Anti-oxidant Emulgents Hygrosc
Chelating agent perfume Co-emulsifiers Chelating
perfume Mixed emulsifier
DEF: These are semisolid preparations meant for external application
to skin or mucous membrane.
Selected after Toxity & Irritability test.
It is one of the most important ingredient used in the formulation of
semisolid dosage form
Ointments and suppository base do not merely acts as the carrier of
the medicaments, but they also control the extent of absorbtion of
medicaments incorporated with them
USFDA- list of ointment bases and their concentrations used.
They should be:
Compatible with skin pH and drug
Inert ,non irritating and non sensitizing
Good solvent and/or emulsifying agent
Emollient , protective , non greasy and easily
Release medicaments easily at the site of
Pharmaceutical elegant and possess good stability.
1. Oleaginous ( hydrocarbon) Bases:
They consist of a combination of more than one oleaginous material
such as water insoluble hydrophobic oils and fats
• Greasy, sticky-non washable
• Retain body heat
• Do not increase absorption
• Prevent drainage on oozing area.
• They are anhydrous, do not absorb water & insoluble in water.
1. Hydrocarbons: Paraffin wax, Soft paraffin, Liquid paraffin
2. Vegetable oils and animal fats: Peanut oil, Coconut oil, Lanolin, Bees
3. Hydrogenated & sulfated oils: Hydrogenated castor oil,
Hydrogenated & sulfated castor oil.
4. Acids, Alcohols & Esters: Stearic acid, Stearyl alcohol, Isopropyl
A) Soft paraffin (Petrolatum):
This is purified mixture of semisolid hydrocarbons obtained
1. Yellow soft paraffin – M.pt=380C, used in ophthalmic
2. White soft paraffin- M.pt=560C, obtained from bleaching
Yellow soft paraffin.
B) Hard paraffin:
purified mixture of solid hydrocarbons obtained from petroleum.
USE- harden/soften ointment base
c) Liquid paraffin (white mineral oil/ liquid petroleum):
mixture of liquid hydrocarbons obtained from petroleum by
USE- Combine with hard/ soft paraffin to harden/soften
• Forms w/o emulsion
• Absorbs 50% water
• Due to the presence of sterol emulgent
• Easily removable by water
1. Non-emulsified bases:
Absorb water and aqueous solutions to produces w/o
emulsions Eg. wool fat, wool alcohol, beeswax, cholesterol.
2. W/0 emulsions:
Absorb more water than non-emulsified bases.
Eg. Hydrous wool fat (lanolin)
2. Absorption (Emulsifiable)Base:
1. Wool fat(Anhydrous lanolin):
This is fat from wool of sheep.
Can absorb 50% water of its weight.
USE: ointment base preparation, ophthalmic ointments.
2. Wool alcohol:
Wool fat is alkalized to obtain cholesterol & alcohol.
USE: Emulsifying agent in preparation of W/O
3. Bees wax:
Wax from honey comb of bees.
2 types- yellow & white bees wax
USE: stiffening agent in paste & ointments.
4. Hydrous wool fat:
Purified fat from wool of sheep.
Insoluble in water, soluble in ether, chloroform.
Contains 70% wool fat+ 30% water.
Advantages of Absorption bases
Compatible withmost of the medicaments
Absorb large quantity of water or aqueous
Relatively heat stable
Less occlusive and good emollients
Aqueous substances can be incorporated
Undesirable due to greasy nature
Chances of microbial contamination.
Ability to absorb water, serum discharges and forms o/w
and w/o emulsions.
Accordingto the type of emulsion these bases are
classified as either W/O or O/W.
1. W/O- greasy, sticky. Ex: Sulfur & zinc ointments
2. O/W- easily removed from skin. Ex: vanishing cream.
Anionic, cationic or non-ionic Emulsifying wax
White soft paraffin
*When applied on skin leaves behind a layer of fat.
3. Emulsion Bases
Advantages Of Emulsion bases
Miscible with exudates from lesions
Does not interfere with skin function
Good contact with skin because of surfactant
High cosmetic acceptability.
Easy removable from the hair.
Disadvantages of Emulsion bases
W/o emulsion greasy and sticky
Its acceptance is less
Difficult to remove from body and clothing.
Carbo waxes (Macrogols/ Polyethylene glycols)
General formula CH2OH. (CH2OCH2)n . CH2OH
These are mixtures of polycondensation products of ethylene
oxide and water
• Average Molecular weight is represented by numbers
Macrogols 200, 300,
-- viscous liquids
-- greasy semi
Macrogols 1540, 3000,4000, 6000 -- waxy solids
• Clear and colourless
• Faint characterisitic odour
• Miscible with water, alcohol and other glycols
• White or cream in colour
• Hard lumps or flakes
• Soluble 1 in 3 in water and 1 in 2 in alcohol
• Solidifying points range from 40 to 60°c
• Non-toxic and non-irritating
• pH – 4 to 7.5
• Can be sterilised by heat (solids – dry heat, liquids – autoclave)
•water soluble, non-volatile and inert substances. Different
carbowax mixture produces different consistency.
1. Hydrocarbon bases:-- soft paraffin , liquid paraffin.
2. Water miscible bases:-- glycerin, emulsifying ointment.
3. Water soluble bases:-- poly ethylene glycols.
Heavy metals cause degradation of gel bases and
medicament. Chelating agents form complex with heavy
metals and prevent degradation. Ex: EDTA
To maintain humidity in the preparation and to prevent
drying. Ex: glucerin, sorbitan.
These prevent quick loss of water due to evaporation in
gels and prevents drying, flake formation.
Ex: glycerol, propylene glycol
These are organic hydrocolloids/ hydrophilic inorganic
1. Natural gelling agents– gum tragacanth, starch, pectin,
gelatin, clays, cellulose derivatives, etc.,
2. Synthetic gelling agents– sodium alginate, carbomer,
poly vinyl alcohol, etc.,
7-20% bentonite is used as dermatological base.
10% aluminium magnesium silicate is used in medicated
Gels are not clear and form powdery residue on skin.
Used for preparations of Lubricating, Medicated & Contraceptive
Concentrations used for Lubricating (2 to 3%) &
Dermatological vehicle (5%).
Tragacanth is poorly wettable
On addition to water lumps are formed which is difficult to disperse
Dispersing agent is generally used to get a homogenous produc
Alcohol, glycerol or volatile liquids are used as dispersing agent
• Obtained from natural sources, so vary in viscosity
• After evaporation, the film left on the skin tends to flake
• Loss viscosity outside the pH range of 4.5 – 7
• Can’t be stored for longer time
• Prone to microbial growth
2. Pectin :
• Good gelling agent suitable for acid products
• Used in many preparations including edible Jellies
• Glycerine is used as dispersing agent & humectant
• Pectin jelly is good medium for bacterial growth, add
Well closed container to prevent loss of moisture by
3. Starch :
Used in combination with other Jellingagent
Provides a water soluble dermatological base
Starch + Gelatin + Glycerin jelly product is still used
Glycerin (up to 50%) may be added which acts as
preservative and humectant
• Must be freshly prepared
• Well closed container to prevent loss of moisture by
4. Gelatin :
Insoluble in cold water (swells and soften)
Soluble in hot water
2% gelatin forms jelly on cooling
Stiff medicated Jellies can be prepared (15%)
Melted before use and after cooling to desired temperature,
applied with a brush.
Affected area covered with bandage and left in place
for several weeks
Suitable preservative is required
5. Cellulose derivatives :
Produce neutral jellies of very stable viscosity
Afford good resistance against microbial growth
High clarity & produce a soft film after drying
• Used for preparation of lubricating & sterile jellies
• Withstand autoclaving temperature without
• Methyl cellulose - 3%
• Sodium carboxy methyl cellulose
1.5 - 5% - lubricant gels, 5% - Dermatological gels
6. Sodium aliginate :
• 1.5 to 2% Used as Lubricant gel & Dermatological vehicle 5 To
• Viscosity can be increased by adding soluble calcium salt
• Salting out is observed with high conc.
• 2-4% alcohol, glycerine, propylene glycol are used as
Advantages over tragacanth
• Available in several grades of standard viscosity
0.3-1% in lubricating gels & 0.5-5% as dermatological
These have high gelling efficiency and used in low
8. Poly vinyl alcohol (PVA):
PVA gels provide protection as they dry quickly to form a
residual film on skin.
These are available in various grades and viscosities.
Methods of Preparation of Ointments & Creams
3. Chemical reaction
Methods of Preparation of Pastes
Method of Preparation of Gels
1. Trituration Method
Widely used method
For extemporaneous preparation of ointments.
When the base is soft and medicament is solid
insoluble Small amount of liquid to incorporated in
Involves mixing as well as size reduction
1. Reduce the solid medicament to fine powder
2. Medicament is mixed with small amount of base on ointment
slab with a stainless steel spatula until a homogeneous
product is formed.
3.Add remaining quantities of base with uniform mixing
4. Incorporate any liquid ingredient if present
(mortar and pestle to be used in case of large quantity of
Eg: Prepare and dispense 100 g of sulphur ointment
Sublimed sulphur, finely sifted - 10 g
Simple ointment - 90g
Prepare an ointment
Direction - Apply the ointment to the affected area as directed.
2. Fusion method:
Suitable when ointment base contains number of solid
ingredients of different melting points.
1. Ointment base are melted in decreasing order of their
2. Highest melting point should be melted first, low melting
3. This avoids over heating of substances of low melting
4. Incorporate medicament slowly to the melted mass
5. Stir thoroughly until mass cools down and
homogeneous product is formed.
6. Liquid ingredients or aqueous substance should be heated
same temperature as the melted bases before addition.
7. If not, wax or solids will cool down quickly and get separated
Strring is done continously- homogeneous mass
Vigorous stirring should be avoided to prevent entrapment of
Rapid cooling should be avoided to get a uniform product.
To remove the dust or foreign particles strain through muslin
Eg: Prepare and dispense 100 g of Citrimide
Cetrimide - 1 g
Cetostearyl alcohol –
White soft paraffin – 10
g Liquid paraffin – 29 g
Pure water – 50 g
1. Melt ointment bases in decreasing order of
2. Dissolve cetrimide in water and heat the
3. Chemical reaction method
Preparation of some ointment involves chemical
reactions Eg – (a)Iodine ointment (iodine free form)
(b)Iodine ointment (iodine combined form with ointment
(a)Ointments containing free iodine
Iodine is slightly soluble in fats and vegetable oils.
Readily soluble is potassium iodide solution in water
due to formation of polyiodides (KI. I2, KI. 2I2 , KI.3I2)
Poly iodides are readily soluble in water, alcohol and glycerin.
These solutions may be incorporated with the molten
absorption type ointment base.
(b) Ointments containing combined iodine
Fixed oils and many fats obtained from vegetable and animal
contain unsaturated constituents
Iodine combines with double
CH3 (CH2)7 CH=CH (CH2)7 COOH + I2 (Oleic acid)
CH3 (CH2)7 CHI.CHI (CH2)7 COOH (Di-iodo stearic acid)
Free iodine is not available, So ointments appear dark, greenish
black in colour
Leaves no stain when rubbed into the skin, Hence known as
non- staining iodine ointment
4. Emulsification method
1. Facts, oils and waxes an melted together to a temperature and
2. Aqueous solution of the heat stable, water soluble
compounds is also heated to the same temperature.
3. Aqueous Solution is slowly added to the melted bases,
with continuous stirring until cool.
Emulsifying agent is needed to make a stable emulsion
Water soluble soaps are commonly used as emulsifier for
semisolid o/w emulsions.
Combination oftriethanolamine stearate soap and cetyl alcohol is
used in o/w emulsion
Bees wax and divalent calcium ions used in w/o emulsion.
Types of gels
Based on its application classified into
(1) Medicated, (2) Lubricating, (3) miscellaneous gels
1. Medicated gels:
• Used on mucous membrane/ skin
• Actions-Lubrication, antiseptic, Vasoconstrictor,
Evaporation of water Produces a cooling sensation to skin
Contents remaining stick as film to the applied area gives
Ex: Ephedrine sulphate Jelly- Vasoconstrictor
Should be thin, transparent & water soluble.
Must be sterile when inserted into sterile regions of the
Used for lubrication in:
• Rectal Thermometers
• Urinary Bladders
• Surgical gloves
• Patch testing
Used as vehicle for allergens applied on skin in
Jellies contain Nacl, pumice powder & glycerin.
To reduce electrical resistance between skin and
Preparation of Gels:
1. Usually prepared by adding thickening agent
2. Thickening agent is added to aqueous solution in which
drug has to be dissolved
3. Mass is triturated in a mortar until a smooth product is
4. When coloured drug to be incorporated glass mortar is
5. Whole gum is preferred to powdered gum to get
clear preparation of uniform consistency
Uses of Emollient creams:
This medication is used as a moisturizer to treat or prevent
dry, rough, scaly, itchy skin and minor skin irritations (such as
diaper rash, skin burns from radiation therapy).
Emollients are substances that soften and moisturize the skin
and decrease itching and flaking. Some products (such as
zinc oxide, white petrolatum) are used mostly to protect the
skin against irritation (such as from wetness).
Dry skin is caused by a loss of water in the upper layer of the
Emollients/moisturizers work by forming an oily layer on the
top of the skin that traps water in the skin
Uses of Emollient creams:
Petrolatum, lanolin, mineral oil and dimethicone are common
Humectants, including glycerin, lecithin, and propylene glycol,
draw water into the outer layer of skin.
Many products also have ingredients that soften the horny
substance (keratin) that holds the top layer of skin cells
together (including urea, alpha hydroxy acids such as
lactic/citric/glycolic acid, and allantoin).
This helps the dead skin cells fall off, helps the skin keep in
more water, and leaves the skin feeling smoother and softer.
Evaluations of ointment and creams:
1. Drug content
2. Release rate of medicament from base
3. Penetration rate of medicament
4. Absorption of medicament into blood stream
5. Consistency of the preparation
6. Irritant effect
1. Drug content: Minimum fill test
Select any 10 filled containers
Weigh the required amount of ointment
Medicament is extracted in a suitable solvent
Drug Content is determined by suitable analytical technique
Results should be with in labeled quantity.
2. Release rate of medicament from base:
Two in vitro techniques are used
1. Agar cup plate method
2. Diffusion method
Agar cup Plate method
• Used to determine the release rate of antibacterial
• Tested in agar medium seeded with staphylococus
• Zone of inhibition of bacterial growth is measured
around circular cups
Used to find the release rate of any type of medicament
A parchment membrane is tied at one end of glass tube
Ointment is filled in the tube, properly spread on the
Tube is dipped in the distilled water maintained at 37±1OC
Samples are withdrawn after a specified period of time.
Samples are immediately replaced with fresh distilled water
Analyzed for the drug content
Plot a graph between drug concentration and time
3. Penetration rate of medicament:
Determined by rubbing weighed amount into defined areas
for a fixed time
Unabsorbed material is removed completely and weighed
Difference in weight provides total base penetrated
Rate is then calculated
4. Absorption of medicament into blood stream:
Diadermic ointments are tested by in-vivo method.
Determined by assaying drug content in either blood, urine,
faeces or tissues after rubbing defined amount under standard
5. Consistency of the preparation:
Determined by sliding a glass plate over the product by
means of a pulley.
Product is spread evenly on another glass plate fixed on a
Weights are added to thepan so that sliding of the movable
plate is obtained
Ointment which require more weights to allow the plate to
slide- over have high consistency or vice-versa
6. Irritant effect:
Test is performed on skin and eyes of rabbit or human skin
Ointment is injected in to thigh muscles and under
abdonimal skin in rats.
Results are observed daily for a week
Irritant effect of dermatological preparation is shown as
lesions on cornea, iris and conjunctiva
Evaluation of gels
1. Rheological properties
2. Determination of yield value
4. Stability test
5. Safety evaluations.
1. Rheological properties:
Gels exhibit non-newtonian rheological behaviour and thixotropy
(gel ↔sol). Brook field viscometer is used fordetermination.
2. Determination of yield value:
Penetrometer is used to measure force required to exudate the
form collapsible tube.
This is related to rheological property of gel, tested using slides.
4. Stability test:
Gel stability at various temperatures is tested for shipping.
5. Safety evaluations:
Safety is determined by evaluating physical properties of
Evaluation of pastes:
1. Evaluation of heat stability
2. Determination of viscosity
3. Compatibility with container
4. Determination of safety of
5. Teat for sensitization
6. Determination of particle size
7. Determination of gelation