Contents

• Definition, advantages & disadvantages, desirable

features.
• Components - Propellants-types, selection, two phase
& three phase systems.
• Containers - Tin Plate, Aluminum, Glass, Plastics, Valve,
& Actuator Standard valve (detail) &
specialized valves (in brief).
• Product concentrates Different formulation systems-
solution, Dispersions, Foams, and Powders.
• Manufacturing and Quality Control testing.
"Aerosol is a pressurized dosage forms containing one or more therapeutic active ingredients

which upon actuation emit a

fine dispersion of liquid and/or solid

materials in a gaseous form"

 Advantages
• Easily withdrawn of drug
• Easy and convenient to apply Disadvantages
• Faster Onset of action
Costly
• No manual/ direct contact with sensitive material
the medicament Provides efficacy of a
• Avoid the first drug
pass metabolism
• A specific amount of dose
or drug can be removed
• No microorganism can enter
• Release the contents in
Controlled and
Uniformly
• Protect the
photosensitive
medicaments and oxygen
• Difficult disposal of
empty aerosol
containers
• Allergic in some cases
• Explosive
• Some formulation is
difficult
• Sometimes propellants
may cause toxic
reactions
 Desired Characteristics
• Less explosive
• Uniform and constant dose delivery
• Non allergic
• Economic/Low cost
• Easy to handle
• Non Breakable
• Eco-friendly
COMPONENTS OF AEROSOLS

• Propellant

• Container

• Valve and actuator

• Product concentrate
PROPELLANTS
•Responsible for developing proper pressure within
the container.
•Provide driving force to expel the product from
the container.

TYPES OF PROPELLANTS
(a) Liquefied gases Propellants
(b) Compressed gases Propellants
PROPELLANTS - TYPES
Depending on the route of administration and use,
I) Type-I Propellant A- Liquefied Gas
1) For oral and inhalation (Fluorinated hydrocarbons)
Tri-chloro-mono-flouro methane (propellant 11)
Di-chloro di-fluro methane (propellant 12)
2) Topical Pharmaceutical aerosols (Hydrocarbons)
Propane
Butane
II) Type-II Propellant B - Compressed Gas Propellants
1) Compound gases
Nitrogen
Carbon di-oxide
 LIQUEFIED GAS PROPELLANTS
• Exist as liquids under pressure.
•Because the aerosol is under pressure
propellant exists mainly as a liquid, but it will
also be in the head space as a gas.
•The product is used up as the valve is opened,
some of the liquid propellant turns to gas and
keeps the head space full of gas.
•In this way the pressure in the can remains
essentially constant and the spray performance
is maintained.
 CHLORO FLUORO CARBONS
• Propellant of choice for oral and inhalation

Advantages Disadvantages
• Chemical inertness • High cost
• •
• Non flammability
• Lack of explosiveness

Examples: Trichloromonofluoromethane - Propellant 11

Dichlorodifluoromethane - Propellant 12
Dichlorotetrafluoroethane - Propellant 114
HYDROCARBONS
• Can be used for water based aerosols and
topical use
Advantages
• Inexpensive Disadvantages
• Inflammable
• Excellent solvents
•Unknown
•It does not
toxicity produced
cause ozone
depletion
- Propellant
Ex: Propane A- 108
Isobutan - Propellant A-31
e - Propellant A-17
Butane
 COMPRESSED GAS PROPELLANTS
•Compressed gas propellants occupy the head
space above the liquid in the can.
•When the aerosol valve is opened the gas
'pushes' the liquid out of the can.
•The amount of gas in the headspace remains
the same but it has more space, and as a
result the pressure will drop during the life of
the can.

• Spray performance is maintained however

by careful choice of the aerosol valve and
actuator. Examples:
Carbon dioxide,
Nitrous oxide and Nitrogen
 AEROSOL CONTAINERS

They must be able to withstand pressures as high

as 140 to 180 psig (pounds per sq. inch gauge)
at 130° F.

AEROSOL CONTAINERS
A . Metals
1.Tinplated
steel
2.Aluminum
3.Stainless
steel
1. Uncoated glass
TIN PLATED STEEL CONTAINERS

•It consist of a sheet of steel plate, this sheet is

coated with tin by electrolytic process.
•The coated sheet is cut into three pieces ( top
, bottom and body) .
• The top, bottom are attached to body by soldering.
•When required it is coated with organic material
usually oleoresin, phenolic , vinyl or epoxy
coating.
•Welding eliminates soldering process, Saves
considerable manufacturing time and decreases
the product/container interaction.
 ALUMINIUM CONTAINERS

• Used for inhalation and topical aerosols

•Light in weight, less fragile, Less incompatibility due
to its seamless nature.
• Greater resistance to corrosion
•Pure water and pure ethanol cause corrosion to Al
containers
•Added resistance can be obtained by coating inside of
the container with organic coating like phenolic , vinyl
or epoxy and polyamide resins
STAINLESS STEEL CONTAINERS

• Used for inhalation aerosols

Advantage :
• Extremely Strong.
• Resistant to many materials.
• No need for internal coating.

Disadvantage :
• Costly
 GLASS CONTAINERS
•These containers are preferred because of its
Aesthetic value and absence of incompatibilities.
•These containers are limited to the products
having a lower pressure (33 psig) and lower
percentage of the propellant.
•Used for topical and MDI
aerosols. Two types of glass
aerosol containers
i) Uncoated glass container:
Less cost and high clarity and contents can be
viewed at all times.
ii) Plastic coated glass containers:
These are protected by plastic coating that
prevents the glass from shattering in the event of
breakage.
 VALVES

• Easy to open and close

•Capable of delivering the content in the
desired form such as spray, foam, solid
stream
etc.
• It can deliver a given amount of medicament

TYPES OF VALVES :
1.Continuous spray
valve 2.Metering
 VALVE ASSEMBLY

LastBenchPharmacist.blogspot.com
 VALVE ASSEMBLY
• Used for topical aerosols

Valves assembly consists:

• Ferrule or mounting cup
• Valve body or housing
• Stem
• Dip tube
• Gasket
• Spring
 VALVE ASSEMBLY
FERRULE OR MOUNTING CUP
• Used to attach valve to container.
• Made from Tin plated steel, Al, Brass
•Under side of the valve cup is coated with single
or double epoxy or vinyl resins.

VALVE BODY OR HOUSING

•Made up of Nylon or Derlin and contains a
opening at the point of attachment of dip tube.
(0.013 to
0.080 inch)

STEM
•Made from Nylon or Derlin, brass and stainless
steel can also be used. (orifice - 0.013 to 0.030 inch).
 VALVE ASSEMBLY
GASKET
• Made from Buna-N and neoprene rubber.

SPRING
• Made from Stainless steel
• Used to hold gasket in place

DIP TUBE
• Made from Poly ethylene or poly propylene.
• Inner diameter 0.120 – 0.125 inch.
•However for capillarydip tube inner diameter is
0.050 inch and for highly viscous products it is
0.195 inch.
 VALVES
• The valves used should be such that it can be easily
opened and closed.
• It should also deliver the content in the desired form. So
three types of valves are used nowadays:
1. Continuous spray valve
2. Metering valve
3. Foam valve
• By using continuous spray valve, the medicament is expelled
continuously as long as pressure is applied on the actuator.
But by using metering valve, only a definite quantity of
medicament is expelled when actuator is pressed.
 ACTUATORS
•These are specially designed buttons which helps in
delivering the drug in desired form i.e., spray, wet stream,
foam or solid stream. It helps in the easy opening and
closing of the valve, whenever it is required.

TYPES OF ACTUATORS
• Spray actuators
• Foam actuators
• Solid steam actuators
• Special actuators
 ACTUATORS
SPRAY ACTUATORS
•It can be used for topical preparation,
such as antiseptics, local anesthetics and
spray on bandages etc.
•It allows the stream of product concentrate
and propellant to pass through various openings
and dispense as spray.
FOAM ACTUATORS
• It consist of large orifice which ranges
from 0.070—0.125 inch .
SOLID STREAM ACTUATORS
•These actuators are required for
dispensing semi solid products such as
ointments SPECIAL ACTUATORS
• These are used for a specific purpose.
•It delivers the medicament to the appropriate
site of action such as throat, nose, dental and
eyes etc.
METERED DOSE INHALERS
• Used to minimize the number of administration errors.
•To improve the drug delivery of aerosolized particles into
the nasal passageways and respiratory tract.
Advantages of MDI:
• It delivers specified amount of dose
• Portable and compact
• Quick to use, no contamination of product
• Dose-dose reproducibility is high
Disadvantages of MDI
• Low lung deposition; high pharyngeal deposition
•Coordination of MDI actuation and patient inhalation
Metered Dose Inhalers (MDIs)
MARKETED PHARMACEUTICAL AEROSOL PRODUCTS
Metered Dose inhalers :
BRAND NAME DRUG USE
Flovent Diskus Fluticasone Asthma
Advair Fluticasone and Asthma
Salmeterol
Aerobid Flunisolide Asthma
Qvar Beclomethasone Asthma
Proventil Albuterol Bronchospasm
 Dip tubes
The dip tubes are made from polyethylene
or polypropylene.
Dip tube is used for the following purposes
(i) It conveys the liquid from the bottom of the
container to the valve at the top.
(ii) It prevents the propellant to come out
without dispensing the contents of the
package.
• The dip tube should be extended almost to
the bottom of the container.
• In case the length of the dip tube is short, the
contents of the aerosol container will not
come out of it.
• However, if the dip tube is touching the bottom
of the container, it will block the passage of liquid.
 FORMULATION OF AEROSOLS
•It consist of two essential components
: 1.Product concentrate and
2. Propellant

Product concentrate
Active ingredient or mixture of active ingredients and
other necessary agents such as solvents, anti oxidants
and surfactants.
Propellant
• Single or blend of various propellants is used
TYPES OF AEROSOL SYSTEMS
TYPES OF AEROSOL SYSTEMS
• Solution system
• Water based system
• Suspension or Dispersion systems
• Foam systems
1. Aqueous stable foams
2. Non aqueous stable foams
3. Quick-breaking foams
4. Thermal foams
•Intranasal aerosols
 SOLUTION SYSTEM
•This system is also referred to as Two phase system consists of vapor
and liquid phase.
•If drug is soluble in propellant, no other solvent is required.
•The vapor pressure of system is reduced by the addition of less volatile
solvents such as ethanol, acetone, propylene glycol, glycerin, ethyl
acetate. This results in production of larger particles upon spraying.
•Amount of Propellant may vary from 5% (for foams) to 95% (for
inhalations).

General formula weight %

Propellant 12/11 (50:50)
- to 10-15
- to 100
INHALATION AEROSOL :
Formulation Weight %
Isoproterenol Hcl – 0.25
Ascorbic acid – 0.1
Ethanol – 35.75
Propellant 12 – 63.9
Packed in 15 -30 ml Stainless Steel, Aluminum or glass container.

HYDROCARBONS IN TOPICAL AEROSOL PHARMACEUTICAL

PREPARATIONS :

Formulation Weight %
Active ingredient -up to10-15
Ethanol - up to 10-15
Water - 10-15
(A-46) - 55-70
 WATER BASED SYSTEM (Three
phase)
Three phase is employed in cases where the product
concentrate (Drug) is immiscible with the propellant. The
medicaments are dissolved in liquid (solvent) which does
not mix with the propellant.
• Produce spray or foam
•Since propellant and solvent is not miscible, a three
phase aerosol forms (propellant, solvent and vapor
phases).
•Ethanol can be used as cosolvent to solubilize
propellant in water. It also reduces surface tension aiding
in the production of smaller particles
 SUSPENSION SYSTEM
•It involves dispersion of active ingredient in the propellant
or mixture of propellants.
•To decrease therate of settling of disperse particles, surfactants
or suspending agents can be added.
•Primarily used for inhalation
aerosols. Example:
Formulation Weight%
Epinephrine bitartrate (1-5 0.50
Microns)
Sorbitan trioleate 0.50
Propellant -114 49.50
Propellant -12 49.50
Epinephrine bitartrate has minimum solubility in
propellant system but soluble in fluids in the
 FOAM SYSTEMS
Foam aerosols consist of product concentrates, aqueous
or non aqueous solvents, surfactant, Propellant and are
dispensed as a stable or quick breaking foam depending
on the nature of the ingredients and the formulation.

AQUEOUS STABLE FOAM :

Formulation %w/w
Active ingredient
Oil waxes
o/w 95-96.5
surfactant
Water
Hydrocarbon Propellant (3 -5%) 3.5-5
 •Total propellant content is usually (3 or 5% w/w or 8-10%
v/v) .
•As the amount of propellant increases a stiffer and dryer
foam is produced.
• Lower propellant concentrations yield wetter foams.
• Hydrocarbon and compressed gas propellants are used.

NON-AQUEOUS STABLE FOAM

Formulation %w/w
Glycol 91-92.5
Emulsifying agent 4
Hydrocarbon propellant 3.5-5
.
• Emulsifying agent is propylene glycol monostearate.
 QUICK BREAKING FOAM
• Propellant is in the external phase. When dispensed
the product is emitted as a foam, which then
collapses into a liquid.
• Especially applicable to topical medications .
Formulation %w/w
Ethyl alcohol 46-66
Surfactant 0.5-5
Water 28-42
Hydrocarbon Propellant 3-15

•Surfactant should be soluble in both alcohol and water

or cationic or anionic type.
 THERMAL FOAM
• Used to produce warm foam for shaving
•Used to dispense hair colors and dyes but were
unsuccessful due to the corrosion problems and are
expensive , inconvenient to use and lack of effectiveness.
INTRANASAL AEROSOLS
•Intended to deposit medication into nasal passages for localor
systemic effect.
ADVANTAGES
• Deliver measured dose of drug.
• Require lower doses compared to other systemic products.
• Excellent depth of penetration into the nasal passage way.
• Decreased mucosal irritability .
La•stMBeancinhPtheanramnacciest.obflosgtseproitl.ictoymfrom dose to dose.
• Greater flexibility in the product formulation.
Manufacture of aerosols
 Packaging of aerosols
• Pressure filling apparatus
• Cold filling apparatus
• Compressed gas filling apparatus
Pressure filling apparatus
•It consists of a pressure burette capable of metering
small volumes of liquefied gas into the aerosol
container under pressure.
•The propellant is allowed to flow with its
own vapor pressure in the container through
aerosol valve.
• The trapped air escapes out from the upper valve.
•The propellant stops flowing when the pressure of burette and
container becomes equal.
•If further propellant is to be added, a hose (rubber pipe) leading to
a cylinder of nitrogen is attached to the upper valve, the pressure
exerted by nitrogen helps in the flow of the propellant into the
container.
•Another pressure filling device makes use of piston arrangement
and is capable of maintaining positive pressure .
be used for filling inhalation
which have metered valves.
Advantages of pressure filling:
•Solutions, emulsions, suspensions can be filled by this method as chilling
does not occur.

• Contamination due to moisture is less.

• High production speed can be achieved.
• Loss of propellant is less.

Disadvantages :
•Certain types of metering valves can be handled only by the cold filling
process

• Process is slower than Cold filling method.

Pressure filling Equipment Pressure burette
 Cold filling apparatus

•Non aqueous products and products which can withstand low temperatures of -
40°F are used in this method.
•The product concentrate is chilled to a temperature of - 40°F and filled into
already chilled container.
•Then the chilled propellant is added completely in 1 or 2 stages, depending on
the amount.
•Another method is to chill both the product concentrate and propellant in a
separate pressure vessel to - 40 °F and then filling them into the container.
• The valve is placed and crimped on to the container.
•Then test for leakage and strength of container is carried out by passing container
into a heated water bath, where the contents of the container are heated to
130°F. After this, the containers are air dried , capped and labeled.
 Cold filling apparatus
•The cold filling method is no longer being used, as it has been
replaced by pressure filling method.

Advantage:
•Easy process

Disadvantages
•Aqueous products, emulsions and those products adversely
affected by cold temperature cannot be filled by this method.
•Hydrocarbon propellant cannot be filled into aerosol containers
using this apparatus because large amount of propellant escapes
out and vaporizes. This may lead to formation of an explosive
mixture
 Compressed gas filling apparatus
PROCEDURE
• The product concentrate is filled into the container.
• Valve is placed and crimped on the container.
•With the help of vacuum pump the air is removed from the

•Filling head is put in the opening of the valve and the valve
is depressed and the gas is allowed to flow into container.
•The gas stops flowing if the delivery pressure and the pressure
within the container become equal.
•Carbon dioxide and nitrous oxide is used if more amount of
gas is required.
•High solubility of the gas in the product can be achieved by
shaking
with the help of mechanical shakers.
•Compressed gases have high pressure hence a pressure
reducing valve is required.
• The apparatus consists of delivery gauge.
•A flexible hose pipe which can withstand 150 pounds per
square inch gauge pressure is attached to the delivery gauge
along with the filling head.
• A flow indicator is also present in specialized equipments.
Evaluation tests
A. Flammability and combustibility
1. Flash point
2. Flame Projection
B.Physicochemical characteristics
1. Vapor pressure
2. Density
3. Moisture content
4. Identification of Propellants
C. Performance
1. Aerosol valve discharge rate
2. Spray pattern
3. Dosage with metered valves
4. Net contents
5. Foam stability
6. Particle size
determination
D. Biological testing
1. Therapeutic activity
2. Toxicity studies
 A. Flammability and combustibility
1. Flash point
Apparatus : Tag Open Cup Apparatus
Product is chilled to – 25°F and test
liquid temperature is allowed to increase
slowly and the temperature
at which vapors ignite is
called as Flash Point
2. Flame Projection
Product is sprayed for 4
sec into a flame and the
flame is
is measured with a ruler.
B. Physicochemical characteristics
Property Method
1. Vapor Pressure » Pressure gauge
» Can Puncturing Device.
2. Density » Hydrometer,
» Pycnometer.
3. Moisture » Karl Fisher Method,
» Gas Chromatography.
4. Identification of » Gas Chromatography,
propellants
» IR Spectroscopy.
C. Performance

1. Aerosol valve discharge rate : Contents of the aerosol

product of known weight is discharged for specific period of time.
By reweighing the container after the time limit, the change in the
weight per time dispensed gives the discharge rate ( g/sec).
The objective of this test is to determine magnitude of valve delivery &
degree of uniformity between individual valves.
• Sampling is done according to standard procedures as
found in Military Standards “MIL-STD-105D”.

• For metered dose aerosol valves, test methods were

developed by
‘Aerosol Specifications Committee’
‘Industrial Pharmaceutical Technology
Section ‘Academy Of Pharmaceutical
Sciences.

Standard test solutions were proposed to rule out

variation in valve delivery.
 TEST SOLUTIONS
C’
Ingredients Test Test Test
% w/w Solutions Solutions ‘B’ Solutions
‘A’ C
Iso Propyl Myristate 0.10% 0.10% 0.10%
Dichloro Difluoro 49.95% 25.0% 50.25%
methane
Dichloro tetrafluoro 49.95% 25.0% 24.75%
ethane
Trichloro monofluoro - - 24.9%
methane
Alcohol USP - 49.9% -
Specific Gravity @ 1.384 1.092 1.388
 Testing Procedure
• Take 25 valves and placed on containers filled with specific
test solution.
• Actuator with 0.020 inch orifice is attached.
• Temperature -25±1°C.
• Valve is actuated to fullest extent for 2 sec and weighed.
• Again the valve is actuated for 2 sec and weighed.
• Difference between them represents delivery in mg.
• Repeat this for a total of 2 individual deliveries from
each of 25 test units.
Individual delivery wt in mg. Specific gravity of test
Valve delivery per actuation in solution
µL =
Deliveries Limit’s
Valve Acceptance: 54µL or less ± 15%
55 to 200 µL ± 10%
Of the 50 individual deliveries,
• If 4 or more are outside the limits : valves are rejected
• If 3 deliveries are outside limits : another 25 valves are tested.
• Lot is rejected if more than 1 delivery is outside the specifications.
2. Spray pattern: The method is based on the impingement of
spray on piece of paper that has been treated with Dye-Talc mixture.
The particles that strike the paper cause the dye to go into solution
and to be adsorbed onto paper giving a record of spray for comparison
purpose.
3. Dosage with metered valves
Reproducibility of dosage can be determined by:
»Assay techniques
»Accurate weighing of filled container followed by dispensing
of several doses. Containers are then reweighed and difference in
weight divided by number of doses dispensed gives average
dose.
4. Net Contents
• Tared cans that have been placed onto the filling lines are
reweighed and the difference in weight is equal to the net
• contents.
In Destructive method : weighing a full container and
then dispensing as much of the content as possible . The
contents are then weighed . This gives the net
content.
5. Foam stability
Methods : » Visual Evaluation,
» Time for given mass to penetrate the foam,
» Time for given rod that is inserted into the
foam to fall,
» Rotational
Viscometer.
6. Particle Size Determination
Methods : » Cascade Impactor,
» Light Scattering
Decay.
D. Biological testing:
1. Therapeutic Activity
»» For Topical Aerosols: is applied to test areas and
adsorption of therapeutic ingredient is determined.
2. Toxicity :
» For Inhalation Aerosols : exposing test animals to vapors
sprayed from aerosol container.

» For Topical Aerosols : Irritation is determined.

References:

“TheTheory&PracticeOfIndustrialPharmacy”byLeon Lachman , H.A.Lieberman